A culture method with berbamine, a plant alkaloid, enhances CAR-T cell efficacy through modulating cellular metabolism.

Memory T cells demonstrate superior in vivo persistence and antitumor efficacy. However, methods for manufacturing less differentiated T cells are not yet well-established. Here, we show that producing chimeric antigen receptor (CAR)-T cells using berbamine (BBM), a natural compound found in the Chinese herbal medicine Berberis amurensis, enhances the antitumor efficacy of CAR-T cells. BBM is identified through cell-based screening of chemical compounds using induced pluripotent stem cell-derived T cells, leading to improved viability with a memory T cell phenotype. Transcriptomics and metabolomics using stem cell memory T cells reveal that BBM broadly enhances lipid metabolism. Furthermore, the addition of BBM downregulates the phosphorylation of p38 mitogen-activated protein kinase and enhanced mitochondrial respiration. CD19-CAR-T cells cultured with BBM also extend the survival of leukaemia mouse models due to their superior in vivo persistence. This technology offers a straightforward approach to enhancing the antitumor efficacy of CAR-T cells.

Effective and stable gene transduction in rhesus macaque iPSCs capable of T-lineage differentiation utilizing the piggyBac system.

Introduction: Genetically modified human induced pluripotent stem cell (iPSC)-based regenerative medicine has substantial potential in the treatment of refractory human diseases. Thus, preclinical studies on the safety and efficacy of these products are essential. Non-human primate (NHP) models such as the rhesus macaque are highly similar to humans in terms of size, lifespan, and immune system, rendering them superior models. However, effective gene transduction in rhesus macaque iPSCs (Rh-iPSCs) remains challenging. In this study, we investigated the effective gene transduction into Rh-iPSCs and its effect on differentiation efficiency. Methods: We established a gene transduction method using the piggyBac transposon vector system. Gene transduced Rh-iPSCs were analyzed for undifferentiated markers. We did teratoma assay to check pluripotency. Gene transduced Rh-iPSCs were differentiated into hematopoietic stem and progenitor cells (HSPCs) and T-cell lineage cells. Additionally, gene transduced Rh-iPSCs were compared the differentiation efficiency with parental Rh-iPSCs. Results: We could establish a gene transduction method using the piggyBac transposon vector system, demonstrating high efficiency and stable transgene expression in Rh-iPSCs. These Rh-iPSCs maintained long-term gene expression while expressing undifferentiated markers. Teratoma assay indicated that these Rh-iPSCs had pluripotency. These Rh-iPSCs could differentiate into HPSCs and T cells that express transgenes. These Rh-iPSCs can differentiate into hematopoietic stem cells and T cells that express transgenes. No significant differences in efficiency of differentiation were observed between parental Rh-iPSCs and these Rh-iPSCs. Conclusions: These results indicate that the piggyBac transposon vector is an excellent gene transfer tool for rhesus macaque iPSCs and could contribute to the advancement of preclinical studies using rhesus macaque iPSCs.

Development of IgA vasculitis with severe glomerulonephritis after COVID-19 vaccination: a case report and literature review.

With the worldwide spread of the COVID-19 vaccine program during the COVID-19 pandemic, the numbers of reported cases with new-onset or relapsed kidney disease/vasculitis such as minimal change nephrotic syndrome, immunoglobulinA (IgA) nephropathy, and IgA vasculitis (IgAV) that developed after COVID-19 vaccination are increasing. We present the case of a 67-year-old Japanese woman who developed IgAV with purpura on her extremities and trunk in the evening of the day that she received the second dose of the Pfizer-BioNTech COVID-19 vaccine. She subsequently presented with acute kidney injury and nephrotic syndrome, and a kidney biopsy performed 14 days after the second vaccination showed diffuse mesangial and endocapillary glomerulonephritis with necrotizing crescent formation, accompanied by IgA deposition. One steroid pulse plus four administrations of a monthly intravenous cyclophosphamide injection were applied, followed by oral azathioprine during oral steroid tapering. Her response to this treatment was unsatisfactory and intractable for some time. Eventually, her renal function improved and nephrotic syndrome was resolved, while microscopic hematuria and proteinuria at ~ 1 g/gCr remained at 6 months post-vaccination. Unlike the previous milder renal-involved IgAV cases following COVID-19 vaccination, our patient's case presented severe glomerulonephritis and took a long time to recover despite intensive initial immunosuppressive treatment.

The association between subjective health perception and lifestyle factors in Shiga prefecture, Japan: a cross-sectional study.

BACKGROUND: The Ministry of Health has reported that in Japan, the Shiga prefecture has the highest life expectancy. Subjective health perception is a predictive indicator of mortality. For this study, we examined the association between subjective health perception and multiple lifestyle factors. METHODS: Data were obtained from the 2015 Health and Nutrition Survey in Shiga prefecture. The analytic sample comprised 6057 adults aged 20 or older. Information on subjective health perception and lifestyle behaviors was obtained from a self-administered questionnaire. As for subjective health perception, participants were divided into 2 groups: (1) Excellent or Good and (2) Average, Poor, or Very Poor. A 1-day dietary survey was also administered. The health behaviors score (HBS) was calculated based on 5 factors: consuming a healthy diet, never smoking, low-risk alcohol drinking, regular exercise, and moderate sleep duration. HBS scores ranged from 0 to 5. Multiple logistic regression was used to calculate the sex-, age- BMI- and energy intake-adjusted odds ratios (ORs) of poor subjective health across HBS, with 0 points as the reference. RESULTS: Among all participants, 2397 (39.6%) individuals were classified into the good subjective health group. Participants with an HBS of 3 (OR 0.59, 95% CI 0.37-0.96), 4 (OR 0.40, 95% CI 0.24-0.65) or 5 (OR 0.33, 95% CI 0.19-0.59) had a lower OR of rating themselves as being average/poor health compared with those having zero. The association with a higher HBS was remarkable (p for trend: < 0.001). Additional analyses revealed that the combinations including regular exercise were particularly associated with a lower risk of subjective average/poor health. CONCLUSIONS: This study showed that the higher the number of healthy lifestyle factors, the lower risk of subjective average/poor health. Combinations of healthy lifestyle factors, especially those involving exercise, suggest good subjective health for individuals living in the Shiga prefecture.

The Association between Combined Lifestyle Factors and All-Cause and Cause-Specific Mortality in Shiga Prefecture, Japan.

BACKGROUND: To decrease mortality, the benefit of combined healthy lifestyles has been suggested but is still unclear, especially for cause-specific mortality. We examined the relationship between combined lifestyle factors and all-cause and cause-specific mortality in Shiga prefecture, Japan. METHODS: This was an ecological study of 19 municipalities, using the data from the 2008-2012 standard mortality ratio (SMR) reported by the Ministry of Health and Welfare and the 2015 Health and Nutrition Survey in Shiga prefecture. The health behaviors score was calculated based on five factors (ranging from 0 to 5): diet quality (assessed adherence to dietary reference intake for Japanese), smoking, alcohol drinking, regular exercise, and sleep duration. In the multiple linear regression, the relationships between the health behaviors score and SMR of all-cause, cancer, heart diseases, and cerebrovascular diseases were estimated by sex. RESULTS: The health behaviors score was negatively associated with the cancer SMR in women (ß = -0.968, p = 0.011). For other causes, no significant association was found for either sex. A greater proportion of those who never smoked (ß = -0.780, p = 0.016) and those who had a higher quality diet (ß = -0.703, p = 0.048) were associated with lower cancer SMR in women. Women's intake of some micronutrients, particularly fruits, was higher than men. This study suggests that a combination of health behaviors, especially never smoking and high-quality diet intake are associated with lower cancer SMR in women and could be helpful in prolonging life expectancy.

The precise long-term outcomes of adult IgA nephropathy by mail questionnaires: Better renal survival compared to earlier cohort studies.

The estimated 20-year renal survival rate of immunoglobulin A (IgA) nephropathy is approx. 60%, but it is difficult to determine the 'big picture' for IgA nephropathy because a biopsy is essential for its diagnosis. Here we attempted to determine the longer and more precise renal prognosis of IgA nephropathy. We examined 310 patients with primary IgA nephropathy. Using the patients' clinical records and histological reports from our hospital and other clinics, we surveyed their renal prognoses and treatments within 1 year post-biopsy, and we sent questionnaires to the patients who had stopped visiting any hospital. We set renal death as the primary endpoint and analyzed factors related to renal death. The total patient cohort was 267: 159 males, 108 females; average age at biopsy, 37.7 years; average estimated glomerular filtration rate (eGFR), 69.7 mL/min/1.73m2; urinary protein, 1.3 g/day. The mean follow-up duration was prolonged to 13.8±8.9 years (vs. 9.2±8.5 years using only medical records). The 10- and 20-year follow-up rates were 61.7% and 27.3%. The 10-, 20-year renal survival rates were 83.6% and 72.5%. Lower eGFR, hypertension, and smoking were revealed as factors independently related to renal death. To study survival of relatively benign diseases such as IgA nephropathy, longer survival rate was affected by many censoring cases. The results regarding the long-term renal prognoses of IgA nephropathy patients (including those with a mild phenotype) obtained by our analysis of a questionnaire sent to the patients provided more precise and longer-term prognoses compared to earlier studies.

Associations of complementation group, ALDH2 genotype, and clonal abnormalities with hematological outcome in Japanese patients with Fanconi anemia.

Fanconi anemia (FA) is a genetically and clinically heterogeneous disorder that predisposes patients to bone marrow failure (BMF), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). To study which genetic and phenotypic factors predict clinical outcomes for Japanese FA patients, we examined the FA genes, bone marrow karyotype, and aldehyde dehydrogenase-2 (ALDH2) genotype; variants of which are associated with accelerated progression of BMF in FA. In 88 patients, we found morphologic MDS/AML in 33 patients, including refractory cytopenia in 16, refractory anemia with excess blasts (RAEB) in 7, and AML in 10. The major mutated FA genes observed in this study were FANCA (n = 52) and FANCG (n = 23). The distribution of the ALDH2 variant alleles did not differ significantly between patients with mutations in FANCA and FANCG. However, patients with FANCG mutations had inferior BMF-free survival and received hematopoietic stem cell transplantation (HSCT) at a younger age than those with FANCA mutations. In FANCA, patients with the c.2546delC mutation (n = 24) related to poorer MDS/AML-free survival and a younger age at HSCT than those without this mutation. All patients with RAEB/AML had an abnormal karyotype and poorer prognosis after HSCT; specifically, the presence of a structurally complex karyotype with a monosomy (n = 6) was associated with dismal prognosis. In conclusion, the best practice for a clinician may be to integrate the morphological, cytogenetic, and genetic data to optimize HSCT timing in Japanese FA patients.

Enhancing T Cell Receptor Stability in Rejuvenated iPSC-Derived T Cells Improves Their Use in Cancer Immunotherapy.

Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of "rejuvenated" induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8αß T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) α chain gene during the CD4/CD8 double positive stage of in vitro differentiation. CRISPR knockout of a recombinase gene in the T-iPSCs prevented this additional TCR rearrangement. Moreover, when CD8αß T cells were differentiated from monocyte-derived iPSCs that were transduced with an antigen-specific TCR, they showed monoclonal expression of the transduced TCR. TCR-stabilized, regenerated CD8αß T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies.

Anaemia is an essential complication of ANCA-associated renal vasculitis: a single center cohort study.

BACKGROUND: Anaemia is a common complication of patients with antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. Nevertheless, the cause and degree of such cases of anaemia have not been elucidated in detail. We aimed to investigate the prevalence, cause, pathogenesis of anaemia and the impact of anaemia on prognosis in patients with ANCA-associated renal vasculitis. METHODS: We identified 45 patients with ANCA-associated renal vasculitis that were clinically and/or histologically diagnosed and treated from 2003 to 2014 at University of Tsukuba Hospital. The relationships between anaemia and various clinicopathological findings were evaluated. RESULTS: At the time of diagnosis of ANCA-associated renal vasculitis, all patients showed anaemia, with a mean haemoglobin level of 7.5 ± 1.3 g/dL. Renal anaemia was diagnosed in 92% of patients, anaemia of chronic disease (ACD) in 56%, and anaemia due to hemorrhage in 20%. Next, the patients were divided into two groups according to anaemia severity: minimum haemoglobin (min Hb) < 7.5 (n = 24) and min Hb ≥ 7.5 (n = 21). A comparison of baseline characteristics showed that serum albumin, maximum serum creatinine, minimum estimated glomerular filtration rate (eGFR), serum cystatin C, and the area of tubulointerstitial damage were significantly different between the haemoglobin groups (p < 0.05). No significant intergroup differences were observed in iron-related or inflammation-related data. With regard to the relationship between anaemia severity and prognosis, patients in the min Hb < 7.5 group tended to have a lower eGFR. Anaemia severity was associated with markedly lower survival (Log-rank test, p = 0.03). CONCLUSIONS: In this cohort of patients with ANCA-associated renal vasculitis, all subjects exhibited anaemia. In regard to the cause and pathogenesis, the most prevalent form of anaemia was renal anaemia, not ACD, and a potential reason for the high prevalence of anaemia in our cohort may have been the interaction between renal anaemia and ACD. Moreover, anaemia severity was significantly associated with the degree of renal dysfunction and life prognosis.

Renal compensatory adaptation for water handling in a patient with adipsic diabetes insipidus after clipping of a ruptured aneurysm of the anterior communicating artery
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A 38-year-old Japanese man who had undergone clipping surgery for a ruptured aneurysm of the anterior communicating artery 2 days prior, suddenly developed refractory hypernatremia (serum sodium (Na) 156 - 162 mmol/L). Symptoms included low plasma vasopressin, fluctuating urine osmolality (120 - 710 mOsm/kg) and lack of thirst, all suggesting adipsic diabetes insipidus (ADI). Hypernatremia was corrected by scheduled water intake with desmopressin administration. During 1-year follow-up after the surgery, his serum Na level normalized despite the suspension of desmopressin, but neither thirst nor osmolality-dependent vasopressin release recovered. Meanwhile, his urine osmolality shifted to a constant high level. The present case suggests that renal compensatory adaptation, apparently independent of the circulating vasopressin level, plays a major role in water handling in longitudinal ADI.
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Different Psychosocial Factors Are Associated With Different Intention and Self-Efficacy Toward Eating Breakfast Among Japanese Breakfast Skippers.

A cross-sectional study was conducted among 7593 adults to clarify lifestyle and psychosocial characteristics of breakfast skippers with different intention and self-efficacy toward eating breakfast. Data were obtained from Japan's national survey in 2009. Multinomial logistic regression analyses were performed to examine the characteristics of each breakfast skipper (having intention and self-efficacy toward eating breakfast [IS], having intention but not self-efficacy [INS], and not having intention to eat breakfast [NI]) compared with breakfast eaters. IS men were less likely to demonstrate understanding of healthy eating. INS and NI men were more likely to eat alone. INS and NI women were less likely to demonstrate understanding of healthy eating. NI men and women were less likely to report weight management behavior. Current smoking and being sleep-deprived were commonly associated with breakfast skipping in both sexes. Our results suggested the need for approaches considering type of breakfast skippers (eg, different intention and self-efficacy).

A case of acute interstitial nephritis and granulomatous hepatitis induced by ingesting quinine.

Quinine is used for the treatment of malarial infection, though not in common use. It is especially valuable for the parenteral treatment of severe illness owing to drug-resistant strains of Plasmodium falciparum. Quinine is also known to occasionally cause acute renal failure (ARF). Although quinine is listed in some reviews as a cause of acute interstitial nephritis, most cases of quinine-associated acute renal failure have been attributed to the hemolytic-uremic syndrome (HUS). Only two cases of acute renal failure due to acute interstitial nephritis associated with quinine have been reported [1, 2]. To our knowledge, there have been 6 reported cases of quinine-induced hepatic granuloma [3-8]. We report a case of quinine-induced acute interstitial nephritis (AIN) along with granulomatous hepatitis, both of which were confirmed on biopsy. A 50-year-old Nigerian man was admitted to the hospital with complaints of fever and general fatigue. He had been prescribed quinine as an antimalarial drug in a Nigerian hospital. The patient was febrile and showed nonoliguric ARF and liver dysfunction. In this case, liver injury showed gradual and spontaneous resolution after discontinuing quinine, and ARF resolved after treatment with oral prednisolone.

[Effectiveness of mirtazapine for digestive symptoms in palliative care - retrospective study of 50 cases].

BACKGROUND: Previous research has reported that mirtazapine, a 5-HT3 antagonist, is effective for alleviation of digestive symptoms. PURPOSE: To elucidate the effect of low-dose mirtazapine on digestive symptoms. PATIENTS AND METHODS: Mirtazapine was administered to 50 cancer patients with digestive symptoms in palliative care, and the data were retrospectively examined. The initial doses ranged from 1.875 to 7.5 mg, and were increased to a maintenance dose according to its effects and the degree of somnolence. RESULTS: The cases were divided into 2 groups based on the cause of the digestive symptoms, including unknown causes(27 cases)and chemotherapy and/or opioid treatment(23 cases). At the initial dose, the efficacy rate was 74.4%, and the effectiveness was significantly higher in patients whose symptoms were due to chemotherapy and/ or opioid use than in those with symptoms of unknown cause(p=0.008). The rate of somnolence was 29.5%. Discontinuation of treatment within 1 week occurred in 10 cases. In 40 cases that continued administration of the maintenance dose, the efficacy rate was 82.5%, and the increased doses provided relief in the patient group with digestive symptoms of unknown cause. CONCLUSIONS: Low-dose mirtazapine showed different effects depending on the cause of digestive symptoms; therefore, the dose should be increased in patients whose symptoms are of unknown cause. Somnolence often appeared even at a low-dose, and this should be taken into consideration in the palliative care setting.

Animal protein intake is associated with higher-level functional capacity in elderly adults: the Ohasama study.

OBJECTIVES: To determine the association between protein intake and risk of higher-level functional decline in older community-dwelling adults. DESIGN: Prospective. SETTING: Ohasama Town, Japan. PARTICIPANTS: Residents (N = 1,007; mean age 67.4 ± 5.5) free of functional decline at baseline; follow-up was conducted for 7 years. MEASUREMENTS: Nutrient and food intakes were determined using a validated 141-item food frequency questionnaire. Participants were divided into quartiles according to intake levels of total, animal, and plant protein. Subscales of the Tokyo Metropolitan Institute of Gerontology Index of Competence subscales were used to assess higher-level functional decline. Logistic regression analysis was used to examine the future risk of higher-level functional decline in relation to protein intake, with lowest protein intake as reference. RESULTS: During the study period, 24.4% of eligible participants reported declines in higher-level functional capacity. After adjustment for putative confounding factors, men in the highest quartile of animal protein intake had significantly lower risk of higher-level functional decline than those in the lowest quartile (odds ratio (OR) = 0.41, 95% confidence interval (CI) = 0.20-0.83; P for trend .01). These associations were not seen in women (OR = 0.76, 95% CI = 0.41-1.34; P for trend .37). No consistent association was observed between plant protein intake and future higher-level functional decline in either sex. CONCLUSION: Higher protein, particularly animal protein, was associated with lower risk of decline in higher-level functional capacity in older men. Animal protein intake may be a modifiable indicator for early detection and prevention of higher-level functional decline in elderly adults.

[Low-dose mirtazapine improved nausea and appetite loss during S-1 therapy].

This paper presents a man in his 80's with pancreatic cancer(cStage IV). He suffered from nausea duringS -1 therapy, and therefore, prochlorperazine maleate at a daily dose of 15 mgwas administered. However, refractory nausea was diagnosed because it did not improve, and mirtazapine at a daily dose of 7. 5 mgbefore bedtime was started. Nausea was improved in the next morning, and the patient ate almost all of his breakfast. After that, no nausea appeared, and his food intake was robust. Mirtazapine is a new antidepressant called noradrenergic and specific serotonergic antidepressant(NaSSA)and blocks 5-HT3 receptors to improve nausea. Mirtazapine is usually started at a daily dose of 15 mg, but this dose induces somnolence. Therefore, mirtazapine was administered at a low daily dose of 7. 5 mgin the present case. No somnolence or disturbance of daily life was seen, and administration was safely continued. We conclude that low-dose mirtazapine is one effective option for refractory nausea duringS -1 therapy.