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Abstract This study aimed to validate the 2022 European LeukemiaNet (ELN) risk stratification for acute myeloid leukemia (AML). A total of 624 newly diagnosed AML patients from 1998 to 2014 were included in the analysis. Genetic profiling was conducted using targeted deep sequencing of 45 genes based on recurrent driver mutations. In total, 134 (21.5%) patients had their risk classification reassessed according to the 2022 ELN risk stratification. Among those initially classified as having a favorable risk in 2017 (n = 218), 31 and 3 patients were reclassified as having intermediate risk or adverse risk, respectively. Among the three subgroups, the 2022 ELN favorable-risk group showed significantly longer survival outcomes than the other groups. Within the 2017 ELN intermediate-risk group (n = 298), 21 and 46 patients were reclassified as having favorable risk or adverse risk, respectively, and each group showed significant stratifications in survival outcomes. Some patients initially classified as having adverse risk in 2017 were reclassified into the intermediate-risk group (33 of 108 patients), but no prognostic improvements were observed in this group. A multivariable analysis identified the 2022 ELN risk stratification, age, and receiving allogeneic hematopoietic cell transplantation as significant prognostic factors for survival. The 2022 ELN risk stratification enables more precise decisions for proceeding with allogeneic hematopoietic cell transplantation for AML patients.

Abstract This study aimed to identify the benefits of autologous-stem cell transplantation (auto-SCT) and allogeneic-SCT (allo-SCT) in patients with aggressive T-cell lymphomas to aid in the selection of transplantation type in clinical practice. This study retrospectively analyzed data from 598 patients who underwent transplantation for T-cell lymphomas from 2010 to 2020. In total, 317 patients underwent up-front SCT as consolidation therapy. The 3-year progression-free survival (PFS) and overall survival (OS) were 68.7% and 76.1%, respectively. Patients who underwent auto-SCT had significantly better OS (p = 0.026) than those who underwent allo-SCT; however, no statistical difference in PFS was found. Transplantation was used as a salvage therapy in 188 patients who had relapsed/refractory disease. Overall, 96 (51.1%) patients underwent auto-SCT and 92 (48.9%) patients underwent allo-SCT. Auto-SCT improved long-term survival in patients with complete remission (CR). Allo-SCT demonstrated better 3-year PFS in patients with partial remission and relapsed/refractory disease status. However, >50% of patients died within 1 year of allo-SCT. As a consolidative therapy, up-front auto-SCT demonstrated a survival benefit. Auto-SCT was also effective in patients who achieved CR after salvage therapy. If the disease persists or cannot be controlled, allo-SCT may be considered with reduced intensity conditioning.

Abstract Background Approximately 50% of limited‐stage ocular adnexal mucosa‐associated lymphoid tissue lymphoma (OAML) patients with adverse prognostic factors relapse after radiotherapy. Chemoimmunotherapy has been proposed as an alternative frontline therapy. However, only a few studies have reported its long‐term treatment outcome. Methods In 2011, we commenced a phase 2 trial to investigate the efficacy of rituximab, cyclophosphamide, doxorubicin, and prednisolone (R‐CVP) in bilateral and non‐conjunctival limited‐stage OAML patients. Results of the clinical trial showed a response rate of 100% and a 4‐year progression‐free survival of 90.3% without significant toxicity. We extended the study period to December 2020 to determine the long‐term efficacy of R‐CVP chemoimmunotherapy. Results At a median observation period of 66.0 months, eight of 33 study patients had relapsed. The cumulative incidence of relapse was 18.9% at 5 years and 44.7% at 8 years. The majority of relapses developed more than 4 years after treatment. Local relapse was more prevalent than distant relapse. The relapse risk of orbital and lacrimal diseases was likely to be higher than that of conjunctival and eyelid diseases (HR: 2.5, 95% CI: 0.498–12.500, p = 0.25). Conclusion Although the response rate was remarkable for chemoimmunotherapy, the risk of late relapse was considerable. Based on our findings, clinical trials for limited‐stage OAML patients should have a long‐term observation period. To minimize radiation toxicity and reduce the risk of delayed relapse (local relapse and distant relapse), a future study with sequential or combination treatment of local low‐dose radiation and systemic chemoimmunotherapy can be considered.

Human failure event (HFE) dependency analysis is a part of human reliability analysis (HRA). For efficient HFE dependency analysis, a maximum number of minimal cut sets (MCSs) that have HFE combinations are generated from the fault trees for the probabilistic safety assessment (PSA) of nuclear power plants (NPPs). After collecting potential HFE combinations, dependency levels of subsequent HFEs on the preceding HFEs in each MCS are analyzed and assigned as conditional probabilities. Then, HFE recovery is performed to reflect these conditional probabilities in MCSs by modifying MCSs.Inappropriate HFE dependency analysis and HFE recovery might lead to an inaccurate core damage frequency (CDF). Using the above process, HFE recovery is performed on MCSs that are generated with a non-zero truncation limit, where many MCSs that have HFE combinations are truncated. As a result, the resultant CDF might be underestimated.In this paper, a new method is suggested to incorporate HFE recovery into the MCS generation stage. Compared to the current approach with a separate HFE recovery after MCS generation, this new method can (1) reduce the total time and burden for MCS generation and HFE recovery, (2) prevent the truncation of MCSs that have dependent HFEs, and (3) avoid CDF underestimation. This new method is a simple but very effective means of performing MCS generation and HFE recovery simultaneously and improving CDF accuracy. The effectiveness and strength of the new method are clearly demonstrated and discussed with fault trees and HFE combinations that have joint probabilities.

Tet methylcytosine dioxygenase 2 (TET2) is one of the most frequently mutated genes in myelodysplastic syndrome (MDS). TET2 is known to involve a demethylation process, and the loss of TET2 is thought to cause DNA hypermethylation. Loss of TET2 function is known to be caused by genetic mutations and miRNA, such as miR-22. We analyzed 41 MDS patients receiving hypomethylating therapy (HMT) to assess whether TET2 mutation status and miR-22 expression status were associated with their clinical characteristics and treatment outcomes. Responsiveness to HMT was not affected by both TET2 mutation (odds ratio (OR) 0.900, p = 0.909) and high miR-22 expression (OR 1.548, p = 0.631). There was a tendency for TET2 mutation to be associated with lower-risk disease based on IPSS (Gamma = −0.674, p = 0.073), lower leukemic transformation (OR 0.170, p = 0.040) and longer survival (Hazard ratio 0.354, p = 0.059). Although high miR-22 expression also showed a similar tendency, this tendency was weaker than that of TET2 mutation. In summary, the loss of TET2 function, including both TET2 mutation and high miR-22 expression, was not a good biomarker for predicting the response to HMT but may be associated with lower-risk disease based on IPSS, lower leukemic transformation and longer survival.

Single-unit probabilistic safety assessment (SUPSA) has complex Boolean logic equations for accident sequences. Multi-unit probabilistic safety assessment (MUPSA) model is developed by revising and combining SUPSA models in order to reflect plant state combinations (PSCs). These PSCs represent combinations of core damage and non-core damage states of nuclear power plants (NPPs). Since all these Boolean logic equations have complemented gates (not gates), it is not easy to generate exact Boolean solutions.Delete-term approximation method (DTAM) has been widely applied for generating approximate minimal cut sets (MCSs) from the complex Boolean logic equations with complemented gates. By applying DTAM, approximate conditional core damage probability (CCDP) has been calculated in SUPSA and MUPSA. It was found that CCDP calculated by DTAM was overestimated when complemented gates have non-rare events. Especially, the CCDP overestimation drastically increases if seismic SUPSA or MUPSA has complemented gates with many non-rare events.The objective of this study is to suggest a new quantification method named probability subtraction method (PSM) that replaces DTAM. The PSM calculates accurate CCDP even when SUPSA or MUPSA has complemented gates with many non-rare events. In this paper, the PSM is explained, and the accuracy of the PSM is validated by its applications to a few MUPSAs.

In a seismic PSA, dependency among seismic failures of components has not been explicitly modeled in the fault tree or event tree. This dependency is separately identified and assigned with numbers that range from zero to unity that reflect the level of the mutual correlation among seismic failures.Because of complexity and difficulty in calculating combination probabilities of correlated seismic failures in complex seismic event tree and fault tree, there has been a great need of development to explicitly model seismic correlation in terms of seismic common cause failures (CCFs). If seismic correlations are converted into seismic CCFs, it is possible to calculate an accurate value of a top event probability or frequency of a complex seismic fault tree by using the same procedure as for internal, fire, and flooding PSA.This study first proposes a methodology to explicitly model seismic dependency by converting correlated seismic failures into seismic CCFs. As a result, this methodology will allow systems analysts to quantify seismic risk as what they have done with the CCF method in internal, fire, and flooding PSA.

Background/Aims Immune reconstitution following allogeneic hematopoietic stem cell transplantation (HSCT) is affected by multiple variables during the transplantation. Methods We assessed the clinical factors contributing to immune function reconstitution at 100 days post-allogeneic HSCT in 114 patients receiving fludarabine-based conditioning. Immunophenotypic analysis using flow cytometry was performed to evaluate the percentage and the absolute numbers of T-cell subsets, natural killer cells, and B-cells as clinical outcomes. Results Tacrolimus-based graft-versus-host disease (GVHD) prophylaxis, T-cell depletion, and acute GVHD were significantly associated with delayed immune reconstitution of T-cell subsets. The incidence of chronic GVHD was significantly increased in the normal recovery group compared to the abnormal group (p = 0.01). Epstein-Barr virus reactivation was more frequently observed in the abnormal group of T-cell subsets (p = 0.045). All viral reactivation events including cytomegalovirus reactivation appeared to be more frequent in the abnormal group of T-cell subsets. Conclusions The immune recovery status post-allogeneic HSCT was affected by GVHD prophylactic regimens, especially in cases receiving tacrolimus-based GVHD prophylaxis, T-cell depletion, and possibly those manifesting acute GVHD. Delayed immune reconstitution might increase the morbidity due to viral reactivation. Treatment strategies are needed to prevent infectious complications and enhance immune reconstitution based on the immune recovery status following allogeneic HSCT with fludarabine-based conditioning.

Probabilistic safety assessments (PSA) have been used for several decades to visualize the risk level of commercial nuclear power plants (NPPs). Since the role of a human reliability analysis (HRA) is to provide human error probabilities for safety critical tasks to support PSA, PSA quality is strongly affected by HRA quality. Therefore, it is important to understand the underlying limitations or problems of HRA techniques. For this reason, this study conducted a survey among 14 subject matter experts who represent the HRA community of domestic Korean NPPs. As a result, five significant HRA issues were identified: (1) providing a technical basis for the K-HRA (Korean HRA) method, and developing dedicated HRA methods applicable to (2) diverse external events to support Level 1 PSA, (3) digital environments, (4) mobile equipment, and (5) severe accident management guideline tasks to support Level 2 PSA. In addition, an HRA method to support multi-unit PSA was emphasized because it plays an important role in the evaluation of site risk, which is one of the hottest current issues. It is believed that creating such a catalog of prioritized issues will be a good indication of research direction to improve HRA and therefore PSA quality. Keywords: Human reliability analysis, Nuclear power plant, Remaining and emerging issues, Expert opinion, Importance, Significance, Issue priority

Background: Peripheral T-cell lymphomas (PTCLs) are uncommon and their frequency is regionally heterogeneous. Several studies have been conducted to evaluate the clinical features and treatment outcomes of this disease entity, but the majority of these were conducted in limited areas, making it difficult to comprehensively analyze their relative frequency and clinical features. Furthermore, no consensus treatment for PTCLs has been established. Therefore, we conducted an Asia-specific study to understand the relative frequency of PTCLs and assess treatments and their outcomes in Asian patients. Methods: We performed a multinational, multicenter, prospective registry of adult patients with PTCLs that was named as the International Cooperative non-Hodgkin T-cell lymphoma prospective registry study where thirty-two institutes from six Asian countries and territories (Korea, China, Taiwan, Singapore, Malaysia, and Indonesia) participated. Findings: A total of 486 patients were registered between April 2016 and February 2019, and more than a half of patients (57%) had stage III or IV. Extranodal natural killer (NK)/T- cell lymphoma was the most common subtype (n = 139,28.6%), followed by angioimmunoblastic T-cell lymphoma (AITL, n = 120,24.7%), PTCL-not otherwise specified (PTCL-NOS, n = 101,20.8%), ALK-positive anaplastic large cell lymphoma (ALCL, n = 34,6.9%), and ALK-negative ALCL (n = 30,6.2%). The median progression-free survival (PFS) and overall survival (OS) were 21.1 months (95% CI,10.6–31.6) and 83.6 months (95% CI, 56.7–110.5), respectively. Upfront use of combined treatment with chemotherapy and radiotherapy showed better PFS than chemotherapy alone in localized ENKTL whereas consolidation with upfront autologous stem cell transplantation (SCT) provided longer PFS in advance stage ENKTL. In patients with PTCLs other than ENKTL, anthracycline-containing chemotherapies were widely used, but the outcome of those regimens was not satisfactory, and upfront autologous SCT was not significantly associated with survival benefit, either. The treatment outcome of salvage chemotherapy was disappointing, and none of the salvage strategies showed superiority to one another. Interpretation: This multinational, multicenter study identified the relative frequency of each subtype of PTCLs across Asian countries, and the survival outcomes according to the therapeutic strategies currently used. Funding: Samsung Biomedical Research Institute

This present work is designed to evaluate the anti-diabetic potential of 22 ginsenosides via the inhibition against rat lens aldose reductase (RLAR), and human recombinant aldose reductase (HRAR), using DL-glyceraldehyde as a substrate. Among the ginsenosides tested, ginsenoside Rh2, (20S) ginsenoside Rg3, (20R) ginsenoside Rg3, and ginsenoside Rh1 inhibited RLAR significantly, with IC50 values of 0.67, 1.25, 4.28, and 7.28 µM, respectively. Moreover, protopanaxadiol, protopanaxatriol, compound K, and ginsenoside Rh1 were potent inhibitors of HRAR, with IC50 values of 0.36, 1.43, 2.23, and 4.66 µM, respectively. The relationship of structure–activity exposed that the existence of hydroxyl groups, linkages, and their stereo-structure, as well as the sugar moieties of the ginsenoside skeleton, represented a significant role in the inhibition of HRAR and RLAR. Additional, various modes of ginsenoside inhibition and molecular docking simulation indicated negative binding energies. It was also indicated that it has a strong capacity and high affinity to bind the active sites of enzymes. Further, active ginsenosides suppressed sorbitol accumulation in rat lenses under high-glucose conditions, demonstrating their potential to prevent sorbitol accumulation ex vivo. The findings of the present study suggest the potential of ginsenoside derivatives for use in the development of therapeutic or preventive agents for diabetic complications.

PurposeWe evaluated the outcomes of decitabine as first-line treatment in older patients with acute myeloid leukemia (AML) and investigated the predictors, including a baseline mini nutritional assessment short form (MNA-SF) score, of response and survival.Patients and methodsBetween 2010 and 2018, 96 AML patients aged 65 and above who received decitabine treatment at 6 centers in Korea were retrospectively evaluated. Response rates, hematologic improvements (HI), progression-free survival (PFS), and overall survival (OS) were analyzed.ResultsThe median age at diagnosis was 73.9 years, and the median number of decitabine treatments administered to the patients was 4 (range, 1-29). Of 85 patients, 15 patients (17.6%) achieved complete remission (CR) or CR with incomplete blood count recovery. Twelve patients (14.1%) showed partial remission (PR), and 18 (21.2%) demonstrated HI without an objective response. The median PFS and OS were 7.0 (95% confidence interval [CI], 4.9-9.0) and 10.6 (95% CI, 7.7-13.5%) months, respectively. In multivariate analyses, MNA-SF score ≥ 8 and the absence of peripheral blood (PB) blasts were significant predictors for improved PFS and OS.ConclusionsFor older patients with newly diagnosed AML, a high MNA-SF score and the absence of PB blasts were independently associated with improved survival.

Abstract Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML‐CP). We investigated the 2‐year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open‐label, multi‐institutional phase 4 study, 110 Philadelphia chromosome‐positive CML‐CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24‐month cumulative MR4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per‐patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow‐up of 22.2 months, the 24‐month cumulative MR4.5 rate was 56.2% (95% confidence interval, 44.0%–8.3%), and the median time to MR4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR4, and MR4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML‐CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511.

It is popular that correlated seismic failures spread over the fault tree of a seismic probabilistic safety assessment (PSA) for a nuclear power plant (NPP). To avoid the calculational difficulty of core damage frequency (CDF), the fault tree has been simplified by replacing correlated seismic failures with one typical seismic failure by assuming a full correlation among the correlated seismic failures. Then, the approximate seismic CDF of a seismic single-unit PSA (SUPSA) has been calculated for decades with this simplified SUPSA fault tree. Furthermore, current seismic multi-unit PSAs (MUPSAs) have been performed with imperfect seismic MUPSA models that were generated by combining such imperfect seismic SUPSA fault trees. The authors of this study recently developed a method that can calculate an accurate seismic CDF by converting correlated seismic failures into seismic common cause failures (CCFs). In this study, accurate and imperfect MUPSA models were created and their seismic CDFs were compared. The results of this study show that the seismic CDFs in SUPSA and MUPSA are drastically distorted and safety margins are accordingly distorted when the full correlation assumption is employed. Thus, this study shows that very careful attention should be paid to calculating and interpreting seismic CDFs for the single-unit and multi-unit NPP regulations.

Astragalus membranaceus BUNGE (AM; 黃芪 huáng qí) has been widely used as a medicinal herb for different kinds of diseases. AM treatment in vitro enhance sperm motility and ameliorates testicular toxicity, it has demonstrated the ability as a potential treatment for male infertility. In order to gain further insights on the molecular understanding of how AM enhances spermatogenesis, this study investigated whether AM has an affect on sperm parameters associated with cAMP response element modulator (CREM) and activator of CREM in testis (ACT) expression. Five-week-old male ICR mice were divided into four groups; control group and three different concentrations of AM treated groups. Each group was treated for 5 days a week for 5 weeks. Testis samples were collected for real time quantitative PCR and western blot analysis. Epididymis was taken out and used for sperm analysis using the computer assisted semen analysis (CASA) system. To facilitate expression of genes required for spermatogenesis, it is controlled by fine-tuning of CREM and its coactivator, ACT. AM treatment promotes CREM and ACT mRNA expression and also protein expression compared to control. AM enhances sperm values such as sperm count and motility compared to control. Overall, the study highlights, the ability of AM to increases CREM and ACT expression to facilitate sperm development and semen quality.

Background: Anticancer agents induce a variety of adverse effects when administered to cancer patients. Busulfan is a known antileukemia agent. When administered for treatment of leukemia in young patients, busulfan could cause damage to the male reproductive system as one of its adverse effects, resulting in sterility. Methods: We investigated the effects of Korean Red Ginseng extract (KRGE) on busulfan-induced damage and/or dysfunction of the male reproductive system. Results: We found that administration of busulfan to mice: decreased testis weight; caused testicular histological damage; reduced the total number of sperm, sperm motility, serum testosterone concentration; and eventually, litter size. Preadministration of KRGE partially attenuated various busulfan-induced damages to the male reproductive system. These results indicate that KRGE has a protective effect against busulfan-induced damage to the male reproduction system. Conclusion: The present study shows a possibility that KRGE could be applied as a useful agent to prevent or protect the male reproductive system from the adverse side effects induced by administration of anticancer agents such as busulfan.

The cation channel of sperm (CatSper) protein family plays important roles in male reproduction and infertility. The four members of this family are expressed exclusively in the testis and are localized differently in sperm. To investigate the effects of Panax ginseng treatment on the expression of CatSper genes and sperm hyperactivation in male mice, sperm motility and CatSper gene expression were assessed using a computer-assisted semen analysis system, a Fluoroskan Ascent microplate fluorometer to assess Ca 2+ influx, real-time polymerase chain reaction, Western blotting and immunofluorescence. The results suggested that the Ca 2+ levels of sperm cells treated with P. ginseng were increased significantly compared with the normal group. The P. ginseng-treated groups showed increased sperm motility parameters, such as the curvilinear velocity and amplitude of lateral head displacement. Taken together, the data suggest that CatSper messenger ribonucleic acid levels were increased significantly in mouse testes in the P. ginseng-treated group, as was the protein level, with the exception of CatSper2. In conclusion, P. ginseng plays an important role in improving sperm hyperactivation via CatSper gene expression.

Objectives : This study was aimed at investigating liver protection mechanism of bear bile juice (Fel Ursi)by inducing liver toxicity through CCl4 in mice and evaluated histological and serological findings. Methods : Experiment groups was categorized into untreated normal group, CCl4 treated control group, and orally administered bear bile juice experiment group. At the termination of experiment, gross examination of the liver as well as histological findings, and Total protein, Albumin, Total bilirubin, Direct bilirubin SGOT, SGPT, and ALP contents in the serum were evaluated. Results : 1. For gross examination and histological findings, CCl4 treated control group showed destroyed lobular structure, increased fibrosis, as well as hepatic cirrhosis. For the group treated with bear bile juice, the lobular structure suffered less damage, and showed lower level of fibrosis and liver cirrhosis compared to the control group. 2. For serum analysis, Total protein and Albumin were significantly increased in the bear bile juice experiment group than the control group. Total bilirubin and Direct bilirubin didn't show significant differences between the two groups. SGOT, SGPT, and ALP were significantly decreased in the normal and bear bile juice experiment groups compared to the control group. Conclusion : Taken together, bear bile juice can be effectively used for recovering the liver functions and further researches must be conducted to verify the efficacies of bear bile juice.

Objectives : Literary investigation of existing data was conducted to verify effects of Bezoar Bovis and its herbal acupuncture, and determine quality management through component analysis. Results : Following results were obtained through literary investigation. 1. Bezoar Bovis is dried cystic stone from a cattle. Its characteristics are cool, no toxicity, and bitter taste. Known actions are: quells heat and detoxifies Fire Poison, extinguishes internal movement of Liver Wind and stops convulsion, vaporizes phlegm, and opens orifice. It is mainly used for treating tremor, stroke, delirium, sore throat, oral furuncle, boil, and others. 2. Bezoar Bovis is effective for eliminating liver toxicity, protecting against brain damage, and has anti-microbial activities. 3. Bezoar Bovis is mixed with bear gall bladder and deer musk to be used as herbal acupuncture, and this mixture is effective is invigorating liver functions as well as treating arthritis, headache, and etc. 4. Principal components of Bezoar Bovis are bilirubin-type pigments and cholic acids. The amount of bilirubin can be used as a standard to determine the quality of Bezoar Bovis.

Background Decitabine was evaluated for its efficacy and safety in Korean patients with myelodysplastic syndrome with IPSS score of 0.5 or over.Design and Methods Decitabine 20 mg/m2/day was given intravenously over one hour for five consecutive days every four weeks. The primary end point was overall response rate.Results A total of 101 patients were analyzed. The International Prognostic Scoring System risk category was Intermediate-2/High in 47.5%. A median of 5 courses (range 1–18) were delivered. The overall response rate was 55.4% (13 complete responses, one partial response, 23 marrow complete responses, and 19 hematologic improvements). Forty-eight patients (47.5%) showed some hematologic improvement. With a median follow-up duration of 478 days (range 69–595), median overall survival was 17.7 months. Patients who showed hematologic improvement had significantly longer overall survival than those who did not (19.2 vs. 15.9 months, P=0.006 by landmark analysis at six months). The difference in overall survival was evident in the Intermediate-2/High risk group but not in the Intermediate-1 risk group. The progression-free survival and acute myeloid leukemia-free survival were 61.9% and 77.9% at one year, respectively. Among 489 assessable treatment courses, there were 97 fever episodes requiring intravenous antimicrobials.Conclusions Decitabine treatment was feasible and effective in Korean patients with myelodysplastic syndrome, and the overall survival was significantly longer in patients showing hematologic improvement.

Anthrax infections are frequently associated with severe and often irreversible hypotensive shock. The isolated toxic proteins of Bacillus anthracis produce a non-cytokine-mediated hypotension in rats by unknown mechanisms. These observations suggest the anthrax toxins have direct cardiovascular effects. Here, we characterize these effects. As a first step, we administered systemically anthrax lethal toxin (LeTx) and edema toxin (EdTx) to cohorts of three to twelve rats at different doses and determined the time of onset, degree of hypotension and mortality. We measured serum concentrations of the protective antigen (PA) toxin component at various time points after infusion. Peak serum levels of PA were in the microg/mL range with half-lives of 10-20 minutes. With doses that produced hypotension with delayed lethality, we then gave bolus intravenous infusions of toxins to groups of four to six instrumented rats and continuously monitored blood pressure by telemetry. Finally, the same doses used in the telemetry experiments were given to additional groups of four rats, and echocardiography was performed pretreatment and one, two, three and twenty-four hours post-treatment. LeTx and EdTx each produced hypotension. We observed a doubling of the velocity of propagation and 20% increases in left ventricular diastolic and systolic areas in LeTx-treated rats, but not in EdTx-treated rats. EdTx-but not LeTx-treated rats showed a significant increase in heart rate. These results indicate that LeTx reduced left ventricular systolic function and EdTx reduced preload. Uptake of toxins occurs readily into tissues with biological effects occurring within minutes to hours of serum toxin concentrations in the microg/mL range. LeTx and EdTx yield an irreversible shock with subsequent death. These findings should provide a basis for the rational design of drug interventions to reduce the dismal prognosis of systemic anthrax infections.

Background: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of blood cells originating from somatically mutated hematopoietic stem cells, is common among the elderly and is associated with an increased risk of hematologic malignancies. We investigated the clinical, mutational, and transcriptomic characteristics in elderly Korean individuals with CHIP mutations. Methods: We investigated CHIP in 90 elderly individuals aged =60 years with normal complete blood counts at a tertiary-care hospital in Korea between June 2021 and February 2022. Clinical and laboratory data were prospectively obtained. Targeted next-generation sequencing of 49 myeloid malignancy driver genes and massively parallel RNA sequencing were performed to explore the molecular spectrum and transcriptomic characteristics of CHIP mutations. Results: We detected 51 mutations in 10 genes in 37 (41%) of the study individuals. CHIP prevalence increased with age. CHIP mutations were observed with high prevalence in DNMT3A (26 individuals) and TET2 (eight individuals) and were also found in various other genes, including KDM6A, SMC3, TP53, BRAF, PPM1D, SRSF2, STAG1, and ZRSR2. Baseline characteristics, including age, confounding diseases, and blood cell parameters, showed no significant differences. Using mRNA sequencing, we characterized the altered gene expression profile, implicating neutrophil degranulation and innate immune system dysregulation. Conclusions: Somatic CHIP driver mutations are common among the elderly in Korea and are detected in various genes, including DNMT3A and TET2. Our study highlights that chronic dysregulation of innate immune signaling is associated with the pathogenesis of various diseases, including hematologic malignancies. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to share our outcomes and experiences on allogeneic hematopoietic stem cell transplantation (HSCT) in elderly patients aged 60 years and older with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in South Korea, and to compare them with other studies. Materials and Methods: We analyzed the clinical outcomes of 116 patients with AML or MDS aged 60 years and older who underwent allogeneic HSCT. We also analyzed which pretreatment factors affect the overall survival (OS) after allogeneic HSCT. Results: Neutrophil and platelet engraftment were achieved at median day +11 [interquartile range (IQR) 10-15] and +14 (IQR 11-19), respectively. A complete donor chimerism was confirmed in 65 (56.0%) patients at 3 weeks and in 63 (54.3%) patients at 3 months after HSCT. The estimated incidence of grade II-IV acute graft-versus-host disease (GVHD) at day 100 was 13.7%. The estimated incidence of chronic GVHD at 2 years was 38.8%. Within a median follow-up of 14 months after HSCT, OS was 64% at 1 year and 55% at 2 years, and non-relapse mortality (NRM) was 20% at 1 year and 28% at 2 years. Multivariate analysis revealed that male sex and Hematopoietic Cell Transplantation-Specific Comorbidity Index =3 were associated with poor OS. Conclusion: This study showed that allogeneic HSCT in elderly adults aged 60 and older can be performed with successful engraftment and acceptable NRM and OS are expected given the generally known survival of patients with higher risk MDS and poor risk AML. [ABSTRACT FROM AUTHOR]