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To establish a novel and widely applicable payload-linker technology for antibody–drug conjugates (ADCs), we have focused our research on applying exatecan mesylate (DX-8951f), a ...potent topoisomerase I inhibitor, which exhibits extensive antitumor activity as well as significant myelotoxicity, as the payload part. Through this study, we discovered a promising exatecan derivative (DX-8951 derivative, DXd), that has the characteristics of low membrane permeability and shows considerably less myelotoxicity than that shown by exatecan mesylate in an in vitro human colony forming unit-granulocyte macrophage assay. DXd was further used for drug conjugation by using commercially or clinically useful monoclonal antibodies to evaluate the potency of the ADC. The result revealed that the DXd-ADCs targeting CD30, CD33, and CD70 were effective against each of their respective target-expressing tumor cell lines. Moreover, a novel DXd-ADC targeting B7-H3, which is a new target for ADCs, also showed potent antitumor efficacy both in vitro and in vivo. In conclusion, this study showed that this novel topoisomerase I inhibitor-based ADC technology is widely applicable to a diverse number of antibodies and is expected to mitigate myelotoxicity, thereby possibly resulting in better safety profiles than that of existing ADC technologies.
Lead (Pb) and cadmium (Cd) are toxic metals that exist ubiquitously in the environment. Children in polluted areas are particularly vulnerable to metal exposure, where clinical signs and symptoms ...could be nonspecific. Absorbed metals are excreted primarily in urine and reflect exposure from all sources. We analyzed Pb and Cd concentrations in blood, feces and urine of children from polluted townships near a lead-zinc mine in Kabwe, Zambia, to determine concurrent childhood exposure to the metals. Moreover, the study determined the Pb and Cd relationships among urine, feces and blood as well as accessed the potential of urine and fecal analysis for biomonitoring of Pb and Cd exposure in children. Fecal Pb (up to 2252 mg/kg, dry weight) and urine Pb (up to 2914 μg/L) were extremely high. Concentrations of Cd in blood (Cd-B) of up to 7.7 μg/L, fecal (up to 4.49 mg/kg, dry weight) and urine (up to 18.1 μg/L) samples were elevated. metal levels were higher in younger children (0–3 years old) than older children (4–7). Positive correlations were recorded for Pb and Cd among blood, urine and fecal samples whereas negative correlations were recorded with age. These findings indicate children are exposed to both metals at their current home environment. Moreover, urine and feces could be useful for biomonitoring of metals due to their strong relationships with blood levels. There is need to conduct a clinical evaluation of the affected children to fully appreciate the health impact of these metal exposure.
•We measured lead and cadmium excretion levels in children near a Pb-Zn mine in Zambia.•Fecal and urine Pb levels up to 2252 mg/kg and 2914 μg/L, respectively, were very high.•Cd in fecal (up to 4.49 mg/kg) and urine (up to 18.1 μg/L) samples were elevated.•Positive correlations were observed between fecal and urinary levels of Pb and Cd.•Children living near the Pb-Zn mine are at serious risks of Pb and Cd poisoning.
•Silver sulfadiazine has been used in burned patients for preventing infection.•Absorption of silver ions through damaged skin could be cytotoxic to human cells.•Ag1+ serum levels reached levels up ...to 558 times over that of the unexposed controls.•Ag1+ toxicity was measured considering the molar concentrations found in patients.•ROS, IL-1β, IL-6, IL-8, IL-10 and TNF-α production by inflammatory cells was decreased.
Silver sulfadiazine (SSD) has been widely used in burned patients for the prevention of local infections. To be biologically active and exert antimicrobial properties, silver needs to be present in the form of silver ions (Ag1+) that bind to negatively charged proteins, namely, the RNA and DNA in microorganisms. However, previous published studies conducted with SSD in the 1990s reported a high level of silver absorption through damaged skin and noted the potential cytotoxicity of Ag1+ to human cells. SSD toxicity, however, had been described in cell cultures using arbitrary silver concentrations. In the present study, we determined the serum silver levels in burned patients treated with SSD and, taking into account the molar Ag1+ concentrations found in these patients, we evaluated the Ag1+ toxicity effects on inflammatory cells (ROS and cytokine production) in vitro.
Twenty patients with an average burned body surface area of 27.68% were included in this study.
Patients’ Ag1+ serum levels reached up to 558 times those of the unexposed controls. Ag1+ was then added to inflammatory cells in vitro at levels up to 2000 times the level of the control, and there was no effect on the viability of the cells nor on the rate of apoptosis. We observed a decrease in reactive oxygen species production by mononuclear (MN) and polymorphonuclear (PMN) cells, as well as a substantial decrease in cytokines IL-1β, IL-6, IL-8, IL-10, and TNF-α production by leukocytes (MN and PNM).
These findings suggest that Ag1+ may contribute to negative outcomes after burns, decreasing the primary defense mechanism (respiratory burst) and altering cytokine production.
Currently, few studies have thoroughly investigated the socioeconomic factors related to sleep problems among evacuees following a disaster.
To examine sleep problems in evacuees using data from a ...large-scale cohort survey of evacuees conducted after the 2011 Great East Japan Earthquake (GEJE).
In sum, 73,433 residents who were living in evacuation zones responded to The 2011 Fukushima Health Management Survey. We excluded 16,659 participants who did not answer the question about sleep problems or those younger than 20 years. Thus, data from 56,774 participants (24,959 men and 31,815 women) were used for this analysis. Evacuees' self-reported sleep dissatisfaction was determined based on their response to the question ‘Are you satisfied with the quality of your sleep? ’. The response options ‘Unsatisfied’ and ‘Very unsatisfied’ were considered as the outcome for the present study. Prevalence ratios (PRs) and 95% confidence intervals (CIs) for the prevalence of self-reported sleep disturbance were estimated using modified Poisson regression models.
Of the qualifying survey respondents, 20.3% (4387 men and 7128 women) reported sleep dissatisfaction. Compared with participants living in their own or a relative's home (PR = 1), those living in temporary housing or rental accommodation had a higher prevalence of sleep dissatisfaction (1.47; 95% CI 1.44–1.50 and 2.16; 95% CI 2.07–2.26 in men; 1.39; 95% CI 1.36–1.41 and 1.92; 95% CI 1.86–1.99 in women). Higher educational attainment was also associated with a higher prevalence of sleep dissatisfaction in men, as were job loss and decreased income in both men and women.
Self-reported sleep dissatisfaction after the GEJE was associated with a deteriorated socioeconomic status among evacuees. However, future longitudinal studies are warranted.
•Our study was conducted in a large scale population which evacuated after a disaster.•Self-reported sleep dissatisfaction after a disaster was associated with living in non-home conditions.•Self-reported sleep dissatisfaction after a disaster was associated with decreased income and unemployment.
After the Fukushima disaster in 2011, affected residents experienced increased radiation-related anxiety and reduced subjective wellbeing. We investigated whether reduction of radiation-related ...anxiety promoted wellbeing among evacuees in Fukushima and assessed the role of mental health distress as a mediator. We used data from questionnaire surveys of evacuees in the 2011 and 2012 fiscal years (N = 34 312). We used radiation risk perception as an indicator of radiation-related anxiety and the frequency of laughter as an indicator of wellbeing. We measured changes in radiation risk perception from 2011 and 2012, and the frequencies of laughter and mental health distress (Kessler 6-item scale) in 2012, and investigated associations between radiation risk perception and frequency of laughter with and without covariates of mental health distress. Perceived genetic risk in 2011 had a significant inverse association with the frequency of laughter. Lowering of radiation risk perception was significantly associated with the frequency of laughter in the absence of covariates of mental health distress, but not in their presence. Lowering of radiation risk perception was also significantly associated with low mental health distress. Reduction of radiation-related anxiety promoted wellbeing via alleviation of mental health distress.
Aims/Introduction
The mechanisms underlying hypertriglyceridemia‐induced impaired glucose tolerance in Japanese individuals remain unclear. We aimed to evaluate the effect of hypertriglyceridemia on ...glucose metabolism in comparison with that of increased low‐density lipoprotein or decreased high‐density lipoprotein levels and to elucidate the sex differences in hypertriglyceridemia‐related dietary intake among Japanese individuals.
Materials and Methods
We randomly selected 898 (384 men and 514 women) participants aged 40–78 years in the Gifu Diabetes Study; those taking medication for dyslipidemia or diabetes mellitus were excluded. Serum levels of glucose metabolism parameters and the food frequency were measured cross‐sectionally. The glycated hemoglobin was measured again after 5 years.
Results
Glucose metabolism parameters and the percentage of individuals with impaired glucose tolerance were significantly higher in the high triglyceride group in men and women. Similar trends were observed in the low high‐density lipoprotein group, but only in men. Meanwhile, only the homeostasis model assessment of insulin resistance was higher in the high low‐density lipoprotein group. In non‐obese men, the percentage of energy intake from alcohol per total daily energy intake was significantly greater in the high triglyceride group. In obese women, the total energy intake was significantly greater in the high triglyceride group. At the 5‐year follow up, the risk of elevated glycated hemoglobin levels with hypertriglyceridemia was increased in men.
Conclusions
Hypertriglyceridemia is a stronger risk factor for impaired glucose tolerance than increased low‐density lipoprotein or decreased high‐density lipoprotein. For dietary habits, increased daily alcohol energy intake in non‐obese men and increased total energy intake in obese women were associated with hypertriglyceridemia.
Hypertriglyceridemia has a negative effect on glucose metabolism by increasing insulin resistance and secretion. Further, such effect was stronger than hyper‐LDL or lower‐HDL cholesterolemia in the Japanese with dyslipidemia‐induced impaired glucose tolerance. For dietary habits, increased daily alcohol energy intake in non‐obese men and increased total energy intake in obese women were associated with hypertriglyceridemia.
Lead poisoning is often considered a traditional disease; however, the specific mechanism of toxicity remains unclear. The study of Pb-induced alterations in cellular metabolic pathways is important ...to understand the biological response and disorders associated with environmental exposure to lead. Metabolomics studies have recently been paid considerable attention to understand in detail the biological response to lead exposure and the associated toxicity mechanisms. In the present study, wild rodents collected from an area contaminated with lead (N = 18) and a control area (N = 10) were investigated. This was the first ever experimental metabolomic study of wildlife exposed to lead in the field. While the levels of plasma phenylalanine and isoleucine were significantly higher in a lead-contaminated area versus the control area, hydroxybutyric acid was marginally significantly higher in the contaminated area, suggesting the possibility of enhancement of lipid metabolism. In the interregional least-absolute shrinkage and selection operator (lasso) regression model analysis, phenylalanine and isoleucine were identified as possible biomarkers, which is in agreement with the random forest model. In addition, in the random forest model, glutaric acid, glutamine, and hydroxybutyric acid were selected. In agreement with previous studies, enrichment analysis showed alterations in the urea cycle and ATP-binding cassette transporter pathways. Although regional rodent species bias was observed in this study, and the relatively small sample size should be taken into account, the present results are to some extent consistent with those of previous studies on humans and laboratory animals.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute-onset mucocutaneous diseases induced by infectious agents and/or inciting drugs. We have reported that the main causative ...drugs for SJS/TEN with severe ocular complications (SOC) were cold medicines, including multi-ingredient cold medications and nonsteroidal anti-inflammatory drugs (NSAIDs). Moreover, we also reported that acetaminophen is the most frequent causative drug in various cold medicines. In this study, we focused on acetaminophen-related SJS/TEN with SOC and analyzed
in addition to
. We studied the histocompatibility antigen genes
and
in addition to
, and
in 80 Japanese patients with acetaminophen-related SJS/TEN with SOC. We performed polymerase chain reaction amplification followed by hybridization with sequence-specific oligonucleotide probes (PCR-SSO) using commercial bead-based typing kits. We also used genotyped data from 113 healthy volunteers for
and
, and 639 healthy volunteers for
.
and
were associated with acetaminophen-related SJS/TEN with SOC, although the results ceased to be significant when we corrected the
-value for the number of alleles detected.
was strongly associated with acetaminophen-related SJS/TEN with SOC (carrier frequency:
= 4.7 × 10
, Pc = 6.6 × 10
, OR = 6.0; gene frequency:
= 8.0 × 10
, Pc = 1.1 × 10
, OR = 4.9).
(carrier frequency:
= 2.0 × 10
, Pc = 0.042, OR = 4.1; gene frequency:
= 2.2 × 10
, Pc = 0.047, OR = 3.9)
(carrier frequency:
= 2.1 × 10
, Pc = 0.045, OR = 2.4) and
(carrier frequency:
= 3.4 × 10
, Pc = 0.045, OR = 2.3) were also significantly associated, while
was inversely associated (gene frequency:
= 6.3 × 10
, Pc = 8.8 × 10
, OR = 0.5). Acetaminophen-related SJS/TEN with SOC was not associated with
. However, for acetaminophen-related SJS/TEN with SOC, we found an association with
and
in addition to
and
, which have been described previously.
ObjectivesThe Fukushima Daiichi Nuclear Power Plant accident, which occurred after the Great East Japan Earthquake and Tsunami in March 2011, may have a considerable long-term impact on the lives of ...area residents. The aims of this study were to determine the trajectories of psychological distress using 3-year consecutive data, and to find predictive factors of severe distress that may also prove useful for public health intervention.MethodsData were obtained on 12 371 residents who were registered in the municipalities categorised as complete evacuation areas for 3 years after the disaster and who completed an assessment in each of the 3 years.ResultsUsing group-based trajectory modelling, we identified four trajectory patterns distinguished by the levels of psychological distress, which gradually improved over time in all trajectories. Subjective sleep insufficiency, problem drinking, poor social support and perception of radiation risk 3 years after the accident were associated with the severity of psychological distress, according to the multivariate analysis.ConclusionsThe identified factors may be useful for community-based mental healthcare over the long term following a nuclear disaster.
Natural disasters force many evacuees to change several aspects of their lifestyles. This longitudinal study aimed to investigate whether factors such as living environment and lifestyle factors were ...related to new-onset hypertension in survivors of the Great East Japan Earthquake over a long-term follow-up of up to 7 years after the earthquake. The present study examined data collected from 29,025 Japanese participants aged 39–89 years, sourced from general health checkups and the Fukushima Mental Health and Lifestyle Survey, which was conducted in 13 communities between 2011 and 2018. A total of 10,861 participants received follow-up examinations. During a median follow-up of 4.3 years, 3744 participants (1588 men, 41.4%; 2,156 women, 30.7%) had newly developed hypertension. Heavy drinking (adjusted hazard ratio 1.38, 95% confidence interval 1.21–1.57, p < 0.001) and obesity (adjusted hazard ratio 1.27, 95% confidence interval 1.19–1.37, p < 0.001) were significantly associated with new-onset hypertension after the disaster in multivariate-adjusted analysis. Furthermore, experiencing evacuation after the disaster was also significantly associated with the risk of new-onset hypertension in men (adjusted hazard ratio 1.14, 95% confidence interval 1.02–1.27, p = 0.016). The present study indicated that lifestyle factors, such as drinking and obesity, and evacuation experience in men had significant effects on the risk of new-onset hypertension in the long term after the earthquake.
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