Evaluation of quercetin as a potential cytoprotector against acetaldehyde using the cultured hepatocyte model with aldehyde dehydrogenase isozyme deficiency.

Protective effect of quercetin against acetaldehyde was evaluated using the cultured hepatocyte models with aldehyde dehydrogenase (ALDH) isozyme deficiency (aldh2-kd and aldh1a1-kd). The quercetin-induced cytoprotection against acetaldehyde in the ALDH1A1-deficient mutant (aldh1a1-kd) was weaker than that in wild type. Furthermore, quercetin did not enhance the ALDH activity in aldh1a1-kd cells, suggesting that ALDH1A1 is involved in the quercetin-induced cytoprotection.

Predictive analysis of breast cancer response to neoadjuvant chemotherapy through plasma metabolomics.

PURPOSE: Preoperative chemotherapy is a critical component of breast cancer management, yet its effectiveness is not uniform. Moreover, the adverse effects associated with chemotherapy necessitate the identification of a patient subgroup that would derive the maximum benefit from this treatment. This study aimed to establish a method for predicting the response to neoadjuvant chemotherapy in breast cancer patients utilizing a metabolomic approach. METHODS: Plasma samples were obtained from 87 breast cancer patients undergoing neoadjuvant chemotherapy at our facility, collected both before the commencement of the treatment and before the second treatment cycle. Metabolite analysis was conducted using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography-mass spectrometry (LC-MS). We performed comparative profiling of metabolite concentrations by assessing the metabolite profiles of patients who achieved a pathological complete response (pCR) against those who did not, both in initial and subsequent treatment cycles. RESULTS: Significant variances were observed in the metabolite profiles between pCR and non-pCR cases, both at the onset of preoperative chemotherapy and before the second cycle. Noteworthy distinctions were also evident between the metabolite profiles from the initial and the second neoadjuvant chemotherapy courses. Furthermore, metabolite profiles exhibited variations associated with intrinsic subtypes at all assessed time points. CONCLUSION: The application of plasma metabolomics, utilizing CE-MS and LC-MS, may serve as a tool for predicting the efficacy of neoadjuvant chemotherapy in breast cancer in the future after all necessary validations have been completed.

Asian flush is a potential protective factor against COVID-19: a web-based retrospective survey in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19), first reported in December 2019, spread worldwide in a short period, resulting in numerous cases and associated deaths; however, the toll was relatively low in East Asia. A genetic polymorphism unique to East Asians, Aldehyde dehydrogenase 2 rs671, has been reported to confer protection against infections. METHOD: We retrospectively investigated the association between the surrogate marker of the rs671 variant, the skin flushing phenomenon after alcohol consumption, and the timing of COVID-19 incidence using a web-based survey tool to test any protective effects of rs671 against COVID-19. RESULTS: A total of 807 valid responses were received from 362 non-flushers and 445 flushers. During the 42 months, from 12/1/2019 to 5/31/2023, 40.6% of non-flushers and 35.7% of flushers experienced COVID-19. Flushers tended to have a later onset (Spearman's partial rank correlation test, p = 0.057, adjusted for sex and age). Similarly, 2.5% of non-flushers and 0.5% of flushers were hospitalized because of COVID-19. Survival analysis estimated lower risks of COVID-19 and associated hospitalization among flushers (p = 0.03 and <0.01, respectively; generalized Wilcoxon test). With the Cox proportional hazards model covering 21 months till 8/31/2021, when approximately half of the Japanese population had received two doses of COVID-19 vaccine, the hazard ratio (95% confidence interval) of COVID-19 incidence was estimated to be 0.21 (0.10-0.46) for flusher versus non-flusher, with adjustment for sex, age, steroid use, and area of residence. CONCLUSIONS: Our study suggests an association between the flushing phenomenon after drinking and a decreased risk of COVID-19 morbidity and hospitalization, suggesting that the rs671 variant is a protective factor. This study provides valuable information for infection control and helps understand the unique constitutional diversity of East Asians.

Predictive factors of coronavirus disease (COVID-19) vaccination series completion: a one-year longitudinal web-based observational study in Japan.

Introduction: Addresing vaccine hesitancy is considered an important goal in management of the COVID-19 pandemic. We sought to understand what factors influenced people, especially those initially hesitant, to receive two or more vaccine doses within a year of the vaccine's release. Methods: We conducted longitudinal Web-based observational studies of 3,870 individuals. The surveys were conducted at four different time points: January 2021, June 2021, September 2021, and December 2021. In the baseline survey (January 2021), we assessed vaccination intention (i.e., "strongly agree" or "agree" [acceptance], "neutral" [not sure], and "disagree" or "strongly disagree" [hesitance]), and assumptions about coronavirus disease (COVID-19), COVID-19 vaccine, COVID-19-related health preventive behavior, and COVID-19 vaccine reliability. In subsequent surveys (December 2021), we assessed vaccination completion (i.e., ≥2 vaccinations). To investigate the relationship between predictors of COVID-19 vaccination completion, a multivariable logistic regression model was applied. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated while adjusting for gender, age, marital status, presence of children, household income category, and presence of diseases under treatment. In a stratified analysis, predictors were determined based on vaccination intention. Results: Approximately 96, 87, and 72% of those who demonstrated acceptance, were not sure, or hesitated had been vaccinated after 1 year, respectively. Overall, significant factors associated with COVID-19 vaccine compliance included the influence of others close to the index participant (social norms) (AOR, 1.80; 95% CI, 1.56-2.08; p < 0.001), vaccine confidence (AOR, 1.39; 95% CI, 1.18-1.64; p < 0.001) and structural constraints (no time, inconvenient location of medical institutions, and other related factors) (AOR, 0.80; 95% CI, 0.70-0.91; p = 0.001). In the group of individuals classified as hesitant, significant factors associated with COVID-19 vaccine compliance included social norms (AOR, 2.43; 95% CI, 1.83-3.22; p < 0.001), confidence (AOR, 1.44; 95% CI, 1.10-1.88; p = 0.008), and knowledge (AOR, 0.69; 95% CI, 0.53-0.88; p = 0.003). Discussion: We found that dissemination of accurate information about vaccines and a reduction in structural barriers to the extent possible enhanced vaccination rates. Once the need for vaccination becomes widespread, it becomes a social norm, and further improvements in these rates can then be anticipated. Our findings may help enhance vaccine uptake in the future.

Associations for progression of cerebral small vessel disease burden in healthy adults: the Kashima scan study.

To investigate the association between vascular risk factors and progression of cerebral small vessel disease (SVD), we conducted a longitudinal study with neurologically healthy cohort composed mostly of middle-aged adults (n = 665, mean age, 57.7 years). Subjects, who had both baseline data of brain health examinations including MRI and follow-up MRI at least 1 year after the baseline MRI, were included this study. The presence of features of SVD, including lacunes, cerebral microbleeds, white matter hyperintensity, and basal ganglia perivascular spaces were summed to obtain "total SVD score" (range, 0-4). Progression of SVD was evaluated among subjects with a total SVD score of ≤ 3 and was defined as a ≥ 1 point increase in that score at follow-up relative to baseline. As the primary analysis, multivariate logistic regression analyses were performed to determine the associations of progression of SVD at baseline. The median follow-up period was 7.3 years and progression of SVD was observed in 154 subjects (23.2%). Even after adjustment with confounders multivariate logistic regression analyses showed that progression of SVD was associated with age (per 10-year increase, odds ratio [OR]: 2.08, 95% confidence interval [CI] 1.62-2.67), hypertension (OR 1.55, 95%CI 1.05-2.29), systolic blood pressure (BP) (per standard deviation [SD] increase, OR 1.27, 95%CI 1.04-1.54), diastolic BP (per SD increase, OR 1.23, 95%CI 1.01-1.50), and mean arterial pressure (per SD increase, OR 1.27, 95%CI 1.04-1.55). Age and high blood pressure appear to play key roles in the progression of cerebral small vessel burden after mid-life.

Extended and adjustable field-of-view of variable interscan time analysis by ammonite-scanning swept-source optical coherence tomography angiography.

A novel scanning protocol, ammonite scan, is proposed for widefield optical coherence tomography angiography (OCTA) and relative retinal blood flow velocity imaging in the human retina using variable interscan time analysis (VISTA). A repeated circle scan using a 400 kHz swept-source was employed to achieve an interscan time of 1.28 ms. The center of the repeated circular scan continuously moved spirally towards the peripheral region, ensuring an extended and adjustable scan range while preserving the short interscan time. Image artifacts due to eye movement were eliminated via extra motion-correction processing using data redundancy. The relative blood flow velocity in superficial and deep plexus layers was calculated from the VISTA image, and their ratio was used to explore the microvascular flow parameter in the healthy human eye.

Excessive whole-body exposure to 28 GHz quasi-millimeter wave induces thermoregulation accompanied by a change in skin blood flow proportion in rats.

Introduction: Limited information is available on the biological effects of whole-body exposure to quasi-millimeter waves (qMMW). The aim of the present study was to determine the intensity of exposure to increase body temperature and investigate whether thermoregulation, including changes in skin blood flow, is induced in rats under whole-body exposure to qMMW. Methods: The backs of conscious rats were extensively exposed to 28 GHz qMMW at absorbed power densities of 0, 122, and 237 W/m2 for 40 minutes. Temperature changes in three regions (dorsal and tail skin, and rectum) and blood flow in the dorsal and tail skin were measured simultaneously using fiber-optic probes. Results: Intensity-dependent temperature increases were observed in the dorsal skin and the rectum. In addition, skin blood flow was altered in the tail but not in the dorsum, accompanied by an increase in rectal temperature and resulting in an increase in tail skin temperature. Discussion: These findings suggest that whole-body exposure to qMMW drives thermoregulation to transport and dissipate heat generated on the exposed body surface. Despite the large differences in size and physiology between humans and rats, our findings may be helpful for discussing the operational health-effect thresholds in the standardization of international exposure guidelines.

Efficacy and safety of dose-dense neoadjuvant chemotherapy with nab-paclitaxel followed by epirubicin and cyclophosphamide for operable breast cancer.

OBJECTIVE: Dose-dense chemotherapy has shown a better prognosis than standard interval chemotherapy in adjuvant settings for high-risk breast cancer. This study aimed to evaluate the efficacy and safety of dose-dense nanoparticle albumin-bound paclitaxel followed by dose-dense epirubicin and cyclophosphamide as neoadjuvant chemotherapy for human epidermal growth factor 2 (HER2)-negative operable breast cancer. METHODS: Patients with histologically confirmed stage I-III HER2-negative breast cancer were enrolled in this study. Patients received nanoparticle albumin-bound paclitaxel (260 mg/m2) followed by epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks with pegfilgrastim. The primary endpoint was the pathological complete response rate. Patients also underwent prophylactic management for peripheral neuropathy, which involved a combination of cryotherapy, compression therapy using elastic stockings and medications including goshajinkigan. RESULTS: Among the 55 patients enrolled in this study, 13 (23.6%) achieved pathological complete response, of whom 10/26 (38.5%) patients had triple-negative disease and 3/29 (10.3%) had luminal disease. The objective response was observed in 46 (83.6%) patients. Of the 36 patients who were initially planned for mastectomy, 11 (30.6%) underwent breast-conserving surgery after neoadjuvant chemotherapy. The most common grade 3-4 adverse events were myalgia (14.5%), fatigue (12.7%) and elevated transaminase levels (9.1%). No patients experienced febrile neutropenia. Eight (14.5%) patients discontinued treatments due to adverse events. CONCLUSIONS: Neoadjuvant dose-dense biweekly nanoparticle albumin-bound paclitaxel followed by dose-dense epirubicin and cyclophosphamide was effective, especially in patients with triple-negative disease, and feasible with pegfilgrastim support.

ALDH2 rs671 variant allele is associated with higher energy intake in middle-aged and elderly Japanese who routinely consume alcohol.

BACKGROUND: According to recent reports, individuals with reduced aldehyde dehydrogenase activity may require more energy for the detoxification of aldehydes. Aldehyde dehydrogenase 2 (ALDH2), an ALDH isozyme, is responsible for detoxifying acetaldehyde, an intermediate metabolite of ethanol. Because the variant allele of the rs671 polymorphism of ALDH2 results in a substantial reduction in enzymatic activity, carriers of this variant allele may have a higher energy demand when consuming alcohol than non-carriers. However, no studies have evaluated this phenomenon to date. METHOD: To test the hypothesis, we statistically examined the interactive effects between the rs671 and ethanol consumption on energy intake using cross-sectional data from a population-based cohort study, the Japan Multi-Institutional Collaborative Cohort Study, which was conducted in Saga city between 2005-2007 (N = 12,068). RESULTS: General linear regression models adjusted for age, sex, ethanol consumption, current smoking status, years of education, dietary restriction, medical history, and physical activity level revealed that energy intake was higher in variant allele carriers than in non-carriers among individuals with alcohol drinking habits, whereas no such correlation was observed among those without drinking habits (≤2 g ethanol/day) (p = 0.03 for interaction between rs671 and ethanol consumption). Energy intake excluding energy from alcoholic beverages, carbohydrate intake, protein intake, and fat intake, showed similar tendencies (p for interaction = 0.01, 0.01, 0.04, and 0.07, respectively). CONCLUSIONS: These findings support the hypothesis that increased energy intake is required for the detoxification of aldehydes in individuals with low ALDH activity. This epidemiological evidence provides a possible scientific basis for understanding aldehyde detoxification mechanisms and suggests a novel phenotype of the ALDH2 rs671 polymorphism.

Ethanol Metabolism and Melanoma.

Malignant melanoma is the deadliest form of skin cancer. Despite significant efforts in sun protection education, melanoma incidence is still rising globally, drawing attention to other socioenvironmental risk factors for melanoma. Ethanol and acetaldehyde (AcAH) are ubiquitous in our diets, medicines, alcoholic beverages, and the environment. In the liver, ethanol is primarily oxidized to AcAH, a toxic intermediate capable of inducing tumors by forming adducts with proteins and DNA. Once in the blood, ethanol and AcAH can reach the skin. Although, like the liver, the skin has metabolic mechanisms to detoxify ethanol and AcAH, the risk of ethanol/AcAH-associated skin diseases increases when the metabolic enzymes become dysfunctional in the skin. This review highlights the evidence linking cutaneous ethanol metabolism and melanoma. We summarize various sources of skin ethanol and AcAH and describe how the reduced activity of each alcohol metabolizing enzyme affects the sensitivity threshold to ethanol/AcAH toxicity. Data from the Gene Expression Omnibus database also show that three ethanol metabolizing enzymes (alcohol dehydrogenase 1B, P450 2E1, and catalase) and an AcAH metabolizing enzyme (aldehyde dehydrogenase 2) are significantly reduced in melanoma tissues.

Acute arterial occlusive disease due to tumor thrombus from lung metastasis of breast cancer with cartilaginous and osseous metaplasia: a case report.

BACKGROUND: Tumor embolization due to venous infiltration of breast cancer pulmonary metastases is very rare. CASE PRESENTATION: A 72-year-old female was diagnosed with triple-negative breast cancer. Neoadjuvant chemotherapy was discontinued because of progressive disease, and a right mastectomy with sentinel lymph node biopsy was performed. The pathological analysis of surgical specimens revealed carcinoma with cartilaginous and/or osseous metaplasia. At 22 months after surgery, lung metastasis was observed, and 6 months after initiating treatment for lung metastases, she complained of sudden numbness in the left-lower limb with trouble walking. Ultrasonography showed an embolism in the left popliteal artery, and contrast computed tomography showed enlarged lung metastases and infiltration of the left-upper lobe disease into the left superior pulmonary vein and left atrium. Acute arterial occlusive disease in the left-lower limb caused by the tumor embolism was suspected, so an endovascular thrombectomy was performed. Tumor emboli were removed by embolectomy catheter. CONCLUSION: This report of lung metastasis from breast cancer with cartilaginous and/or osseous metaplasia and acute lower-limb artery occlusion due to a tumor thrombus adds useful information to the literature on these extremely rare cases.

[Two Cases of the Significant Liver Damage by Regorafenib].

There is a liver damage in a serious side effect of regorafenib. Case 1 was a 54-year-old woman, and she had an operation of rectal cancer and metastasized to multiple organs afterwards and started regorafenib as third-line. Erythema exudativum multiform developed on the 8th day after a start and regorafenib was canceled once and reduced on the 21st day when a skin symptom was relieved and restarted. However, because a significant rise of AST, ALT, T -Bil was recognized afterwards, regorafenib was canceled on the 27th day and enforced steroid pulse therapy and was relieved afterwards. Case 2 was a 61-year-old woman, and she had an operation of ascending colon cancer, ovarian metastasis and peritoneum dissemination. Regorafenib was started by frequent occurrence lung metastasis, cancerous pleurisy afterwards as fifth-line. Dissemination erythema developed on the 16th day and a liver damage developed on the 22nd day. Because a rise of AST, ALT went and was prolonged, liver biopsy was enforced in a cause close inspection purpose on the 45th day. A medicamentosus liver damage was diagnosed. The liver enzyme decreased afterwards. It may be easy to make the liver damage by regorafenib serious, and attention is necessary.

Management of Crohn's disease relapse during neoadjuvant chemotherapy for bilateral breast cancer: a case report.

Diagnosis of breast cancer in a patient with Crohn's disease (CD) is uncommon. However, cytotoxic chemotherapy might help control CD during the treatment period. Here, we report a case of CD relapse during treatment with neoadjuvant chemotherapy (NAC) for bilateral breast cancer. A 39-year-old woman with CD controlled by infliximab and mesalazine was diagnosed with bilateral breast cancer. Infliximab treatment was discontinued temporarily so that the patient could receive NAC. However, her CD symptoms intensified during chemotherapy, and after her symptoms improved after a one-time administration of infliximab, the remainder of NAC was completed with a corticosteroid. Bilateral breast conservation surgery was performed. Histopathological examination revealed partial response of the left breast cancer and no residual cancer in the right breast. Breast irradiation and hormone therapy were added and no signs of recurrence have been observed for 5 years. CD has been well controlled with adalimumab and mesalazine.

Establishment of a deep-learning system to diagnose BI-RADS4a or higher using breast ultrasound for clinical application.

Although the categorization of ultrasound using the Breast Imaging Reporting and Data System (BI-RADS) has become widespread worldwide, the problem of inter-observer variability remains. To maintain uniformity in diagnostic accuracy, we have developed a system in which artificial intelligence (AI) can distinguish whether a static image obtained using a breast ultrasound represents BI-RADS3 or lower or BI-RADS4a or higher to determine the medical management that should be performed on a patient whose breast ultrasound shows abnormalities. To establish and validate the AI system, a training dataset consisting of 4028 images containing 5014 lesions and a test dataset consisting of 3166 images containing 3656 lesions were collected and annotated. We selected a setting that maximized the area under the curve (AUC) and minimized the difference in sensitivity and specificity by adjusting the internal parameters of the AI system, achieving an AUC, sensitivity, and specificity of 0.95, 91.2%, and 90.7%, respectively. Furthermore, based on 30 images extracted from the test data, the diagnostic accuracy of 20 clinicians and the AI system was compared, and the AI system was found to be significantly superior to the clinicians (McNemar test, p < 0.001). Although deep-learning methods to categorize benign and malignant tumors using breast ultrasound have been extensively reported, our work represents the first attempt to establish an AI system to classify BI-RADS3 or lower and BI-RADS4a or higher successfully, providing important implications for clinical actions. These results suggest that the AI diagnostic system is sufficient to proceed to the next stage of clinical application.

Variant Allele of ALDH2, rs671, Associates with Attenuated Post-Vaccination Response in Anti-SARS-CoV-2 Spike Protein IgG: A Prospective Study in the Japanese General Population.

Uncovering the predictors of vaccine immunogenicity is essential for infection control. We have reported that the most prevalent polymorphism of the aldehyde dehydrogenase 2 gene (ALDH2), rs671, may be associated with an attenuated immune system. To test the inverse relationship between rs671 and antibody production after COVID-19 vaccination, the levels of anti-SARS-CoV-2 Spike protein S1 subunit (S1) IgG were repeatedly measured for four months before and after vaccination with BNT162b2 or mRNA-1273, in 88 Japanese workers and students (including 45 females, aged 21-56 years, with an rs671 variant allele frequency of 0.3). The mixed model including fixed effects of the vaccine type, weeks post vaccination (categorical variable), sex, age, height, smoking status, ethanol intake, exercise habit, perceived stress, steroid use, allergic diseases, and dyslipidemia, indicated an inverse association between log-transformed anti-S1 IgG levels and the number of rs671 variant alleles (partial regression coefficient = -0.15, p = 0.002). Our study indicated for the first time that the variant allele of ALDH2, rs671, is associated with the attenuated immunogenicity of COVID-19 mRNA vaccines. Our finding may provide a basis for personalized disease prevention based on a genetic polymorphism that is prevalent among East Asians.

Acceptance of Booster COVID-19 Vaccine and Its Association with Components of Vaccination Readiness in the General Population: A Cross-Sectional Survey for Starting Booster Dose in Japan.

The Japanese government approved COVID-19 vaccine booster doses in November 2021. However, intentions and readiness for booster vaccines among the general population were unknown. This survey measured the intentions for COVID-19 booster vaccination. Among 6172 participants (53.2% female), 4832 (78.3%) accepted booster doses; 415 (6.7%) hesitated. Vaccination intention was associated with higher age, marital status, having children, underlying diseases, and social norms. To evaluate the readiness for vaccination, the seven component (7C) vaccination readiness scale was employed, comprising "Confidence", "Complacency", "Constraints", "Calculation", "Collective responsibility", "Compliance", and "Conspiracy". Participants with acceptance showed significantly higher 7C scores (p < 0.001) than those who hesitated or were unsure. Multivariable logistic regression analysis revealed that the "social norms" predictor was the strongest predictor of acceptance (adjusted odds ratio (AOR) 4.02, 95% confidence interval (CI): 3.64−4.45). "Constraints" (AOR: 2.27, 95% CI: 2.11−2.45) and "complacency" (AOR: 2.18, 95% CI: 2.03−2.34) were also strongly associated with acceptance, but "compliance" (AOR: 1.24, 95% CI: 1.18−1.31) and "conspiracy" (AOR: 1.42, 95% CI: 1.33−1.52) were weakly associated. The "7C vaccination readiness scale" is useful for measuring vaccine acceptance in the Japanese population. However, "social norms" might be more suitable than "compliance" and "conspiracy" for measuring vaccine acceptance in Japan.