Foxl2 is required for the initiation of the female pathway in a temperature-dependent sex determination system in Trachemys scripta.

KDM6B-mediated epigenetic modification of the testicular regulator Dmrt1 has previously been identified as the primary switch of the male pathway in a temperature-dependent sex-determination (TSD) system; however, the molecular network of the female pathway has not yet been established. Here, we have functionally characterized for the first time an upstream regulator of the female pathway, the forkhead transcription factor FOXL2, in Trachemys scripta, a turtle species with a TSD system. FOXL2 exhibited temperature-dependent female-specific expression patterns before the onset of gonadal differentiation and was preferentially localized in ovarian somatic cells. Foxl2 responded rapidly to temperature shifts and estrogen. Importantly, forced expression of Foxl2 at the male-producing temperature led to male-to-female sex reversal, as evidenced by the formation of an ovary-like structure, and upregulation of the ovarian regulators Cyp19a1 and R-spondin1. Additionally, knockdown of Foxl2 caused masculinization at the female-producing temperature, which was confirmed by loss of the female phenotype, development of seminiferous tubules, and elevated expression of Dmrt1 and Sox9. Collectively, we demonstrate that Foxl2 expression is necessary and sufficient to drive ovarian determination in T. scripta, suggesting a crucial role of Foxl2 in female sex determination in the TSD system.

Evidence for RA-dependent meiosis onset in a turtle embryo.

Meiotic entry is one of the earliest sex determination events of the germ cell in higher vertebrates. Although advances in meiosis onset have been achieved in mammals, birds and fish, how this process functions in reptiles is largely unknown. In this study, we present the molecular analysis of meiosis onset and the role of retinoic acid (RA) in this process in the red-eared slider turtle. Our results using Stra8 as a pre-meiosis indicator show that in the female embryonic gonad, meiosis commitment starts around stage 19. Additionally, signals of the meiosis marker Sycp3 could be detected at stage 19 and become highly expressed by stage 23. No expression of these genes was detected in male embryonic gonads, suggesting the entry into meiosis prophase I was restricted to female embryonic germ cells. Notably, RA activity in fetal gonads is likely to be elevated in females than that in males, as evidenced by the higher expression of RA synthase Aldh1a1 and lower expression of RA-degrading enzyme Cyp26a1 in female gonads prior to meiotic entry. In addition, exogenous RA treatment induced the expression of Stra8 and Sycp3 in both sexes, whether in vivo or in vitro. Together, these results indicate that high levels of RA in the embryonic female gonads can lead to the initiation of meiosis in the turtle.

Pharmacokinetics and tumor delivery of nanoparticles.

Nanoparticles (NPs) have been widely used in different areas, including consumer products and medicine. In terms of biomedical applications, NPs or NP-based drug formulations have been extensively investigated for cancer diagnostics and therapy in preclinical studies, but the clinical translation rate is low. Therefore, a thorough and comprehensive understanding of the pharmacokinetics of NPs, especially in drug delivery efficiency to the target therapeutic tissue tumor, is important to design more effective nanomedicines and for proper assessment of the safety and risk of NPs. This review article focuses on the pharmacokinetics of both organic and inorganic NPs and their tumor delivery efficiencies, as well as the associated mechanisms involved. We discuss the absorption, distribution, metabolism, and excretion (ADME) processes following different routes of exposure and the mechanisms involved. Many physicochemical properties and experimental factors, including particle type, size, surface charge, zeta potential, surface coating, protein binding, dose, exposure route, species, cancer type, and tumor size can affect NP pharmacokinetics and tumor delivery efficiency. NPs can be absorbed with varying degrees following different exposure routes and mainly accumulate in liver and spleen, but also distribute to other tissues such as heart, lung, kidney and tumor tissues; and subsequently get metabolized and/or excreted mainly through hepatobiliary and renal elimination. Passive and active targeting strategies are the two major mechanisms of tumor delivery, while active targeting tends to have less toxicity and higher delivery efficiency through direct interaction between ligands and receptors. We also discuss challenges and perspectives remaining in the field of pharmacokinetics and tumor delivery efficiency of NPs.

Integration of Toxicogenomics and Physiologically Based Pharmacokinetic Modeling in Human Health Risk Assessment of Perfluorooctane Sulfonate.

Toxicogenomics and physiologically based pharmacokinetic (PBPK) models are useful approaches in chemical risk assessment, but the methodology to incorporate toxicogenomic data into a PBPK model to inform risk assessment remains to be developed. This study aimed to develop a probabilistic human health risk assessment approach by integrating toxicogenomic dose-response data and PBPK modeling using perfluorooctane sulfonate (PFOS) as a case study. Based on the available human in vitro and mouse in vivo toxicogenomic data, we identified the differentially expressed genes (DEGs) at each exposure paradigm/duration. Kyoto Encyclopedia of Genes and Genomes and disease ontology enrichment analyses were conducted on the DEGs to identify significantly enriched pathways and diseases. The dose-response data of DEGs were analyzed using the Bayesian benchmark dose (BMD) method. Using a previously published PBPK model, the gene BMDs were converted to human equivalent doses (HEDs), which were summarized to pathway and disease HEDs and then extrapolated to reference doses (RfDs) by considering an uncertainty factor of 30 for mouse in vivo data and 10 for human in vitro data. The results suggested that the median RfDs at different exposure paradigms were similar to the 2016 U.S. Environmental Protection Agency's recommended RfD, while the RfDs for the most sensitive pathways and diseases were closer to the recent European Food Safety Authority's guidance values. In conclusion, genomic dose-response data and PBPK modeling can be integrated to become a useful alternative approach in risk assessment of environmental chemicals. This approach considers multiple endpoints, provides toxicity mechanistic insights, and does not rely on apical toxicity endpoints.

Developmental regulatory system of ocular-side-specific asymmetric pigmentation in flounder: Critical role of retinoic acid signaling.

The body color of the Pleuronectiformes is bilaterally asymmetric between right and left halves, with a dark ocular-side and a white blind-side. This body color asymmetry develops by restricted differentiation of melanophores and xanthophores on the ocular-side during metamorphosis, accompanied by migration of one eye to the future ocular-side. In this study, we elucidated the developmental regulatory system of this lateralized pigmentation. We found that in flounder, Sox10-positive chromatophore progenitors appear bilaterally both in the ocular- and blind-side skin of metamorphosing larvae, and that those arriving at the ocular-side skin differentiate into gch2-positive chromatoblasts and then chromatophores. Transient exposure of metamorphosing larvae to retinoic acid (RA)-induced progenitors on the blind-side to differentiate into gch2-positive chromatoblasts. On the contrary, exposure to an RA receptor antagonist, BMS493, suppressed the differentiation of gch2-positive chromatoblasts on the ocular-side. Thus, we demonstrated that RA is essential for flounder chromatophore progenitors to differentiate into chromatoblasts. At the time of chromatoblast differentiation on the ocular-side, cyp26b1, which inactivates RA, was upregulated on the blind-side skin compared with the ocular-side. Therefore, we surmise that ocular-side-specific pigmentation is regulated by the inhibition of RA-signaling by cyp26b1 on the blind-side.

BN-Embedded Tetrabenzopentacene: A Pentacene Derivative with Improved Stability.

Considerable efforts have been devoted to achieving stable acene derivatives for electronic applications; however, the instability is still a major issue for such derivatives. To achieve higher stability with minimum structural change, CC units in the acenes were replaced with isoelectronic BN units to produce a novel BN-embedded tetrabenzopentacene (BNTBP). BNTBP, with a planar structure, is highly stable to air, moisture, light, and heat. Compared with its carbon analogue tetrabenzopentacene (TBP), BN embedment lowered the highest occupied molecular orbital (HOMO) energy level of BNTBP, changed the orbital distribution, and decreased the HOMO orbital coefficients at the central carbon atoms, which stabilize BNTBP molecules upon exposure to oxygen and sunlight. The single-crystal microribbons of BNTBP exhibited good performance in field-effect transistors (FETs). The high stability and good mobility of BNTBP indicates that BN incorporation is an effective approach to afford stable large-sized acenes with desired properties.

Expression profiles of RA synthases and catabolic enzymes in newly hatched and metamorphosing larvae of Japanese flounder, Paralichthys olivaceus.

Retinoic acid (RA) plays various embryogenesis and post-embryogenesis roles in vertebrates. As exposure of metamorphosing flounder larvae to RA has teratogenic effects on skin color and vertebral column development, harmonized RA synthesis and catabolism are likely essential in metamorphic development. To approach understanding of the roles of RA in flounder metamorphic development, we here examined the tissue mRNA expression of RA synthases (aldh1a1, aldh1a2, aldh1a3) and catabolic enzymes (cyp26a1, cyp26b1, cyp26c1) in newly hatched and metamorphosing larvae, and three-month-old juveniles by in situ hybridization (ISH). No ISH signal was detected for any genes from the skin and vertebral column susceptible to the teratogenic effects by RA. Since the intestine expressed aldh1a2 at high level in larvae but not in juvenile, it is a possibility that the larval intestine serves as a source of RA, and RA catabolic enzymes function at the level below sensitivity of ISH at vertebral column and skin development. We found that aldh1a2 and aldh1a3 were expressed along the margin of the tectum and the neurohypophysis of pituitary, respectively, both in contact with the cerebrospinal fluid (CSF), and cyp26b1 at the posterior tectum and cerebellum. We hypothesize that RA is supplied from the tectum and pituitary via the CSF for brain growth and maintenance, and cyp26b1 locally regulates RA contents in the brain.

External Asymmetry and Pectoral Fin Loss in the Bamboo Sole (Heteromycteris japonica): Small-Sized Sole with Potential as a Pleuronectiformes Experimental Model.

Pleuronectiform fish develop marked external asymmetry in eye location and skin color at metamorphosis. The bamboo sole, Heteromycteris japonica, also exhibits loss of the pectoral fins at metamorphosis. Because of its small body size, short generation time, and long spawning season, we focused on the bamboo sole as an experimental model to investigate metamorphic asymmetry and pectoral fin loss during development. In the present study, we utilized a small-scale culture system to evaluate bamboo sole larvae and larval development, and a microinjection system for fertilized eggs. The culture system described here uses an 18 L culture tank for rotifers (the first diet for larvae) and 5 L plastic beakers for larval culture. Under this system, most larvae completed metamorphosis, including one-eye migration and pigmentation of the ocular side, by 23 days postfertilization (dpf) at 25°C. Larvae at density of 120-150 per liter were grown from hatching to 23 dpf with a survival ratio of 60-75% per beaker. Pectoral fins, including coracoid and disk cartilage, formed but were completely lost in late metamorphosis without formation of proximal radials and fin rays. The microinjection system designed here is adequate for the bamboo sole and allows injection of 100 one-cell-stage embryos per day. We expect that the culture and microinjection systems described here will facilitate the use of the bamboo sole as an experimental model organism in developmental biology.

Excess Retinoic Acid Induces Fusion of Centra by Degenerating Intervertebral Ligament Cells in Japanese flounder, Paralichthys olivaceus.

In marine aquaculture fish, excessive supplement of vitamin A (VA) to zooplanktons for larval culture and experimental exposure of larvae to retinoic acid (RA: active form of VA) have been known to cause vertebral deformity. However, the tissues in the developing vertebral column that are affected by RA and the progression of vertebral deformity remain undetermined. To examine these questions, we histologically traced the progress of vertebral deformity induced by RA in Japanese flounder (Paralichthys olivaceus). Larvae were exposed to RA for 3 days at mid-metamorphosis (G-stage), a critical stage for vertebral deformity. Intervertebral ligament, which is known to form intervertebral joints in cooperation with the notochord, was severely degenerated by RA, leading to fusion of centra. During further development to adult, growth of centra was severely suppressed in an anterior-posterior direction in RA-treated fish and the notochord tissue was lost from fused centra, resulting in complete loss of intervertebral joints and fusion of centra. We conclude that RA initially damages the intervertebral ligaments, and these defects lead to fusion, narrowing of centra, and loss of intervertebral joints in the vertebral column. The cumulative effect of these modifications is a truncated body form.

A mode of action-based probabilistic framework of dose-response assessment for nonmutagenic liver carcinogens: a case study of PCB-126.

A main function of dose-response assessment is to estimate a "safe" dose in the target population to support chemical risk assessment. Typically, a "safe" dose is developed differently for cancer and noncancer effects based on a 2-step procedure, ie, point of departure (POD) derivation and low-dose extrapolation. However, the current dose-response assessment framework is criticized for its dichotomized strategy without integrating the mode of action (MOA) information. The objective of this study was, based on our previous work, to develop a MOA-based probabilistic dose-response framework that quantitatively synthesizes a biological pathway in a dose-response modeling process to estimate the risk of chemicals that have carcinogenic potential. 3,3',4,4',5-Pentachlorobiphenyl (PCB-126) was exemplified to demonstrate our proposed approach. There were 4 major steps in the new modeling framework, including (1) key quantifiable events (KQEs) identification and extraction, (2) essential dose calculation, (3) MOA-based POD derivation, and (4) MOA-based probabilistic reference dose (RfD) estimation. Compared with reported PODs and traditional RfDs, the MOA-based estimates derived from our approach were comparable and plausible. One key feature of our approach was the use of overall MOA information to build the dose-response relationship on the entire dose continuum including the low-dose region. On the other hand, by adjusting uncertainty and variability in a probabilistic manner, the MOA-based probabilistic RfDs can provide useful insights of health protection for the specific proportion of population. Moreover, the proposed framework had important potential to be generalized to assess different types of chemicals other than nonmutagenic carcinogens, highlighting its utility to improve current chemical risk assessment.

Quantitative Integration of Mode of Action Information in Dose-Response Modeling and POD Estimation for Nonmutagenic Carcinogens: A Case Study of TCDD.

BACKGROUND: Traditional dose-response assessment applies different low-dose extrapolation methods for cancer and noncancer effects and assumes that all carcinogens are mutagenic unless strong evidence suggests otherwise. Additionally, primarily focusing on one critical effect, dose-response modeling utilizes limited mode of action (MOA) data to inform low-dose risk. OBJECTIVE: We aimed to build a dose-response modeling framework that continuously extends the curve into the low-dose region via a quantitative integration of MOA information and to estimate MOA-based points of departure (PODs) for nonmutagenic carcinogens. METHODS: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was used as an example to demonstrate the new dose-response modeling framework. There were three major steps included: a) identifying and extracting key quantifiable events (KQEs), b) calculating essential doses that sequentially activate KQEs using the benchmark dose (BMD) methodology, and c) characterizing pathway dose-response relationship for MOA-based POD estimation. RESULTS: We identified and extracted six KQEs and corresponding essential events composing the MOA of TCDD-induced liver tumors. With the essential doses estimated from the BMD method using various settings, three link functions were applied to model the pathway dose-response relationship. Given a toxicologically plausible definition of adversity, an MOA-based POD was derived from the pathway dose-response curve. The estimated MOA-based PODs were generally comparable with traditional PODs and can be further used to calculate reference doses (RfDs). CONCLUSIONS: The proposed framework quantitatively integrated mechanistic information in the modeling process and provided a promising strategy to harmonize cancer and noncancer dose-response assessment through pathway dose-response modeling. However, the framework can also be limited by data availability and the understanding of the underlying mechanism. https://doi.org/10.1289/EHP12677.

An artificial intelligence-assisted physiologically-based pharmacokinetic model to predict nanoparticle delivery to tumors in mice.

The critical barrier for clinical translation of cancer nanomedicine stems from the inefficient delivery of nanoparticles (NPs) to target solid tumors. Rapid growth of computational power, new machine learning and artificial intelligence (AI) approaches provide new tools to address this challenge. In this study, we established an AI-assisted physiologically based pharmacokinetic (PBPK) model by integrating an AI-based quantitative structure-activity relationship (QSAR) model with a PBPK model to simulate tumor-targeted delivery efficiency (DE) and biodistribution of various NPs. The AI-based QSAR model was developed using machine learning and deep neural network algorithms that were trained with datasets from a published "Nano-Tumor Database" to predict critical input parameters of the PBPK model. The PBPK model with optimized NP cellular uptake kinetic parameters was used to predict the maximum delivery efficiency (DEmax) and DE at 24 (DE24) and 168 h (DE168) of different NPs in the tumor after intravenous injection and achieved a determination coefficient of R2 = 0.83 [root mean squared error (RMSE) = 3.01] for DE24, R2 = 0.56 (RMSE = 2.27) for DE168, and R2 = 0.82 (RMSE = 3.51) for DEmax. The AI-PBPK model predictions correlated well with available experimentally-measured pharmacokinetic profiles of different NPs in tumors after intravenous injection (R2 ≥ 0.70 for 133 out of 288 datasets). This AI-based PBPK model provides an efficient screening tool to rapidly predict delivery efficiency of a NP based on its physicochemical properties without relying on an animal training dataset.

Pharmacokinetics, tissue residue depletion, and withdrawal interval estimations of florfenicol in goats following repeated subcutaneous administrations.

Florfenicol is a broad-spectrum antibiotic commonly used in the U.S. to treat respiratory and enteric infections in goats in an extra-label manner, which requires scientifically based withdrawal intervals (WDIs) for edible tissues. This study aimed to determine the depletion profiles for florfenicol and florfenicol amine in plasma and tissues samples and to estimate WDIs for goats following subcutaneous injection of 40 mg/kg florfenicol, twice, 96 h apart. The samples were collected up to 50 days after the second dose. Pharmacokinetic parameters were calculated using non-compartmental analysis. Three different pharmacostatistical methods with different operational tolerances were used to calculate WDIs. The plasma half-life was 101.80 h for florfenicol and 207.69 h for florfenicol amine after the second dose. Using the FDA tolerance limit method, WDIs were 202 and 101 days, while the EMA maximum residue limit method estimated 179 and 96 days for the respective tissue concentrations to fall below limits of detection (0.12 µg/g for liver and 0.05 µg/g for kidney). This study characterizes plasma pharmacokinetics and tissue depletion profiles of florfenicol and florfenicol amine in goats following subcutaneous injections and reports estimated WDIs for food safety assessment of florfenicol in goats.

Meta-Analysis of Nanoparticle Distribution in Tumors and Major Organs in Tumor-Bearing Mice.

Low tumor delivery efficiency is a critical barrier in cancer nanomedicine. This study reports an updated version of "Nano-Tumor Database", which increases the number of time-dependent concentration data sets for different nanoparticles (NPs) in tumors from the previous version of 376 data sets with 1732 data points from 200 studies to the current version of 534 data sets with 2345 data points from 297 studies published from 2005 to 2021. Additionally, the current database includes 1972 data sets for five major organs (i.e., liver, spleen, lung, heart, and kidney) with a total of 8461 concentration data points. Tumor delivery and organ distribution are calculated using three pharmacokinetic parameters, including delivery efficiency, maximum concentration, and distribution coefficient. The median tumor delivery efficiency is 0.67% injected dose (ID), which is low but is consistent with previous studies. Employing the best regression model for tumor delivery efficiency, we generate hypothetical scenarios with different combinations of NP factors that may lead to a higher delivery efficiency of >3%ID, which requires further experimentation to confirm. In healthy organs, the highest NP accumulation is in the liver (10.69%ID/g), followed by the spleen 6.93%ID/g and the kidney 3.22%ID/g. Our perspective on how to facilitate NP design and clinical translation is presented. This study reports a substantially expanded "Nano-Tumor Database" and several statistical models that may help nanomedicine design in the future.

The impact of non-optimum temperatures, heatwaves and cold spells on out-of-hospital cardiac arrest onset in a changing climate in China: a multi-center, time-stratified, case-crossover study.

Background: Out-of-hospital cardiac arrest (OHCA) is a time-critical and fatal medical emergency that has been linked to non-optimal temperatures. However, the future burden of OHCA due to non-optimal temperatures, heatwaves, and cold spells under climate change has not been well evaluated. Methods: We conducted a time-stratified case-crossover study in 15 Northern Chinese cities throughout 2020 to estimate the exposure-response relationships of non-optimal temperatures, heatwaves, and cold spells with hourly OHCA onset in hot and cold seasons. We obtained future daily average temperatures by using 20 general circulation models under two greenhouse gas emission scenarios: one with certain emission control and the other with relaxed control. Lastly, we projected the change of OHCA burden under these two climate scenarios. Findings: We analyzed a total of 29,671 OHCA patients and found that high temperatures and heatwaves as well as low temperatures and cold spells were all significantly associated with an increased risk of OHCA onset. Under the scenario of uncontrolled emissions, the attributable fraction (AF) of OHCA due to high temperatures and heatwaves would increase by 4.94% and 6.99% from the 2010s to 2090s, respectively. The AF due to low temperatures would decrease by 1.27% by the 2090s and the effects of cold spells were projected to be marginal after the 2050s. Under a medium emission control scenario, the upward trend of heat-related OHCA burden would become flat, and the decline in cold-related OHCA burden would also slow down. Interpretation: Our study provides evidence of significant morbidity risk and burden of OHCA associated with global warming across Northern China. Our findings indicate that the increase in OHCA burden attributable to heat could not be offset by the decrements attributable to cold, emphasizing the importance of mitigation policies for limiting global warming and reducing the associated risks of OHCA onset. Funding: National Science & Technology Fundamental Resources Investigation Project (2018FY100600, 2018FY100602), National Key R&D Program of China (2020YFC1512700, 2020YFC1512705, 2020YFC1512703), Key R&D Program of Shandong Province (2021ZLGX02, 2021SFGC0503), Natural Science Foundation of Shandong Province (ZR2021MH231), Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), the Interdisciplinary Young Researcher Groups Program of Shandong University (2020QNQT004), ECCM Program of Clinical Research Center of Shandong University (2021SDUCRCA001, 2021SDUCRCA002), foundation from Clinical Research Center of Shandong University (2020SDUCRCB003), National Natural Science Foundation of China (82272240).

Fine and coarse particulate air pollution and out-of-hospital cardiac arrest onset: a nationwide case-crossover study in China.

Out-of-hospital cardiac arrest (OHCA) is a global public health concern. Nationwide studies on the effects of short-term exposure to particulate matter (PM) on OHCA risk are rare in regions with high PM levels, and evidence for coarse PM (PM2.5-10) is limited and inconsistent. To evaluate the associations between fine PM (PM2.5) and PM2.5-10 and OHCA onset, a time-stratified case-crossover study was conducted on 77,261 patients with cardiac OHCA in 26 cities across China in 2020. Daily PM2.5 and PM2.5-10 concentrations were assessed with high-resolution and full-coverage PM estimations. Conditional logistic regression models were applied in analyses. Each interquartile range of PM increase in 3-day moving average was associated with an increased risk of cardiac OHCA onset of 2.37% (95% CI, 1.20-3.56%) for PM2.5 and 2.12% (95% CI, 0.70-3.56%) for PM2.5-10. Stratified analyses showed higher susceptibility in patients over 75 years for PM2.5 exposure and with diabetes for PM2.5-10. This first nationwide study in region with high PM levels and great PM variability found not only PM2.5 but also PM2.5-10 were associated with a higher risk of OHCA onset, which could add powerful epidemiological evidence to this field and provide new evidence for the formulation of air quality guidelines.

Toxicokinetics, dose-response, and risk assessment of nanomaterials: Methodology, challenges, and future perspectives.

The rapid growth of nanomaterial applications has raised safety concerns for human health. A number of studies have been conducted to assess the toxicokinetics, toxicology, dose-response, and risk assessment of different nanomaterials using in vitro and in vivo animal and human models. However, current studies cannot meet the demand for efficient assessment of toxicokinetics, dose-response relationships, or the toxicological risk arising from the rapidly increasing number of newly synthesized nanomaterials. In this article, we review the methods for conducting toxicokinetics, hazard identification, dose-response, exposure, and risk assessment studies of nanomaterials, identify the knowledge gaps, and discuss the challenges remaining. We provide the rationale behind the appropriate design of nanomaterial plasma toxicokinetic and tissue distribution studies, including caveats on the interpretation and correlation of in vitro and in vivo toxicology studies. The potential of using physiologically based pharmacokinetic (PBPK) models to extrapolate toxicokinetic and toxicity findings from in vitro to in vivo and from animals to humans is discussed, and the knowledge gaps of PBPK modeling for nanomaterials are identified. While challenges still exist, there has been progress in the toxicokinetics, hazard identification, and risk assessment of nanomaterials in the past two decades. Recent advancements in the field are highlighted with relevant examples. We also share latest guidelines as well as our perspectives on future studies needed to characterize the toxicokinetics, toxicity, and dose-response relationship in support of nanomaterial risk assessment. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

Effects of Health Belief About COVID-19 on Knowledge Sharing: The Mediating Role of Self-Efficacy.

While existing studies have explored factors that affect knowledge sharing among employees from different perspectives, there are still research gaps regarding whether health belief affects knowledge sharing among employees, specifically against the backdrop of the COVID-19 pandemic, and how such effects work. Thus, the purpose of this study is to determine the effect of bank employees' health beliefs about COVID-19 on knowledge sharing mediated by their self-efficacy. From the perspective of social cognitive theory and the health belief model, this study investigates whether employees' perception of susceptibility and severity of COVID-19 affects formal as well as informal knowledge sharing through knowledge sharing self-efficacy. A sample of 407 bank employees (200 women and 207 men) in China was used for the study. The formulated hypotheses were tested using structural equation modeling and bootstrapping. The results showed that employees' perceived susceptibility to COVID-19 significantly undermines formal and informal knowledge sharing self-efficacy. However, there was no significant difference in the extent of its indirect effects on formal and informal knowledge sharing. Further, employees' perceived severity of COVID-19 had no effect on knowledge sharing self-efficacy and on formal and informal knowledge sharing, which could have resulted from the COVID-19 outbreak in China.

Quantifying association between liver tumor incidence and early-stage liver weight increase - An NTP data analysis.

Two-year toxicology and carcinogenesis rodent studies conducted at the National Toxicology Program (NTP) are used to identify potential adverse health effects in humans due to chemical exposure, including cancer. Liver tumor, the most frequently diagnosed tumor type of chemically induced neoplastic effects documented in NTP's carcinogenicity studies, is usually difficult to be detected at early stage due to the inconspicuous symptoms. However, the abnormal growth of liver cells can lead to liver weight increase, so it is hypothesized that liver tumor incidence is associated with early stage liver weight increase. In this study, the association between liver weight increase and liver tumor incidence are quantified by (1) calculating the correlation coefficient of and (2) building quantitative linear relationship between benchmark dose estimates derived from these two types of data collected from NTP studies. Together with 151 chemical/species/sex combinations of liver tumor data showing positive evidence collected from 76 NTP long-term studies, short-term liver weight data reported in the same NTP report were extracted to be paired with the liver tumor data for the analyses. Results show that the estimated correlation coefficients (as high as 0.78) along with the adequately fitted linear models suggest that the association between relative liver weight increase and aggregated liver tumor incidence are relatively strong. Additional analyses focused on some more specific situations (e.g., specific tumor type or specific strain/sex combination) further confirmed the strong association. Given the design of this study, the interpretation of the findings is not that liver weight increase can be used to predict liver tumor incidence, instead, evident increase in liver weight might be used as a reason to prioritize the test article for a two-year toxicology and carcinogenesis study.

Association of herbal/botanic supplement use with quality of life, recurrence, and survival in newly diagnosed stage II colon cancer patients: A 2-y follow-up study.

OBJECTIVES: Our objective was to investigate the association between herbal/botanic supplement use and perceived quality of life (QoL), cancer recurrence, and all-cause mortality in colon cancer patients. METHODS: Patients (n = 453) newly diagnosed with stage II adenocarcinoma of the colon between 2009 and 2011 were recruited from the North Carolina Central Cancer Registry. Data including demographic variables, herbal medicine use and frequency, lifestyle, diet, cancer treatment, and QoL were collected by interviews at diagnosis (baseline) and 1 and 2 y after diagnosis. Mortality information was obtained via the National Death Index. The Functional Assessment of Cancer Therapy-Colorectal (FACT-C) and Medical Outcomes Short Form 12 (SF-12) were used to evaluate QoL. RESULTS: At baseline, herbal/botanic supplement users were more likely to have a healthier lifestyle than non-users, including more physical activity (P <0.01), more fruit and vegetable consumption (P = 0.01), less smoking (P <0.01), and less energy intake from fat (P = 0.02). After adjustment for potential confounders, no significant association was found between herbal/botanic supplement use and QoL assessed by FACT-C and SF-12. Similarly, herbal/botanic supplement use was not associated with the risk of recurrence, all-cause mortality or the combined. CONCLUSION: In this study, patients with stage II colon cancer using herbal/botanic supplements had no significant improvement in their QoL and no difference in odds of colon cancer recurrence and all-cause mortality over 2 y after diagnosis compared with those who did not use herbs/botanicals. Further studies are warranted to confirm the findings and to focus on types of herbal/botanic supplements.