Identification of a circulating three-miRNA panel for the diagnosis of primary open angle glaucoma.

PURPOSE: Conventional diagnosis of primary open angle glaucoma (POAG) needs a combination of ophthalmic examinations. An efficient assay is urgently needed for a timely POAG diagnosis. We aim to explore differential expressions of circulating microRNAs (miRNA) and provide novel miRNA biomarkers for POAG diagnosis. METHODS: A total of 180 POAG patients and 210 age-related cataract (ARC) patients were enrolled. We collected aqueous humor (AH) and plasma samples from the recruited patients. The expressions of candidate miRNAs were measured using quantitative real time polymerase chain reaction. The diagnostic ability of candidate miRNAs was analyzed by receiver operating characteristic curve. RESULTS: The expressions of miR-21-5p and miR-29b-3p were downregulated significantly in AH and plasma of POAG and miR-24-3p expression was significantly increased in AH and plasma of POAG, comparing with those of ARC. A three-miRNA panel was constructed by a binary logistic regression. And the panel could differentiate between POAG and ARC with an area under the curve of 0.8867 (sensitivity = 78.0%, specificity = 83.3%) in aqueous humor and 0.7547 (sensitivity = 73.8%, specificity = 81.2%) in plasma. Next, we verified the three-miRNA panel working as a potential diagnostic biomarker stable and reliable. At last, we identified related function and regulation pathways in vitro. CONCLUSIONS: In conclusion, we built and identified a circulating three-miRNA panel as a potential diagnostic biomarker for POAG. It may be developed into an efficient assay and help improve the POAG diagnosis in the future.

Salvage haploidentical transplantation for graft failure after first haploidentical allogeneic stem cell transplantation: an updated experience.

Graft failure is a fatal complication following allogeneic stem cell transplantation where a second transplantation is usually required for salvage. However, there are no recommended regimens for second transplantations for graft failure, especially in the haploidentical transplant setting. We recently reported encouraging outcomes using a novel method (haploidentical transplantation from a different donor after conditioning with fludarabine and cyclophosphamide). Herein, we report updated outcomes in 30 patients using this method. The median time of the second transplantation was 96.5 (33-215) days after the first transplantation. Except for one patient who died at +19d and before engraftment, neutrophil engraftments were achieved in all patients at 11 (8-24) days, while platelet engraftments were achieved in 22 (75.8%) patients at 17.5 (9-140) days. The 1-year OS and DFS were 60% and 53.3%, and CIR and TRM was 6.7% and 33.3%, respectively. Compared with the historical group, neutrophil engraftment (100% versus 58.5%, p < 0.001) and platelet engraftment (75.8% versus 32.3%, p < 0.001) were better in the novel regimen group, and OS was also improved (60.0% versus 26.4%, p = 0.011). In conclusion, salvage haploidentical transplantation from a different donor using the novel regimen represents a promising option to rescue patients with graft failure after the first haploidentical transplantation.

Decreasing the steroid rapidly may help to improve the clinical outcomes of patients with intestinal steroid-refractory acute graft-versus-host disease receiving basiliximab treatment.

Intestinal steroid refractory acute graft-versus-host disease (SR-aGVHD) is the major cause of mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). This retrospective cohort study aimed to identify the relationship between different steroid decreasing velocity and therapeutic response in patients with intestinal SR-aGVHD receiving basiliximab treatment, and also aimed to propose a reasonable steroid decreasing regimen for these patients. The median time for steroid dose decreasing to the 50% of initial dose and decreasing to the low-dose steroid for patients achieving ORR was 5 days and 12 days, respectively, which was both shorter than patients without achieving ORR. The ORR, NRM and survival in rapid and medium steroid decreasing group were all better than slow group. The cumulative incidence of ORR at any time was 90.4%, 78.1% and 62.3%, respectively, in rapid, medium, and slow group. The cumulative incidence of NRM at 1 year after basiliximab treatment was 18.7% (95% CI 11.3%-26.1%), 22.8% (95% CI 14.2%-31.4%) and 32.8% (95% CI 24.1%-41.5%), respectively, in rapid, medium, and slow group. The probability of OS at 1 year after basiliximab treatment was 76.9% (95% CI 68.9%-84.9%), 72.7% (95% CI 63.7%-81.7%), and 62.3% (95% CI 53.5%-71.1%), respectively, in rapid, medium, and slow group. Hence, it was helpful to decrease steroid to the 50% of initial dose ≤ 5 days and to the low-dose steroid ≤ 12 days after basiliximab treatment for intestinal SR-aGVHD patients, which may also be the reasonable steroid decrease protocol for these patients.

Clinical implications of hepatitis B virus core antigen-mediated immunopathologic T cell responses in chronic hepatitis B.

Hepatitis B virus (HBV) infection significantly impacts Asian populations. The influences of continuous HBV antigen and inflammatory stimulation to T cells in chronic hepatitis B (CHB) remain unclear. In this study, we first conducted bioinformatics analysis to assess T-cell signaling pathways in CHB patients. In a Taiwanese cohort, we examined the phenotypic features of HBVcore -specific T cells and their correlation with clinical parameters. We used core protein overlapping peptides from the Taiwan prevalent genotype B HBV to investigate the antiviral response and the functional implication of HBV-specific T cells. In line with Taiwanese dominant HLA-alleles, we also evaluated ex vivo HBVcore -specific T cells by pMHC-tetramers targeting epitopes within HBV core protein. Compared to healthy subjects, we disclosed CD8 T cells from CHB patients had higher activation marker CD38 levels but showed an upregulation in the inhibitory receptor PD-1. Our parallel study showed HBV-specific CD8 T cells were more activated with greater PD-1 expression than CMV-specific subset and bulk CD8 T cells. Moreover, our longitudinal study demonstrated a correlation between the PD-1 fluctuation pattern of HBVcore -specific CD8 T cells and liver inflammation in CHB patients. Our research reveals the HBV core antigen-mediated immunopathologic profile of CD8 T cells in chronic HBV infection. Our findings suggest the PD-1 levels of HBVcore -specific CD8 T cells can be used as a valuable indicator of personal immune response for clinical application in hepatitis management.

Concentrated growth factor therapy as cosmetic treatment in discoid lupus erythematosus.

Discoid lupus erythematosus (DLE) is a disfigurement disease. The atrophic scar and hair loss of this disease are followed by cosmetic defects and profoundly impact psychological health. Concentrated growth factor (CGF) has been widely adopted in medical cosmetology. Here we report a 36-year-old female systemic lupus erythematosus patient with a 5-year history of alopecia in DLE, who was recommended for CGF therapy and experienced hair regrowth. We suggest that CGF may be an effective cosmetic treatment for DLE.

A highly sensitive fluorescent probe RN-NA reveals peroxynitrite as a novel biomarker for primary open angle glaucoma.

AIM: To directly quantify peroxynitrite (ONOO-) using a highly sensitive fluorescence resonance energy transfer probe RN-NA, investigate the association between ONOO- and primary open angle glaucoma (POAG), and clarify whether RN-NA could be used as a potential tool for POAG diagnosis. METHODS: Plasma and aqueous humor (AH) samples were collected from POAG patients (n=100, age: 59.70±6.87y) and age-related cataract (ARC) patients (n=100, age: 61.15±4.60y) admitted to our hospital. Next, RN-NA was used to detect ONOO- in plasma and AH samples, and the relationship between ONOO- level and POAG was analyzed using binary logistic regression. Besides, Pearson correlation analysis was applied to characterize the correlation of the levels of ONOO- with the patients' age, intraocular pressure (IOP), and mean deviation of visual field testing. The ONOO- scavenger MnTMPyP was employed to treat the 3-morpholinosyndnomine (SIN-1)-induced ocular hypertension in mice (n=7, 6-8wk). Finally, the IOP and ONOO- in both eyes were measured 30min after the last drug treatment. RESULTS: ONOO- levels of AH and plasma were significantly higher in the POAG group than in the ARC group (P<0.01). Additionally, ONOO- levels were closely correlated with POAG in a binary logistic regression analysis [odds ratio (OR)=1.008, 95% confidence interval (CI): 1.002-1.013, P<0.01 for AH; OR=1.004, 95%CI: 1.002-1.006, P<0.001 for plasma]. Pearson correlation analysis showed that ONOO- levels in AH or plasma were positively associated with visual field defects (R=0.51, P<0.01 for AH; R=0.45, P<0.001 for plasma), and ONOO- levels in plasma and AH were correlated in the POAG group (R=0.69, P<0.001). However, administering MnTMPyP to mouse eyes reversed the elevated IOP caused by SIN-1 (P<0.05). CONCLUSION: ONOO- levels in AH and plasma, detected by RN-NA, are significantly related to POAG and positively correlated with visual field defects in POAG patients. Hence, ONOO- is a potential biomarker of POAG, especially advanced POAG. Besides, anti-nitration compounds may be novel ocular hypotensive agents based on the animal study.

Peripheral blood stem cell transplantation from haploidentical related donor could achieve satisfactory clinical outcomes for intermediate- or high-risk adult acute myeloid leukemia patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most important curative method for intermediate- and high-risk adult acute myeloid leukemia (AML) patients. We aimed to identify the clinical outcomes of haploidentical related donor (HID) peripheral blood stem cell transplantation (PBSCT) who receiving peripheral blood (G-PB) harvest, and the patients receiving bone marrow (BM) plus G-PB harvest (BM + PB) as grafts were enrolled as control. The engraftments of neutrophil and platelet in G-PB group were both faster than those in BM + PB group. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGVHD), and moderate to severe chronic GVHD (cGVHD) were all comparable between G-PB and BM + PB groups. The cumulative incidence of relapse and non-relapse mortality at 3 years after HID HSCT was 12.6% versus 13.7% (p = 0.899) and 3.6% versus 7.3% (p = 0.295), respectively, in G-PB and BM + PB group. While the probabilities of GVHD-free/relapse-free survival, leukemia-free survival, and overall survival at 3 years after HID HSCT were 60.6% versus 53.4% (p = 0.333), 83.8% versus 79.0% (p = 0.603), and were 87.3% versus 82.9% (p = 0.670), respectively. We confirmed the safety and efficacy of HID PBSCT in intermediate- and high-risk AML patients in a large cohort.

Clinical risk factors and prognostic model for patients with bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

Bronchiolitis obliterans syndrome (BOS) is a common and potentially devastating noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, predictive tools for BOS are not available. We aimed to identify the clinical risk factors and establish a prognostic model for BOS in patients who undergo allo-HSCT. We retrospectively identified a cohort comprising 195 BOS patients from 6100 consecutive patients who were allografted between 2008 and 2022. The entire cohort was divided into a derivation cohort and a validation cohort based on the time of transplantation. Via multivariable Cox regression methods, declining forced expiratory volume at 1 s (FEV1) to <40%, pneumonia, cGVHD except lung, and respiratory failure were found to be independent risk factors for the 3-year mortality of BOS. A risk score called FACT was constructed based on the regression coefficients. The FACT model had an AUC of 0.863 (95% CI: 0.797-0.928) in internal validation and 0.749 (95% CI: 0.621-0.876) in external validation. The calibration curves showed good agreement between the FACT-predicted probabilities and actual observations. The FACT risk score will help to identify patients at high risk and facilitate future research on developing novel, effective interventions to personalize treatment.

Long-term follow-up of haploidentical haematopoietic stem cell transplantation in paediatric patients with high-risk acute myeloid leukaemia: Report from a single centre.

Data from 200 children with high-risk acute myeloid leukaemia who underwent their first haploidentical haematopoietic stem cell transplantation (haplo-HSCT) between 2015 and 2021 at our institution were analysed. The 4-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 71.9%, 62.3% and 32.4% respectively. The 100-day cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease (aGVHD) were 41.1% and 9.5% respectively. The 4-year cumulative incidence of chronic GVHD (cGVHD) was 56.1%, and that of moderate-to-severe cGVHD was 27.3%. Minimal residual disease (MRD)-positive (MRD+) status pre-HSCT was significantly associated with lower survival and a higher risk of relapse. The 4-year OS, EFS and CIR differed significantly between patients with MRD+ pre-HSCT (n = 97; 63.4%, 51.4% and 41.0% respectively) and those with MRD-negative (MRD-) pre-HSCT (n = 103; 80.5%, 73.3% and 23.8% respectively). Multivariate analysis also revealed that acute megakaryoblastic leukaemia without Down syndrome (non-DS-AMKL) was associated with extremely poor outcomes (hazard ratios and 95% CIs for OS, EFS and CIR: 3.110 (1.430-6.763), 3.145 (1.628-6.074) and 3.250 (1.529-6.910) respectively; p-values were 0.004, 0.001 and 0.002 respectively). Thus, haplo-HSCT can be a therapy option for these patients, and MRD status pre-HSCT significantly affects the outcomes. As patients with non-DS-AMKL have extremely poor outcomes, even with haplo-HSCT, a combination of novel therapies is urgently needed.

Prognostic Factors and Outcomes in Patients With Septic Shock After Allogeneic Hematopoietic Stem Cell Transplantation.

Septic shock remains a potentially life-threatening complication among allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. There is a paucity of information on the clinical characteristics, outcome and prognostic factors of septic shock patients after allo-HSCT. We aimed to describe the clinical characteristics of septic shock after allo-HSCT and its associated health outcomes and to evaluate the role of patient demographics, transplantation-related laboratory and clinical variables associated with the short-term mortality of septic shock after allo-HSCT. We retrospectively studied 242 septic shock patients from 6105 consecutive patients allografted between 2007 and 2021. We assessed 29 risk factors as candidate predictors and used multivariable logistic regression to establish clinical model. The primary outcome was 28-day mortality. The median age of the subjects was 34 (IQR 24 to 45) years. A total of 148 patients (61.2%) had positive blood cultures. Gram-negative bacilli accounted for 61.5% of the positive isolates, gram-positive cocci accounted for 12.2%, and fungi accounted for 6.1%. Coinfections were found in 30 (20.3%) patients. Escherichia coli was the dominant isolated pathogen (31.1%), followed by Pseudomonas spp. (12.8%) and Klebsiella pneumoniae (10.1%). With a median follow-up of 34 (IQR: 2 to 528) days, a total of 142 (58.7%) patients died, of whom 118 (48.8%) died within the first 28 days after septic shock diagnosis, 131 (54.1%) died within 90 days, and 141 (58.3%) died within 1 year. A large majority of deaths (83.1% [118/142]) occurred within 28 days of septic shock diagnosis. Finally, 6 independent predictive variables of 28-day mortality were identified by multivariable logistic regression: time of septic shock, albumin, bilirubin, PaO2/FiO2, lactate, and sepsis-induced coagulopathy. Patients with late onset shock had higher 28-day mortality rates (64.6% versus 25.5%, P < .001) and more ICU admission (32.6% versus 7.1%, P < .001) than those with early onset shock. We highlight the poor survival outcomes in patients who develop septic shock, emphasizing the need for increasing awareness regarding septic shock after allo-HSCT. The information from the current study may help to assist clinicians in identifying high-risk patients.

Anti-Inflammatory Ergosteroid Derivatives from the Coral-Associated Fungi Penicillium oxalicum HL-44.

To obtain the optimal fermentation condition for more abundant secondary metabolites, Potato Dextrose Agar (PDA) medium was chosen for the scale-up fermentation of the fungus Penicillium oxalicum HL-44 associated with the soft coral Sinularia gaweli. The EtOAc extract of the fungi HL-44 was subjected to repeated column chromatography (CC) on silica gel and Sephadex LH-20 and semipreparative RP-HPLC to afford a new ergostane-type sterol ester (1) together with fifteen derivatives (2-16). Their structures were determined with spectroscopic analyses and comparisons with reported data. The anti-inflammatory activity of the tested isolates was assessed by evaluating the expression of pro-inflammatory factors Tnfα and Ifnb1 in Raw264.7 cells stimulated with LPS or DMXAA. Compounds 2, 9, and 14 exhibited significant inhibition of Ifnb1 expression, while compounds 2, 4, and 5 showed strong inhibition of Tnfα expression in LPS-stimulated cells. In DMXAA-stimulated cells, compounds 1, 5, and 7 effectively suppressed Ifnb1 expression, whereas compounds 7, 8, and 11 demonstrated the most potent inhibition of Tnfα expression. These findings suggest that the tested compounds may exert their anti-inflammatory effects by modulating the cGAS-STING pathway. This study provides valuable insight into the chemical diversity of ergosteroid derivatives and their potential as anti-inflammatory agents.

A predictive model of herpes zoster after allogeneic hematopoietic stem cell transplantation: VZV reactivation following antiviral prophylaxis discontinuation.

Herpes zoster (HZ) refers to the rash appearing on dermatomes due to varicella zoster virus (VZV) reactivation. The incidence of HZ is significantly higher in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients than in non-HSCT recipients. Although acyclovir prophylaxis is routinely administered to every allo-HSCT recipient for 1 year after transplantation, some individuals eventually develop late-onset HZ after completing prophylaxis. Little information is known about the clinical features of HZ after prophylactic antiviral treatment discontinuation, and an effective predictive model of late-onset HZ needs to be established. A total of 3366 patients who had received allo-HSCT from 2012 to 2017 were included in our study, among whom 201 developed HZ after 1 year (late-onset HZ). We designed a nested case-control study to identify potential predictors of late-onset HZ. Finally, we established a predictive model using binary logistic regression analysis. Age (p < .001), use of immunosuppressants at +1 year (p < .001), CD4-CD8 ratio at +1 year (p < .001), certain mental disorders (depression, anxiety, insomnia and adjustment disorder) (p < .001), engraftment time of neutrophils (p < .001), and CD8+ cell count at +30 days (p < .001) were independent predictors of late-onset HZ. A risk grading system was established based on regression coefficients. Discrimination and calibration analysis indicated that the model had good performance. We also identified several predictive factors of the incidence of HZ-related complications. This is the first scoring system for predicting the incidence of late-onset HZ after allo-HSCT. This model can be applied to identify individuals at high risk of late-onset HZ in the early period after receiving allo-HSCT.

Modulating the organic photovoltaic properties of non-fullerene acceptors by molecular modification based on Y6: a theoretical study.

Developing non-fullerene acceptors (NFAs) by modifying the backbone, side chains and end groups is the most important strategy to improve the power conversion efficiency of organic solar cells (OSCs). Among numerous developed NFAs, Y6 and its derivatives are famous NFAs in the OSC field due to their good performance. Herein, in order to understand the mechanism of tuning the photovoltaic performance by modifying the Y6's center backbone, π-spacer and side-chains, we selected the PM6:Y6 OSC as a reference and systematically studied PM6:AQx-2, PM6:Y6-T, PM6:Y6-2T, PM6:Y6-O, PM6:Y6-1O and PM6:Y6-2O OSC systems based on extensive quantum chemistry calculations. The results indicate that introducing quinoxaline to substitute thiadiazole in the backbone induces a blue-shift of absorption spectra, reduces the charge transfer (CT) distance (Δd) and average electrostatic potential (ESP), and increases the singlet-triplet energy gap (ΔEST), CT excitation energy and the number of CT states in low-lying excitations. Inserting thienyl and dithiophenyl as π spacers generates a red-shift of absorption spectra, enlarges Δd and average ESP, and reduces ΔEST and the number of CT states. Introducing furo[3,2-b]furan for substituting one thieno[3,2-b]thiophene unit in the Y6's backbone causes a red-shift of absorption spectra and increases ΔEST, Δd and average ESP as well as CT excitation energy. Introducing alkoxyl as a side chain results in a blue-shift of absorption spectra, and increases ΔEST, Δd, average ESP, CT excitation energy and the number of CT states. The rate constants calculated using Marcus theory suggest that all the molecular modifications of Y6 reduce the exciton dissociation and charge recombination rates at the heterojunction interface, while introducing furo[3,2-b]furan and alkoxyl enlarges CT rates.

Mendelian randomization evidence for the causal effects of socio-economic inequality on human longevity among Europeans.

Human longevity correlates with socio-economic status, and there is evidence that educational attainment increases human lifespan. However, to inform meaningful health policies, we need fine-grained causal evidence on which dimensions of socio-economic status affect longevity and the mediating roles of modifiable factors such as lifestyle and disease. Here we performed two-sample Mendelian randomization analyses applying genetic instruments of education, income and occupation (n = 248,847 to 1,131,881) to estimate their causal effects and consequences on parental lifespan and self-longevity (n = 28,967 to 1,012,240) from the largest available genome-wide association studies in populations of European ancestry. Each 4.20 years of additional educational attainment were causally associated with a 3.23-year-longer parental lifespan independently of income and occupation and were causally associated with 30-59% higher odds of self-longevity, suggesting that education was the primary determinant. By contrast, each one-standard-deviation-higher income and one-point-higher occupation was causally associated with 3.06-year-longer and 1.29-year-longer parental lifespans, respectively, but not independently of the other socio-economic indicators. We found no evidence for causal effects of income or occupation on self-longevity. Mediation analyses conducted in predominantly European-descent individuals through two-step Mendelian randomization suggested that among 59 candidates, cigarettes per day, body mass index, waist-to-hip ratio, hypertension, coronary heart disease, myocardial infarction, stroke, Alzheimer's disease, type 2 diabetes, heart failure and lung cancer individually played substantial mediating roles (proportion mediated, >10%) in the effect of education on specific longevity outcomes. These findings inform interventions for remediating longevity disparities attributable to socio-economic inequality.

The evaluation of JAK inhibitors on effect and safety in alopecia areata: a systematic review and meta-analysis of 2018 patients.

Background: JAK inhibitors treat various autoimmune diseases, but an updated systematic review in treating alopecia areata is currently lacking. Objective: Evaluate the specific efficacy and safety of JAK inhibitors in alopecia areata by systematic review and meta-analysis. Methods: Eligible studies in PubMed, Embase, Web of Science, and Clinical Trials up to May 30, 2022, were searched. We enrolled in randomized controlled trials and observational studies of applying JAK inhibitors in alopecia areata. Results: 6 randomized controlled trials with 1455 patients exhibited SALT50 (odd ratio [OR], 5.08; 95% confidence interval [CI], 3.49-7.38), SALT90 (OR, 7.40; 95% CI, 4.34-12.67) and change in SALT score (weighted mean difference [WSD], 5.55; 95% CI, 2.60-8.50) compared to the placebo. The proportion of 26 observational studies with 563 patients of SALT5 was 0.71(95% CI, 0.65-0.78), SALT50 was 0.54(95% CI 0.46-0.63), SALT90 was 0.33(95% CI, 0.24-0.42), and SALT score (WSD, -2.18; 95% CI, -3.12 to -1.23) compared with baseline. Any adverse effects occurred in 921 of 1508 patients; a total of 30 patients discontinued the trial owing to adverse reactions. Limitations: Few randomized controlled trials met the inclusion criteria and insufficiency of eligible data. Conclusion: JAK inhibitors are effective in alopecia areata, although associated with an increased risk.

Outcomes of haploidentical haematopoietic stem cell transplantation for adolescent and young adults with acute myeloid leukaemia.

We aimed to identify the efficacy of haploidentical related donor (HID) haematopoietic stem cell transplantation (HSCT) in adolescent and young adults (AYAs) with acute myeloid leukaemia (AML) in a large cohort. Consecutive AML AYAs (15-39 years old, n = 599) receiving HID HSCT in complete remission (CR) were included. The 3-year cumulative incidence of measurable residual disease occurrence, relapse and non-relapse mortality after HID HSCT was 28.6% (95% CI: 25.0-32.2), 11.6% (95% CI: 9.0-14.2) and 6.7% (95% CI: 4.7-8.7) respectively. The 3-year probability of event-free survival, leukaemia-free survival (LFS) and overall survival (OS) after HID HSCT was 60.7% (95% CI: 56.9-64.8), 81.7% (95% CI: 78.7-84.9) and 85.6% (95% CI: 82.8-88.4) respectively. In multivariable analysis, AML risk category at diagnosis and comorbidity burdens before HID HSCT were independently associated with LFS and OS. Compared to the older adults (≥ 40 years, n = 355) with AML receiving HID HSCT in CR during the same time period, AYAs have a lower incidence of non-relapse mortality and higher probabilities of LFS and OS. Thus, we firstly confirmed the safety and efficacy of HID HSCT in AYAs with AML-CR.

Expanded clinical-grade NK cells exhibit stronger effects than primary NK cells against HCMV infection.

Cytomegalovirus (CMV) reactivation remains a common complication and leads to high mortality in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Early natural killer (NK) cell reconstitution may protect against the development of human CMV (HCMV) infection post-HSCT. Our previous data showed that ex vivo mbIL21/4-1BBL-expanded NK cells exhibited high cytotoxicity against leukemia cells. Nevertheless, whether expanded NK cells have stronger anti-HCMV function is unknown. Herein, we compared the anti-HCMV functions of ex vivo expanded NK cells and primary NK cells. Expanded NK cells showed higher expression of activating receptors, chemokine receptors and adhesion molecules; stronger cytotoxicity against HCMV-infected fibroblasts; and better inhibition of HCMV propagation in vitro than primary NK cells. In HCMV-infected humanized mice, expanded NK cell infusion resulted in higher NK cell persistence and more effective tissue HCMV elimination than primary NK cell infusion. A clinical cohort of 20 post-HSCT patients who underwent adoptive NK cell infusion had a significantly lower cumulative incidence of HCMV infection (HR = 0.54, 95% CI = 0.32-0.93, p = 0.042) and refractory HCMV infection (HR = 0.34, 95% CI = 0.18-0.65, p = 0.009) than controls and better NK cell reconstitution on day 30 post NK cell infusion. In conclusion, expanded NK cells exhibit stronger effects than primary NK cells against HCMV infection both in vivo and in vitro.

Effects of isolated central nervous system involvement evaluated by multiparameter flow cytometry prior to allografting on outcomes of patients with acute lymphoblastic leukemia.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a major strategy to cure patients with acute lymphoblastic leukemia (ALL). The aim of this study was to evaluate whether isolated flow cytometry (FCM)-positive central nervous system (CNS) involvement before allo-HSCT is clinically significant. Methods: The effects of isolated FCM-positive CNS involvement prior to transplantation on the outcomes of 1406 ALL patients with complete remission (CR) were retrospectively investigated. Results: Patients were classified into isolated FCM-positive CNS involvement (n=31), cytology-positive CNS involvement (n = 43), and negative CNS involvement (n = 1332) groups. Among the three groups, the 5-year cumulative incidence of relapse (CIR) values were 42.3%, 48.8%, and 23.4%, respectively (P<0.001). The 5-year leukemia-free survival (LFS) values were 44.7%, 34.9%, and 60.8%, respectively (P<0.001). Compared with the negative CNS group (n=1332), the 5-year CIR of the pre-HSCT CNS involvement group (n=74) was higher (46.3% vs. 23.4%, P<0.001], and the 5-year LFS was inferior (39.1% vs. 60.8%, P<0.001). Multivariate analysis indicated that four variables, T-cell ALL, in second complete remission or beyond (CR2+) at HSCT, pre-HSCT measurable residual disease positivity, and pre-HSCT CNS involvement, were independently associated with a higher CIR and inferior LFS. A new scoring system was developed using the following four variables: low-risk, intermediate-risk, high-risk, and extremely high-risk groups. The 5-year CIR values were 16.9%, 27.8%, 50.9%, and 66.7%, respectively (P<0.001), while the 5-year LFS values were 67.6%, 56.9%, 31.0%, and 13.3%, respectively (P<0.001). Conclusion: Our results suggest that ALL patients with isolated FCM-positive CNS involvement are at a higher risk of recurrence after transplantation. Patients with pre-HSCT CNS involvement had higher CIR and inferior survival outcomes.

CSRP2 transcript levels after consolidation therapy increase prognostic prediction ability in B-cell acute lymphoblastic leukaemia.

Quantification of measurable residual disease (MRD) correlates with the risk of leukemia recurrence in adults with B-cell acute lymphoblastic leukemia (ALL). However, it remains unknown whether collecting data on cysteine and glycine-rich protein 2 (CSRP2) transcript levels, after completing the second course of consolidation, improves prognosis prediction accuracy. A total of 204 subjects with B-cell ALL were tested for CSPR2 transcripts after completing the second course of consolidation using quantitative real-time polymerase chain reaction (qRT-PCR) and divided into high (N = 32) and low (N = 172) CSRP2 expression cohorts. In multivariable analyses, subjects with high expression of CSRP2 had a higher 5-year cumulative incidence of relapse (CIR) (hazard ratio [HR] = 2.57, 95% confidence interval [CI] 1.38-4.76; P = 0.003), lower 5-year relapse-free survival (RFS) (HR = 3.22, 95% CI 1.75-5.93; P < 0.001), and overall survival (OS) (HR = 4.59, 95% CI 2.64-7.99; P < 0.001) in the whole cohort, as well as in the multi-parameter flow cytometry (MPFC) MRD-negative cohort (for CIR, HR = 2.70, 95% CI 1.19-6.12; for RFS, HR = 4.37, 95% CI 1.94-9.85; for OS, HR = 4.90, 95% CI 2.43-9.90; all P < 0.05). Prognostic analysis showed that allogeneic hematopoietic stem cell transplantation (allo-HSCT) could significantly improve the prognosis of patients with high CSRP2 expression (allo-HSCT vs chemotherapy: 5-year CIR, 52% vs 91%; RFS, 41% vs 9%; OS, 38% vs 20%; all P < 0.05). Our data indicate that incorporating data from CSPR2 transcript levels to the MRD-testing at the end of the second course of consolidation therapy enhances prognosis prediction accuracy in adults with B-cell ALL.