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Although the potential risk of silver nanoparticles (AgNPs) to humans has recently increased due to widespread application, the potential effects of AgNPs on embryo-fetal development have not yet been determined. This study investigated the potential effects of AgNPs on pregnant dams and embryo-fetal development after maternal exposure on gestational days (GD) 6-19 in rats. AgNPs were administered to pregnant rats by gavage at concentrations of 0, 100, 300, and 1000 mg/kg/day. All dams were subjected to Cesarean section on GD 20 and the fetuses were examined for signs of embryotoxic and teratogenic effects. Examinations of hepatic oxidant/antioxidant balance and serum biochemistry were also added to the routine developmental toxicity study. Treatment with AgNPs caused a decrease in catalase and glutathione reductase activities at ≥100 mg/kg/day and a reduction in glutathione content at 1000 mg/kg/day in maternal liver tissues. However, no treatment-related deaths or clinical signs were observed in any of the animals treated with AgNPs. No treatment-related differences in maternal body weight, food consumption, gross findings, serum biochemistry, organ weight, gestation index, fetal deaths, fetal and placental weights, sex ratio, or morphological alterations were observed between the groups. The results show that repeated oral doses of AgNPs during pregnancy caused oxidative stress in hepatic tissues at ≥100 mg/kg/day, but did not cause developmental toxicity at doses of up to 1000 mg/kg/day. The no-observed-adverse-effect level of AgNPs is considered to be <100 mg/kg/day for dams and 1000 mg/kg/day for embryo-fetal development. [ABSTRACT FROM AUTHOR]

Background. Moxibustion has been traditionally used to manage pain related to chronic diseases, including cancer. This study aims to investigate the efficacy and safety of moxibustion for relieving cancer pain in patients with metastatic cancer. Methods. A total of 16 patients were randomly divided into a true moxibustion (TM) group or a sham moxibustion (SM) group. In both groups, moxibustion was applied for 10 minutes, once daily for 7 consecutive days. In the SM group, the moxa cone was removed earlier than in the TM group, so as not to deliver heat stimulation completely into the skin. The changes of pain severity using the Brief Pain Inventory (BPI) and quality of life measured by the Functional Assessment of Cancer Therapy–General (FACT-G) were observed. A blinding credibility test was done to validate the sham moxibustion procedure. Results. The total BPI score significantly decreased in the TM group compared with the SM group (TM vs SM: −0.97 ± 1.05 vs 0.35 ± 0.60, P = .025). The 2 subsets of BPI, pain intensity score and pain interference score, also significantly decreased in the TM group (TM vs SM: intensity, −0.82 ± 0.93 vs 0.46 ± 0.87, P = .020; interference, −1.12 ± 1.31 vs 0.24 ± 0.61, P = .047). Even after adjusting for the values of opioid consumption, these results remained significant. FACT-G did not significantly improve in the TM group. The blinding to sham moxibustion was credible and no serious adverse events occurred. Conclusion. We suggest that moxibustion could be a safe and potential modality for cancer-related pain in patients with metastatic cancer. With the limitation of small sample size, a larger and long-term follow-up study is necessary to determine more definitely the efficacy of moxibustion. [ABSTRACT FROM PUBLISHER]

Background: We sought to assess the prognostic significance of lymph node ratio (LNR) and N stage in patients undergoing D2 gastrectomy and adjuvant chemotherapy, S-1, and XELOX and to compare the efficacy of them according to LNRs and N stages to evaluate the clinical impact of using LNRs compared with using N staging.Methods: Patients undergoing D2 gastrectomy with adequate lymph node dissection and adjuvant chemotherapy for stage II/III gastric cancer between Mar 2011 and Dec 2016 were analysed. Of the 477 patients enrolled, 331 received S-1 and 146 received XELOX. LNR groups were segregated as 0, 0-0.1, 0.1-0.25, and > 0.25 (LNR0, 1, 2, and 3, respectively). Propensity score matching (PSM) was used to minimise potential selection bias and compare DFS and OS stratified by LNRs and N stages in the two treatment groups.Results: After PSM, the sample size of each group was 110 patients, and variables were well balanced. All patients had more than 15 examined lymph nodes (median 51, range 16~124). In multivariate analysis, LNR (> 0.25) and N stage (N3) showed independent prognostic value in OS and DFS, but LNR (> 0.25) showed better prognostic value. In subgroup analysis, the LNR3 group showed better 5-year DFS (20% vs 54%; HR 0.29; p = 0.004) and 5-year OS (26% vs 67%; HR 0.28; p = 0.020) in the XELOX group. The N3 group showed better 5-year DFS (38% vs 66%; HR 0.40; p = 0.004) and 5-year OS (47% vs 71%; HR 0.45; p = 0.019) in the XELOX group. Stage IIIC showed better 5-year DFS (22% vs 57%; HR 0.32; p = 0.004) and 5-year OS (27% vs 68%; HR 0.32; p = 0.009) in the XELOX group. The LNR3 group within N3 patients showed better 5-year DFS (21% vs 55%; HR 0.31; p = 0.004) and 5-year OS (27% vs 68%; HR 0.34; p = 0.018) in the XELOX group.Conclusions: LNR showed better prognostic value than N staging. LNR3, N3 and stage IIIC groups showed the superior efficacy of XELOX to that of S-1. And the LNR3 group within N3 patients showed more survival benefit from XELOX. LNR > 0.25, N3 stage and stage IIIC were the discriminant factors for selecting XELOX over S-1.Trial Registration: Not applicable (retrospective study). [ABSTRACT FROM AUTHOR]

This research examines how organizational error management culture influences organizational commitment and employee turnover intention through employee psychological safety and perceived fairness. Data was collected from 173 hotel employees in Hong Kong. Using structural equation modeling, this study found that (1) error management culture positively influences employee psychological safety and perceived fairness; (2) error management culture had significant indirect effect on employee' s turnover intentions, sequentially mediated by perceived fairness, psychological safety and organization commitment. [ABSTRACT FROM AUTHOR]

Acetogenic bacteria demonstrate industrial potential for utilizing carbon dioxide (CO 2) for biochemical production using the Wood-Ljungdahl pathway. However, the metabolic engineering of acetogenic bacteria has been hampered by the limited number of available genetic bioparts for gene expression. Here, we integrated RNA sequencing, ribosome profiling, differential RNA sequencing, and RNA 3′-end sequencing results of Eubacterium limosum to establish genetic bioparts, such as promoters, 5′ untranslated regions, and transcript terminators, to regulate transcriptional and translational expression of genes composing of biosynthetic pathways. In addition, a transformation method for the strain was developed to efficiently deliver the obtained genetic bioparts into cells, resulting in a transformation efficiency of 2.5 × 105 CFU/μg DNA. Using this method, the genetic bioparts were efficiently introduced, and their strengths were measured, which were then applied to optimize the heterologous expression of acetolactate synthase and acetolactate decarboxylase for non-native biochemical acetoin production. The strategy developed in this study is the first report on integrating multi-omics data for biopart development of CO 2 or syngas utilizing acetogenic bacteria, which lays a foundation for the efficient production of biochemicals from CO 2 or syngas as a carbon feedstock under autotrophic growth conditions. • Development of genetic tools for CO2-fixing Eubacterium limosum. • Unraveling transcript architecture using transcript start sites and 3՛ end sites. • Utilizing transcript 3՛ end position as metabolic valves to regulate gene expression. • Autotrophic acetoin production using bioparts designed by the multi-omics dataset. [ABSTRACT FROM AUTHOR]

Abstract: We present a method to pattern solution-processed oxide semiconductor thin films by all laser process. A metal thin film is first photoetched by a spatially-modulated pulsed Nd–YAG laser beam and this layer is then covered with a semiconductor film. Uniform irradiation by the same laser generates a thermo-elastic force on the underlying metal layer and this force serves to detach it from the substrate, leaving only a patterned semiconductor structure. Sharp-edged zinc–tin oxide (ZTO) patterns at the micrometer scales could be fabricated over a few square centimeters by a single pulse of 850mJ. A mobility of 7.6×10−2 cm2 V−1 s−1, an on/off ratio higher than 106, and an off-current of 1.91×10−11 A were achieved from a thin film transistor (TFT) with the patterned ZTO channel. These values were similar to those from a reference TFT, demonstrating the feasibility of this patterning process for electronic devices. [Copyright &y& Elsevier]

Bisphenol F (BPF, 4,4′-methylenediphenol) has recently been selected as an alternative to bisphenol A (BPA), which is used in the manufacturing of polycarbonates and epoxy resins. This study aimed to investigate the general, and reproductive/developmental effects of BPF. Therefore, BPF at dose levels of 0, 1, 5, 20, and 100 mg/kg/day was administered daily by oral gavage to Sprague-Dawley rats during the pre-mating, mating, gestation, and early lactation periods, and reproductive and developmental toxicities including general systemic toxicities were investigated. A decrease in body weight and food consumption was observed in the female rats treated with BPF at 20 and 100 mg/kg/day during the pre-mating and gestation periods. Additionally, gamma glutamyl transpeptidase levels were increased in the female rats administered 100 mg/kg/day. At 100 mg/kg/day, ovarian weight decreased and vaginal mucification increased according to a necropsy and histopathological examination, respectively. Moreover, the number of implantation sites and litter size decreased at 100 mg/kg/day. However, no significant BPF-related changes were observed in the male rats. Based on the results of this study, the no-observed-adverse-effect levels (NOAELs) of BPF for general systemic and reproductive effects were 5 and 20 mg/kg/day, respectively. • A bisphenol F(BPF)-related decrease in body weight and food consumption was observed in female rats. • BPF decreased gamma glutamyl transpeptidase levels and ovarian weight, and increased vaginal mucification. • BPF treatment induced a decrease in the number of implantation sites and litter size. • The NOAELs were considered 5 and 20 mg/kg/day for general systemic and reproductive/developmental effects, respectively. [ABSTRACT FROM AUTHOR]

Abstract Background As the Resource Description Framework (RDF) data model is widely used for modeling and sharing a lot of online bioinformatics resources such as Uniprot (dev.isb-sib.ch/projects/uniprot-rdf) or Bio2RDF (bio2rdf.org), SPARQL - a W3C recommendation query for RDF databases - has become an important query language for querying the bioinformatics knowledge bases. Moreover, due to the diversity of users’ requests for extracting information from the RDF data as well as the lack of users’ knowledge about the exact value of each fact in the RDF databases, it is desirable to use the SPARQL query with regular expression patterns for querying the RDF data. To the best of our knowledge, there is currently no work that efficiently supports regular expression processing in SPARQL over RDF databases. Most of the existing techniques for processing regular expressions are designed for querying a text corpus, or only for supporting the matching over the paths in an RDF graph. Results In this paper, we propose a novel framework for supporting regular expression processing in SPARQL query. Our contributions can be summarized as follows. 1) We propose an efficient framework for processing SPARQL queries with regular expression patterns in RDF databases. 2) We propose a cost model in order to adapt the proposed framework in the existing query optimizers. 3) We build a prototype for the proposed framework in C++ and conduct extensive experiments demonstrating the efficiency and effectiveness of our technique. Conclusions Experiments with a full-blown RDF engine show that our framework outperforms the existing ones by up to two orders of magnitude in processing SPARQL queries with regular expression patterns.

Sore throat lozenges, which are over-the-counter drugs, contain 2,4-dichlorobenzyl alcohol (DCBA) as the primary ingredient. However, comprehensive data on the prenatal developmental toxicity of DCBA is limited. Therefore, this study was conducted to determine the effects of DCBA on pregnant rats and prenatal development. Sprague-Dawley rats were administered different doses of DCBA (0, 25, 100, 400, and 800 mg/kg/day) daily via an oral gavage from gestation day (GD) 6–19. Thereafter, all the live dams were sacrificed on GD 20, and caesarean sections were conducted. Live fetuses and their placenta were weighed and then examined for external, visceral, and skeletal malformations and variations. Based on the results obtained, dams at 800 mg/kg/day showed systemic toxicities, including a decrease in body weight and food consumption, and liver changes. Additionally, this treatment induced decreases in fetal and placental weights, as well as the increased incidence of retarded ossifications and full supernumery rib, and the decreased number of ossification centers. Therefore, based on these findings, the no-observed-adverse-effect level of DCBA was determined to be 400 mg/kg/day for dams and prenatal development. • Prenatal development toxicities of 2,4-dichlorobenzyl alcohol (DCBA) were evaluated. • A DCBA dose of 800 mg/kg/day induced systemic toxicities on pregnant rats. • The 800 mg/kg/day DCBA treatment also decreased fetal and placental weights. • This DCBA dose increased the incidence of retarded ossification-related findings and full supernumerary rib. • The no-observed-adverse-effect level of DCBA was determined to be 400 mg/kg/day. [ABSTRACT FROM AUTHOR]

Abstract: Antitumor effects of a ginsenoside Rg3-fortified red ginseng preparation (Rg3-RGP) were investigated in human non-small cell lung carcinoma (H460) cells using in vitro cytotoxicity assay and in vivo nude mouse xenograft model. Immunomodulatory effects of the preparation were also assessed by measuring the facilitating activities on the nitric oxide (NO) release from peritoneal macrophages, in vitro and in vivo lymphocyte proliferation, and the carbon clearance from circulating blood. In a cell level, Rg3-RGP exerted H460 cytotoxicity and facilitated splenocyte proliferation at very high concentrations, without affecting NO production. However, oral administration of Rg3-RGP (100–300mg/kg) enhanced carbon particle-phagocytic index of blood macrophages up to 360–397% of control value. In addition, Rg3-RGP significantly increased the splenocyte proliferation (23% at 100mg/kg). In tumor-bearing mice, 28-day oral treatment with Rg3-RGP (100mg/kg) remarkably suppressed the tumor growth, leading to the decrease of the tumor volume and weight by 30–31%, which was comparable to the effect (27–29% reduction) of doxorubicin (2mg/kg at 3-day intervals). While Rg3-RGP did not cause adverse effects, intravenous injection of doxorubicin markedly decreased body and testes weights, and exhibited severe depletion of spermatogenic cells in the atrophic seminiferous tubules. These results indicate that Rg3-RGP exerts antitumor activities via indirect immunomodulatory actions, without causing adverse effects as seen in doxorubicin. [Copyright &y& Elsevier]

Abstract Background Functional dyspepsia (FD) is characterized by a high prevalence rate and no standard conventional treatments. Alternative therapies, such as herbal formulas, are widely used to treat FD. However, there are inadequate evidences regarding the safety and efficacy of these formulas. Moreover, the mechanisms by which herbal formulas act in the gastrointestinal tract are controversial. In traditional Korean medicine, Banha-sasim-tang has long been one of the most frequently prescribed herbal formulas for treating dyspepsia. The current study is designed to evaluate the efficacy and safety of Banha-sasim-tang for FD patients and to examine whether there will be a significant correlation between cutaneous electrogastrography recordings and dyspeptic symptoms in FD patients, and between changes in gastric myoelectrical activity and improvement in dyspeptic symptoms during Banha-sasim-tang administration. Methods This randomized, double-blind, placebo-controlled trial will be performed at two centers and will include a Banha-sasim-tang group and placebo group. Each group will consist of 50 FD patients. Six weeks of administration of Banha-sasim-tang or placebo will be conducted. During the subsequent 2 months, follow-up observations of primary and secondary outcomes will be performed. The primary outcomes are differences as measured on the gastrointestinal symptom scale, and the secondary outcomes are differences as measured on the visual analogue scale for dyspepsia and on the questionnaire for FD-related quality of life. All outcomes will be measured at baseline, at 2, 4, and 6 weeks of treatment, and at the 1 and 2 month follow-up. Cutaneous electrogastrography will be performed and assessed at baseline and at 6 weeks. Discussion This trial will provide evidence of the safety and efficacy of Banha-sasim-tang for the treatment for FD. Furthermore, based on the assessment of the relationship between cutaneous electrogastrography recordings and dyspeptic symptoms in this trial, the possibility of clinical applications of cutaneous electrogastrography in the treatment of FD will be elucidated. Trial Registration Current Controlled Trials (ISRCTN 51910678); Clinical Trials.gov Identifier: NCT00987805

Intratracheal instillation (ITI) is considered the most pragmatic approach for investigating the potential toxicities of various respiratory exposure materials. Various respiratory exposure materials, including nanomaterials, hazardous air pollutants, fine dust, and household biocides, have raised public health concerns because of limited toxicological information and increasing consumption. Hence, toxicity studies using ITI in laboratory animals are important to accurately assess the human risks associated with these respiratory-exposed materials. However, data to adequately support the study design of ITI toxicity studies, particularly those examining the effects of commonly used vehicles following repeated exposure are insufficient. Therefore, in this study, we examined the effects of 16 types of commonly used vehicles in toxicity studies following 14-day repeated ITI in mice. General health endpoints (mortality, clinical signs, and body weight) were monitored throughout the study period, and terminal endpoints (gross observation, lung weight, bronchoalveolar lavage fluid analysis, and lung histopathological examination) were assessed after terminal sacrifice. Saline and phosphate-buffered saline elicited the least response, whereas corn oil (50 µL) showed the most severe toxicity findings. In addition, several commonly used vehicles, including distilled water, sodium carboxymethyl cellulose, dimethyl sulfoxide, ethanol, Tween 20, and Tween 80, induced mild-to-severe toxicity in the respiratory system. Based on the results of this study, some commonly used vehicles in toxicity studies should be used with caution when the ITI exposure route is considered. These results provide important background information on the effects of vehicles in ITI toxicity studies along with valuable insights for designing toxicity studies using respiratory exposure materials., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Here, we present the reproductive toxicology profile of ISIS 838707, a GalNAc-conjugated antisense oligonucleotide (ASO) targeting mouse Apolipoprotein C-III (ApoC-III) mRNA. ISIS 838707 was subcutaneously administered during the premating, mating, and gestation periods to male and female mice at 0, 5, 10, and 20 mg/kg/week. Key focus areas included fertility, reproductive cell functions, estrus cycle, tubal transport, implantation, embryo development stages, and teratogenic potential. We also investigated the toxicokinetics and target mRNA knockdown effects. The treatment was well-tolerated at all dose levels, with no overt toxicity. Treatment led to decreased total cholesterol and/or triglyceride levels at doses ≥5 mg/kg/week, concordant with effective knockdown of ApoC-III mRNA (>85% reduction at all dose levels). Toxicokinetic analysis revealed predominant distribution to the liver of parental animals and minimally to the placenta, with no detectable transfer to fetal liver. Despite these pharmacological effects, there were no discernible adverse impacts on developmental and reproductive functions. These findings suggest that ISIS 838707, while effective in modulating ApoC-III mRNA and lipid profiles, does not adversely impact on reproductive and developmental functions in mice. The study contributes insights into the safety profile of ASOs and reduction of ApoC - III expression, particularly in the context of reproductive and developmental health.

Backgruound: Thyroid-associated ophthalmopathy (TAO) involves tissue expansion and inflammation, potentially causing a hypoxic microenvironment. Hypoxia-inducible factor (HIF)-1α is crucial in fibrosis and adipogenesis, which are observed in TAO progression. We investigated the effects of hypoxia on orbital fibroblasts (OFs) in TAO, focusing on the role of HIF-1α in TAO progression., Methods: OFs were isolated from TAO and non-TAO patients (as controls). In addition to HIF-1α, adipogenic differentiation markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (CEBP) were measured by Western blot, and phenotype changes were evaluated by Oil Red O staining under both normoxia and hypoxia. To elucidate the effect of HIF-1α inhibition, protein expression changes after HIF-1α inhibitor treatment were evaluated under normoxia and hypoxia., Results: TAO OFs exhibited significantly higher HIF-1α expression than non-TAO OFs, and the difference was more distinct under hypoxia than under normoxia. Oil Red O staining showed that adipogenic differentiation of TAO OFs was prominent under hypoxia. Hypoxic conditions increased the expression of adipogenic markers, namely PPARγ and CEBP, as well as HIF-1α in TAO OFs. Interleukin 6 levels also increased in response to hypoxia. The effect of hypoxia on adipogenesis was reduced at the protein level after HIF-1α inhibitor treatment, and this inhibitory effect was sustained even with IGF-1 stimulation in addition to hypoxia., Conclusion: Hypoxia induces tissue remodeling in TAO by stimulating adipogenesis through HIF-1α activation. These data could provide insights into new treatment strategies and the mechanisms of adipose tissue remodeling in TAO.

Ethnopharmacological Relevance: Deer (Cervus elaphus Linnaeus) antler extract has been traditionally used in many Asian countries to prevent and treat various diseases. Deer antler extract is generally considered to be safe because humans have been exposed to it for a long time and it has been used as a tonic medicine originating from naturally occurring product. However, the comprehensive toxicological potential of deer antler extract during the juvenile period has not been investigated and its safety for juveniles remains unclear., Aim of the Study: The aim of the present study was to comprehensively investigate the potential toxicological effects of deer antler extract during the juvenile period., Materials and Methods: As part of a safety assessment of the juvenile period, two separate studies, a juvenile toxicity study and a uterotrophic bioassay, were conducted in accordance with Good Laboratory Practice regulations and test guidelines. In the juvenile toxicity study, deer antler extract was administered daily by oral gavage to Sprague-Dawley rats at doses of 0, 500, 1000, and 2000 mg/kg during the juvenile period to investigate potential toxicities on general systemic, developmental, and reproductive functions. For the uterotrophic bioassay, deer antler extract was administered daily by oral gavage to Sprague-Dawley rats at doses of 0, 1000, and 2000 mg/kg on postnatal days 19-21 to investigate the estrogen-mimicking effects., Results: The results showed that deer antler extract was non-toxic and no observable adverse effects on general systemic function, developmental and reproductive function, and estrogen-mimetic effects were observed with dosing up to 2000 mg/kg during the juvenile period., Conclusion: The safety of deer antler extracts was demonstrated in these studies and the results of this study can be used to evaluate human risk or determine the maximum recommended starting dose of deer antler extract for further clinical trials., Competing Interests: Declaration of competing interest Byung-Cheol Han is currently an employee of the Korea Ginseng Corporation which is responsible for the development and marketing of deer antler extract. The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Bis-diamine was developed as amebicidal and male contraceptive agents; however, it is also reported to induce characteristic congenital heart defects especially in the cardiac conotruncal area of rats. Because of its characteristic congenital heart defects, bis-diamine-induced animal models can be used for studying congenital heart defects. However, comprehensive toxicological information regarding bis-diamine-induced congenital heart defects in this animal model is not available., Methods: In this study, we investigated and characterized an animal model for bis-diamine-induced congenital heart defects. A single dose of 200-mg bis-diamine was administered by oral gavage to pregnant rats on gestation day 10, and then observed the representative toxicological endpoints for general systemic health of pregnant rats, embryo-fetal development, and parturition., Results: Characteristic congenital heart defects and other birth defects similar to DiGeorge syndrome were observed in bis-diamine-administered pregnant rats. In addition, developmental and reproductive toxicity findings, including increased postimplantation loss, decreased fetal weight, increased perinatal death, and increased gestation period, were observed in bis-diamine-administered pregnant rats. In particular, these developmental and reproductive toxicities were observed without maternal toxicity findings., Conclusion: These results will be useful to use this animal model for further studies in congenital heart defects, cardiovascular defects, and understanding their mechanisms., (© 2022 Wiley Periodicals LLC.)

Inhalation exposure to polyhexamethylene guanidine phosphate (PHMG-P), one of the primary biocides used in humidifier disinfectants, caused a fatal pulmonary disease in Korea. Pregnant women were also exposed to PHMG-P, and subsequent studies showed that PHMG-P inhalation during pregnancy adversely affects their health and embryo-fetal development. However, the postnatal developmental effects after birth on prenatally PHMG-P-exposed offspring have not yet been investigated. Therefore, in this study, we aimed to examine the postnatal development of prenatally PHMG-P-exposed offspring. Pregnant rats (22 or 24 females per group) were exposed to PHMG-P during pregnancy in a whole-body inhalation chamber at the target concentrations of 0, 0.14, 1.60, and 3.20 mg/m 3 . After parturition, the prenatally exposed offspring were transferred to non-exposed surrogate mothers to minimize the secondary effects of severe maternal toxicities. Postnatal development of offspring was then examined with a modified extended one-generation reproductive toxicity study design. At 3.20 mg/m 3 PHMG-P, increased perinatal death rates and decreased viability index (postnatal survival of offspring between birth and postnatal day 4) were observed. In addition, F1 offspring had lower body weight at birth that persisted throughout the study. PHMG-P-exposed pregnant rats also had severe systemic toxicities and increased gestation period. At 1.60 mg/m 3 PHMG-P, a decreased viability index was also observed with systemic toxicities of PHMG-P-exposed pregnant rats. These results indicate that prenatal PHMG-P exposure adversely affects the offspring's future health and could be used for human risk assessment., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Serial blood sampling for toxicokinetics is generally conducted in regulatory embryo-fetal development (EFD) studies in rats. EFD studies are designed to detect the potential adverse effects of pharmaceuticals on pregnant females and their fetuses; this information is useful for understanding the relationships between systemic exposure levels and toxicity profiles. However, additional satellite pregnant females are needed for toxicokinetics because comprehensive information regarding the potential impact of serial blood sampling on pregnant females is scarce. Here, in this study, we investigated the potential impact of serial blood sampling in pregnant female rats using a typical EFD study design. Additionally, we investigated the additional endpoints (clinical pathology, organ weights, and histopathology) that were deemed likely to be sensitive to blood sampling. Results indicated that serial blood sampling in pregnant females induced physiological adaptive changes and did not affect the general endpoints in EFD studies. Nevertheless, inclusion of satellite groups in EFD studies may be a more prudent approach considering the physiological changes in pregnant females and potential off-target effects of candidate pharmaceuticals. These results provide background information on the impact of serial blood sampling in pregnant females and will be useful to design the regulatory EFD studies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background/aims: Lymphocytes are an important component of the cell-mediated immune system. As lymphopenia is reportedly associated with poor prognoses in patients with various cancers, we investigated this notion in patients who underwent curative gastrectomy., Methods: We retrospectively analyzed the association between absolute lymphocyte count (ALC) and prognosis in patients with stage I-III gastric cancer who underwent curative surgical resection. Ever lymphopenic patients were defined as those with ALCs < 1,000/μL at any time post-diagnosis except within 30 days post-surgery. Adjusted multivariable regression models were used to evaluate the associations between lymphopenia and overall mortality, gastric cancer-specific mortality, and disease-free survival., Results: We investigated 1,222 patients diagnosed between January 2011 and December 2015. Fifty-six patients (4.6%) were lymphopenic at diagnosis and nearly one-quarter (24.8%) were ever lymphopenic with a mean minimum ALC of 640/μL. Older age (odds ratio [OR], 1.02) and higher stage (stage III vs. I; OR, 3.01) were positively associated with ever lymphopenia. On multivariable analysis, ever lymphopenia predicted higher overall mortality (hazard ratio [HR], 1.83; p = 0.008), higher gastric cancer-specific mortality (HR, 1.58; p = 0.048), and shorter disease-free survival (HR, 1.83; p = 0.006). The 5-year gastric cancer-specific mortality rates for ever- and never lymphopenic patients were 10.9% and 3.7%, respectively; their 5-year cumulative recurrence rates were 15.1% and 4.6%, respectively., Conclusion: This study demonstrate that ever lymphopenia is independent prognostic factor for overall mortality and recurrence in patients with potentially curable gastric cancer; hence, ALCs may be a biomarker for predicting the prognoses of patients with stage I-III gastric cancer who had curative gastrectomy.

Biocides are widely used for their effective antiseptic and disinfectant properties, including polyhexamethylene guanidine phosphate (PHMG-P), which is also used as a biocide as it selectively disrupts bacterial cell membrane. It is used to clean humidifiers commonly used in the dry winter season in South Korea, which exposes people to PHMG-P inhalation. However, comprehensive toxicological data on PHMG-P inhalation exposure, including in pregnant women, and the potential occurrence of lung disease is lacking. Therefore, in this study, we investigated PHMG-P inhalation exposure-induced toxicities in pregnant rats and prenatal development of their conceptus. Pregnant rats were exposed to PHMG-P via inhalation at target concentrations of 0, 0.14, 1.60, and 3.20 mg/m 3 from implantation to nearly parturition (from gestation day 6-20) and then analyzed for relevant abnormalities. Results showed systemic toxicities in the pregnant rats including respiratory function abnormalities, decreased body weight gain, and decreased food consumption at ≥1.60 mg/m 3 . Prenatal development toxicities, including decreased fetal weight with ossification retardations of fetal bones, were observed at 3.20 mg/m 3 . These results will contribute to clarifying the PHMG-P inhalation exposure-induced toxicities during pregnancy and support its risk assessment in humans., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Sex-determining region Y-box 2 (SOX2) is a transcriptional factor that drives embryonic stem cells to neuroendocrine cells in lung development and is highly expressed in small-cell lung cancer (SCLC). However, the prognostic role of SOX2 and its relationship with tumor-infiltrating lymphocytes (TILs) has not been determined in SCLC. Herein, we assessed the expression of SOX2 and CD8+ TILs to obtain insights into the prognostic role of SOX2 and CD8+ TILs in limited-stage (LS)-SCLC., Methods: A total of 75 patients with LS-SCLC was enrolled. The SOX2 expression and CD8+ TILs were evaluated by immunohistochemistry., Results: High SOX2 and CD8+ TIL levels were identified in 52 (69.3%) and 40 (53.3%) patients, respectively. High SOX2 expression was correlated with increased density of CD8+ TILs (p = 0.041). Unlike SOX2, high CD8+ TIL numbers were associated with significantly longer progression-free survival (PFS; 13.9 vs. 8.0 months, p = 0.014). Patients with both high SOX2 expression and CD8+ TIL numbers (n = 29, 38.7%) had significantly longer PFS and overall survival (OS) compared to those from the other groups (median PFS 19.3 vs. 8.4 months; p = 0.002 and median OS 35.7 vs. 17.4 months; p = 0.004, respectively). Multivariate Cox regression analysis showed that the combination of high SOX2 expression and CD8+ TIL levels was an independent good prognostic factor for OS (HR = 0.471, 95% CI, 0.250-0.887, p = 0.02) and PFS (HR = 0.447, 95% CI, 0.250-0.801, p = 0.007) in SCLC., Conclusions: Evaluation of the combination of SOX2 and CD8+ TIL levels may be of a prognostic value in LS-SCLC., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Cerium oxide nanoparticles (CeO 2 NPs) are widely used in various commercial applications because of their characteristic properties. People can be easily exposed to CeO 2 NPs in real life, but the safety assessment of CeO 2 NPs has not been fully investigated. Therefore, in this study, we conducted a combined repeated-dose and reproductive/developmental toxicity screening study (OECD testing guideline 422) to investigate the potential hazards on human health, including reproductive/developmental functions, after repeated daily CeO 2 NPs oral gavage administration to both males and females. In addition, tissues from parental animals and their pups were collected to analyze the internal accumulation of cerium. CeO 2 NPs were orally administered to Sprague-Dawley rats at doses of 0, 100, 300 and 1000 mg/kg during their pre-mating, mating, gestation and early lactation periods. In the general systemic and reproductive/developmental examinations, no marked toxicities were observed in any in-life and terminal observation parameters in this study. In the biodistribution analysis, cerium was not detected in either parental or pup tissues (blood, liver, lungs and kidneys). Repeated oral exposure of CeO 2 NPs did not induce marked toxicities affecting general systemic and reproductive/developmental functions up to the dose level of 1000 mg/kg and the CeO 2 NPs were not systemically absorbed in parental animals or their pups. This result could be used in risk assessment for humans, and additional toxicity studies with CeO 2 NPs will be necessary considering various physicochemical properties and exposure probabilities of these nanoparticles.

Polyhexamethylene guanidine phosphate (PHMG-P) has effective antimicrobial activity against various microorganisms and has been widely used as a biocide in commercial products. However, its use as a humidifier disinfectant has provoked fatal idiopathic lung disease in South Korea, especially in pregnant or postpartum women and their young children. PHMG-P-related toxicological studies of reproduction and development in experimental animals have not been identified, and thus, we investigated the potential effects of early-stage oral exposure to PHMG-P by assessing its toxicological properties. PHMG-P was repeatedly administered by oral gavage at dose levels of 0, 13, 40 and 120 mg/kg to Sprague-Dawley rats during the pre-mating, mating, gestation and early lactation periods, and then general systemic and reproductive/developmental toxicities were investigated. At 120 mg/kg, PHMG-P-related toxicities including subdued behavior, thin appearance, decreased body weight, decreased food consumption and decreased F1 pup body weight were observed. Based on the results of this study, the no-observed-adverse-effect levels (NOAELs) of PHMG-P for both general systemic effects and development are considered to be 40 mg/kg/day., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Titanium dioxide (TiO 2 ) nanoparticles are among the most manufactured nanomaterials in the industry, and are used in food products, toothpastes, cosmetics and paints. Pregnant women as well as their conceptuses may be exposed to TiO 2 nanoparticles; however, the potential effects of these nanoparticles during pregnancy are controversial, and their internal distribution has not been investigated. Therefore, in this study, we investigated the potential effects of oral exposure to TiO 2 nanoparticles and their distribution during pregnancy. TiO 2 nanoparticles were orally administered to pregnant Sprague-Dawley rats (12 females per group) from gestation days (GDs) 6 to 19 at dosage levels of 0, 100, 300 and 1000 mg/kg/day, and then cesarean sections were conducted on GD 20., Results: In the maternal and embryo-fetal examinations, there were no marked toxicities in terms of general clinical signs, body weight, food consumption, organ weights, macroscopic findings, cesarean section parameters and fetal morphological examinations. In the distribution analysis, titanium contents were increased in the maternal liver, maternal brain and placenta after exposure to high doses of TiO 2 nanoparticles., Conclusion: Oral exposure to TiO 2 during pregnancy increased the titanium concentrations in the maternal liver, maternal brain and placenta, but these levels did not induce marked toxicities in maternal animals or affect embryo-fetal development. These results could be used to evaluate the human risk assessment of TiO 2 nanoparticle oral exposure during pregnancy, and additional comprehensive toxicity studies are deemed necessary considering the possibility of complex exposure scenarios and the various sizes of TiO 2 nanoparticles.

Background: Korean Red Ginseng has been widely used in traditional oriental medicine for a prolonged period, and its pharmacological effects have been extensively investigated. In addition, Angelica gigas and deer antlers were also used as a tonic medicine with Korean Red Ginseng as the oriental herbal therapy., Methods: This study was conducted to evaluate the potential toxicological effect of KGC-HJ3, Korean Red Ginseng with angelica gigas and deer antlers , on reproductive and developmental functions including fertility, early embryonic development, maternal function, and embryo-fetal development. KGC-HJ3 was administered by oral gavage to Sprague-Dawley rats (22 animals per sex per group) at dose levels of 0 mg/kg (control), 500 mg/kg, 1000 mg/kg, and 2000 mg/kg to evaluate the potential toxicological effect on fertility and early embryonic development. In addition, KGC-HJ3 was also administered by oral gavage to mating-proven Sprague-Dawley rats (22 females per group) during the major organogenesis period at dose levels of 0 mg/kg (control), 500 mg/kg, 1000 mg/kg, and 2000 mg/kg to evaluate the potential toxicological effect on maternal function and embryo-fetal development., Results and Conclusion: No test item-related changes in parameters for fertility, early embryonic development, maternal function, and embryo-fetal development were observed during the study period. On the basis of these results, it was concluded that KGC-HJ3 did not have toxicological potential on developmental and reproductive functions. Therefore, no observed adverse effect levels of KGC-HJ3 for fertility, early embryonic development, maternal function, and embryo-fetal development is considered to be at least 2000 mg/kg/day.