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HSCs have a fate choice when they divide; they can self-renew, producing new HSCs, or produce daughter cells that will mature to become committed cells. Technical challenges, however, have long obscured the mechanics of these choices. Advances in flow-sorting have made possible the purification of HSC populations, but available HSC-enriched fractions still include substantial heterogeneity, and single HSCs have proven extremely difficult to track and observe. Advances in single-cell approaches, however, have led to the identification of a highly purified population of hematopoietic stem cells (HSCs) that make a critical contribution to hematopoietic homeostasis through a preference for self-renewing division. Metabolic cues are key regulators of this cell fate choice, and the importance of controlling the population and quality of mitochondria has recently been highlighted to maintain the equilibrium of HSC populations. Leukemic cells also demand tightly regulated metabolism, and shifting the division balance of leukemic cells toward commitment has been considered as a promising therapeutic strategy. A deeper understanding of precisely how specific modes of metabolism control HSC fate is, therefore, of great biological interest, and more importantly will be critical to the development of new therapeutic strategies that target HSC division balance for the treatment of hematological disease.

Leukemia stem cells (LSCs, also known as leukemia-initiating cells) not only drive leukemia initiation and progression, but also contribute to drug resistance and/or disease relapse. Therefore, eradication of every last LSC is critical for a patient’s long-term cure. Chronic myeloid leukemia (CML) is a myeloproliferative disorder that arises from multipotent hematopoietic stem and progenitor cells. Tyrosine kinase inhibitors (TKIs) have dramatically improved long-term outcomes and quality of life for patients with CML in the chronic phase. Point mutations of the kinase domain of BCR-ABL1 lead to TKI resistance through a reduction in drug binding, and as a result, several new generations of TKIs have been introduced to the clinic. Some patients develop TKI resistance without known mutations, however, and the presence of LSCs is believed to be at least partially associated with resistance development and CML relapse. We previously proposed targeting quiescent LSCs as a therapeutic approach to CML, and a number of potential strategies for targeting insensitive LSCs have been presented over the last decade. The identification of specific markers distinguishing CML-LSCs from healthy HSCs, and the potential contributions of the bone marrow microenvironment to CML pathogenesis, have also been explored. Nonetheless, 25% of CML patients are still expected to switch TKIs at least once, and various TKI discontinuation studies have shown a wide range in the incidence of molecular relapse (from 30% to 60%). In this review, we revisit the current knowledge regarding the role(s) of LSCs in CML leukemogenesis and response to pharmacological treatment and explore how durable treatment-free remission may be achieved and maintained after discontinuing TKI treatment.

Objectives: To evaluate lifestyle and weight changes in new male employees of Japanese companies and clarify the effects of environmental and lifestyle changes on weight changes in early years after joining the company.Methods: We analyzed health checkup results and lifestyle questionnaires of 160 male graduates hired by a particular company between fiscal years 2009 and 2012. The data obtained included health examinations from the time of the job offer to the fourth year at the company. Weight changes were analyzed using a Friedman test. Lifestyle questionnaires were analyzed using a McNemar test. Twelve male employees who had been with the company for 5-10 years were interviewed about their lives before and after joining. The results were transcribed and analyzed using the Steps for Coding and Theorization method.Results: Compared with employees’ weight at the time of the job offer, their weight at the time of joining the company and in the second and third years increased significantly. (P <.001). An increasing number of participants ate dinner late, missed opportunities for exercise, and did not get sufficient sleep. Interview results indicated that overtime, commuting, and work-related drinking parties among new employees led to late dinners and difficulty in maintaining exercise habits, and that stress at work led to overeating.Conclusions: New employees gained weight during their first 3 years at the company, and lifestyle changes such as overtime work, late dinners due to drinking parties, and loss of opportunities for exercise during the same period had an impact.

Although it has been established that patients with chronic kidney disease and iron deficiency, as indicated by a transferrin saturation of < 20%, are at increased risk of all-cause mortality and cardiovascular events, the optimal management of such patients has not yet been determined. In this post hoc subgroup analysis, we aimed to clarify the effect of ferric citrate hydrate on transferrin saturation in patients with chronic kidney disease and low transferrin saturation (< 20%) undergoing hemodialysis. To accomplish this, we extracted the relevant data on a subset of patients drawn from two previous studies: the ASTRIO study (A Study examining the contribution to Renal anemia treatment with ferric citrate hydrate, Iron-based Oral phosphate binder, UMIN000019176) and a post-marketing surveillance study. The subset of patients used for the present study were those with baseline transferrin saturation < 20%. We found that administration of ferric citrate hydrate increased transferrin saturation and maintained transferrin saturation at approximately 30%. However, because we did not have access to data on all-cause mortality or cardiovascular events, we could not ascertain whether the frequency of these outcomes was reduced in parallel with improvements in transferrin saturation. Further large studies are required.

Background The purpose of this study was to establish an estimating equation to predict the 5-level EQ-5D version (EQ-5D-5L) utility score in patients taking iron preparations for heavy menstrual bleeding (HMB) or anemia and to evaluate whether the presence of nausea or vomiting was a significant predictor of EQ-5D-5L-based quality of life. Methods A cross-sectional survey was conducted to collect EQ-5D-5L utility scores and other patient reported outcomes from 385 patients taking iron preparations for HMB or anemia who were selected from the disease patient panel. Using the utility scores as objective variables, explanatory variable candidates were selected considering correlations, multicollinearity, and clinical validity. Predicting models were constructed using regression-based models (linear model, generalized linear model (GLM), Tobit model). Stepwise regression method was applied for selecting statistically significant (p < 0.05) predictors. Goodness-of-fit of models were assessed by mean absolute error and mean squared error (MSE). Results The EQ-5D-5L utility scores (mean ± standard deviation) of 96 patients with nausea/vomiting and 289 patients without nausea/vomiting were 0.67 ± 0.16 and 0.84 ± 0.14, respectively (p < 0.001). The presence of nausea/vomiting was shown to be the most significant factor reducing the utility score in the statistical models using the explanatory variable candidates selected in the study. As the results of the goodness-of-fit test, GLM with the smallest MSE was selected to establish the estimating equation. Conclusion The estimating equation to predict the EQ-5D-5L utility scores in patients taking iron preparations for HMB or anemia was established. The presence of nausea/vomiting was found to be a factor significantly reducing utility scores, with a decrement of the value estimated to be -0.117. Trial registration UMIN000045700 ( http://www.umin.ac.jp/ctr/ ). Registered on October 11, 2021.

Background Patients with iron deficiency anemia are treated with iron preparations, but gastrointestinal symptoms such as nausea and vomiting occur frequently. These symptoms may negatively affect the quality of life and work productivity in patients with iron deficiency anemia. This study assessed the impact of nausea and vomiting on the quality of life and work productivity of patients taking iron preparations for heavy menstrual bleeding or anemia. Methods An online survey was conducted among patients taking iron preparations for heavy menstrual bleeding or anemia. Demographic data and information about medication use and the health condition were collected. The patients were asked to answer the 5-level EQ-5D version, and work productivity and activity impairment questionnaires. The outcomes were reported by patients in the presences of nausea, vomiting, and nausea or vomiting. The association with the 5-level EQ-5D version utility score for the severity and frequency of the symptoms were also assessed. Results A total of 385 patients were enrolled, and 96 were patients with nausea or vomiting, of which 94 were with nausea and 27 were with vomiting. The 5-level EQ-5D version utility scores for the patients with nausea, vomiting, and nausea or vomiting were significantly lower than those of the patients without these symptoms ( p  < 0.001 for each). The 5-level EQ-5D version utility score was correlated with the severity of nausea and the frequency of vomiting per day ( p  < 0.001 for each). As for the work productivity and activity impairment, the presenteeism, the overall work impairment, and the activity impairment of the patients with nausea, vomiting, and nausea or vomiting were significantly higher than those without these symptoms ( p  < 0.001 for each). The absenteeism was slightly higher trend was observed, but not significant. Conclusion Patients taking iron preparations who have nausea or vomiting experience a significant burden in terms of poorer quality of life and higher work productivity impairment. Trial registration UMIN000045700 ( http://www.umin.ac.jp/ctr/ ). Registered on October 11, 2021.

The ASTRIO study was a randomised, multicentre, 24-week study that compared the effects of ferric citrate hydrate (FC) and non-iron-based phosphate binders (control) on anaemia management in haemodialysis (HD) patients receiving erythropoiesis-stimulating agents (ESAs). In that study, FC reduced the doses of ESAs and intravenous iron without affecting haemoglobin (Hb); however, the cost-effectiveness of FC was unclear. We retrospectively implemented a cost-effectiveness analysis comparing the incremental cost-effectiveness ratios (ICERs) in FC (n = 42) and control (n = 40) groups in patients with serum phosphate and Hb controlled within the ranges of 3.5–6.0 mg/dL and 10–12 g/dL, respectively. Costs included drug costs of phosphate binders, ESAs, and intravenous iron. Elevated red cell distribution width (RDW) has been reported to be associated with mortality in HD patients and was therefore used as an effectiveness index. The mean (95% confidence interval) differences in drug costs and RDW between the FC and control groups were US$ − 421.36 (− 778.94 to − 63.78, p  = 0.02) and − 0.83% (− 1.61 to – 0.05, p  = 0.04), respectively. ICER indicated a decrease of US$ 507.66 per 1% decrease in RDW. FC was more cost-effective than non-iron-based phosphate binders. Iron absorbed via FC could promote erythropoiesis and contribute to renal anaemia treatment.

This study investigated the association between climate parameters and intraocular pressure (IOP). We used two large, multicenter cross-sectional datasets: the Japan Ningen Dock Study (JNDS), with 1,477,066 participants (52.3 ± 10.8 years), and the Jikei dataset, with 10,361 participants (50.3 ± 11.0 years). In both, IOP was measured via noncontact tonometry. We obtained daily average air temperature, station-level air pressure, and relative humidity from the Japan Meteorological Agency. We used multiple linear regression, adjusting for known IOP-related factors, to evaluate the relationship between climate parameters and IOP; the same analysis was also performed by prefecture as a sensitivity analysis. The mean right-eye IOP was 13.4 ± 3.0 mmHg (JNDS) and 12.7 ± 2.8 mmHg (Jikei). Air temperature showed a significant negative correlation with IOP (JNDS: β = − 0.032, 95% CI: − 0.033 to − 0.032, P  < 0.001; Jikei: β = − 0.023, 95% CI: − 0.031 to − 0.016, P  < 0.001), whereas neither air pressure nor humidity was associated with IOP. Sensitivity analysis indicated a stronger, though not significant, relationship between IOP and temperature in colder regions (correlation coefficient R = − 0.21, P  = 0.174). These findings underscore the importance of considering climate, particularly temperature, in IOP fluctuations.

We aimed to investigate the association between respiratory function and intraocular pressure (IOP). We included the Jikei and Japan Ningen Dock Study (JNDS) datasets that included data from 10,361 (50.3 ± 11.0 years) and 283,199 (51.7 ± 10.3 years) participants, respectively. IOP was measured using non-contact tonometry, and respiratory function was assessed using spirometry, focusing on the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio, percent predicted values of FEV1 (ppFEV1), and percent predicted values of FVC (ppFVC). The relationship between respiratory function indices and IOP was assessed using multiple linear regression. The mean IOP was 12.7 ± 2.8 and 13.3 ± 2.9 mmHg in the Jikei and JNDS datasets, respectively, with a significant positive linear correlation between FEV1/FVC and IOP (β = 0.020, 95% confidence interval [CI]: 0.011 − 0.029, P  < 0.001 in the Jikei dataset; β = 0.015, 95% CI: 0.013 − 0.016, P  < 0.001 in the JNDS dataset). Compared with healthy individuals, 505 and 2,228 participants with FEV1/FVC < 70% (Jikei dataset) and FEV1/FVC < 60% (JNDS dataset) had lower IOPs of 0.641 (95% CI: 0.286 − 0.996, P  < 0.001) mmHg and 0.888 (95% CI: 0.729 − 1.047, P  < 0.001) mmHg, respectively. Both ppFEV1 and ppFVC showed no association with IOP. This possible association between obstructive ventilatory disorders and IOP suggests the importance of considering respiratory function in IOP management.

The persistence of covalently closed circular DNA (cccDNA) poses a major obstacle to curing chronic hepatitis B (CHB). Here, we used droplet digital PCR (ddPCR) for cccDNA quantitation. The cccDNA-specific ddPCR showed high accuracy with the dynamic range of cccDNA detection from 10 1 to 10 5 copies/assay. The ddPCR had higher sensitivity, specificity and precisely than qPCR. The results of ddPCR correlated closely with serum HB core-related antigen and HB surface antigen (HBsAg) in 24 HBV-infected human-liver-chimeric mice (PXB-mice). We demonstrated that in 2 PXB-mice after entecavir treatment, the total cccDNA content did not change during liver repopulation, although the cccDNA content per hepatocyte was reduced after the treatment. In the 6 patients with HBV-related hepatocellular carcinoma, ddPCR detected cccDNA in both tumor and non-tumor tissues. In 13 HBeAg-negative CHB patients with pegylated interferon alpha-2a, cccDNA contents from paired biopsies were more significantly reduced in virological response (VR) than in non-VR at week 48 (p = 0.0051). Interestingly, cccDNA levels were the lowest in VR with HBsAg clearance but remained detectable after the treatment. Collectively, ddPCR revealed that cccDNA content is stable during hepatocyte proliferation and persists at quantifiable levels, even after serum HBsAg clearance.