Activation of PPARδ in bone marrow endothelial progenitor cells improves their hematopoiesis-supporting ability after myelosuppressive injury.

Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor graft function (PGF) patients with acute leukemia or myelodysplastic neoplasms post-allotransplant. However, the underlying mechanism by which BM EPCs regulate their intracellular ROS levels and the capacity to support hematopoiesis have not been well clarified. Herein, we demonstrated decreased levels of peroxisome proliferator-activated receptor delta (PPARδ), a lipid-activated nuclear receptor, in BM EPCs of PGF patients compared with those with good graft function (GGF). In vitro assays further identified that PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, characterized by the impaired ability to support hematopoiesis, which were restored by PPARδ overexpression. Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Clinically, activation of PPARδ by GW501516 benefited the damaged BM EPCs from PGF patients or acute leukemia patients in complete remission (CR) post-chemotherapy. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers.

COVID-19 was associated with the complications after allogeneic hematopoietic stem cell transplantation.

We aimed to identify the severity and duration of COVID-19 infection on complications after allo-HSCT. Enrolled 179 hospitalized patients with COVID-19 were categorized into long-term infection (> 18 days, n = 90) or short-term infection group (≤ 18 days, n = 89) according to the median duration of COVID-19. The severity of COVID-19 was categorized as asymptomatic infection, mild, moderate, severe, and critical illness according to guidelines of National Institutes of Health. Particularly, severe illness and critical illness were classified as serious infection. Asymptomatic infection, mild illness and moderate illness were classified as non-serious infection. The 150-day probabilities of poor graft function (PGF), cytomegalovirus (CMV) pneumonia and non-relapse mortality (NRM) were significantly higher in long-term infection group. The 150-day probabilities of CMV pneumonia and NRM after COVID-19 were higher in serious infection group. The 150-day probabilities of overall survival (OS) was significantly lower in long-term and serious infection group. In multivariable analysis, the severity of COVID-19 was associated with NRM and OS, and the duration of COVID-19 was associated with PGF. In summary, our data reported that the severity and duration of COVID-19 were associated with several complications and contribute to poor outcomes after allo-HSCT.

Study on the bioactive ingredients and mechanism of Huangqi against diabetic retinopathy based on network pharmacology and experimental verification.

BACKGROUND: Diabetic retinopathy (DR) is one of the most well-known microvascular complications of diabetes mellitus. As a traditional Chinese medicine, Huangqi (HQ), has been used for treating DR for a long time. However, its anti-DR active ingredients and mechanism are still unknown. Therefore, we designed this study to explore the active components and mechanism of HQ against DR via network pharmacology analysis. METHODS: The ingredients of HQ, potential targets of HQ and DR were obtained from public databases. We employed the protein-protein interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis to identify core targets and pathways of HQ against DR. Finally, molecular docking and vitro experiments were applied to validate our results. RESULTS: A total of 34 potential targets of HQ against DR were obtained. Based on PPI network, VEGFA, PTGS2, IL6 and CCL2 were considered as core targets. GO analysis involved 692 biological processes, 21 cellular components and 35 molecular functions. KEGG enrichment analysis manifested that the anti-DR effect of HQ was mainly mediated via the AGE-RAGE signaling pathway in diabetic complications. The molecular docking results indicated that kaempferol had higher affinity with CCL2, IL-6, VEGFA and PTGS2. The vitro experiments showed that the mRNA expressions of CCL2, IL-6, VEGFA and PTGS2 in ARPE-19 cell were differentially decreased after kaempferol treatment. CONCLUSION: This study preliminarily unveiled that the therapeutic efficacy of HQ against DR might be attributed to the reduced expression of CCL2, IL-6, VEGFA and PTGS2.

Biochemical risk factors and outcomes of acute promyelocytic leukemia patients with thrombotic events: a matched pair analysis.

Acute promyelocytic leukemia (APL) stands out as a distinctive form of acute leukemia, exhibiting a higher occurrence of thrombotic events when contrasted with other leukemia subtypes. Since thrombosis is a relatively rare but unfavorable condition with poor prognostic implications, it is crucial to determine the risk factors for thrombotic events in APL(thrombosis in large venous or arterial from onset to differentiation therapy in 30d). We performed a retrospective study involving 950 APL patients between January 2000 and October 2022, from which 123 were excluded by younger than 16 years of age, 95 were excluded by incomplete data, and 6 were excluded by thrombosis related to CVC or PICC. A total of 23 APL patients with thrombosis for inclusion in our analysis were performed a 1:5 ratio matching based on sex (perfect match) and age (within 5 years) to patients without thrombosis. These patients were continuously monitored in the outpatient department over a period of 5 years. We meticulously examined clinical and laboratory data to pinpoint the risk factors related to thrombotic events in APL. Our primary clinical endpoints were all-cause mortality and achieving complete remission, while secondary clinical outcomes included APL relapse. Thrombotic events were observed in 2.4% (23/950) of APL patients. Compared to patients without thrombosis, patients with thrombosis had higher lactate dehydrogenase (LDH) [313 (223, 486) vs. 233 (188, 367) U/L, p = 0.020], higher indirect bilirubin [11.2 (7.4, 18.6) vs.8.3 (6.0, 10.7) umol/L, p = 0.004], higher creatinine [72 (62, 85) vs. 63 (54, 74) umol/L, p = 0.026], higher CD2 expression (65.2 vs. 15.2%, p < 0.001), higher CD15 expression (60.9 vs. 24.3%, p = 0.001), and PML/RARαisoforms (p < 0.001). Multivariate-logistic-regression analysis revealed several factors that were markedly related to thrombosis, including LDH (OR≈1.003, CIs≈1.000-1.006, p = 0.021), indirect bilirubin (OR≈1.084, CIs≈1.000-1.188, p = 0.043), CD2 expression positive (OR≈16.629, CIs≈4.001-62.832, p < 0.001), and CD15 expression positive (OR≈7.747, CIs≈2.005-29.941, p = 0.003). The S-type (OR≈0.012, CIs≈0.000-0.310, p = 0.008) and L-type (OR≈0.033, CIs≈0.002-0.609, p = 0.022) PML/RARα isoforms were negatively associated with thrombosis. Kaplan-Meier curves indicated that the survival rates were remarkably varied between APL patients with and without thrombosis (HR:21.34, p < 0.001). LDH and indirect bilirubin are variables significantly associated with thrombosis in APL, S-type and L-type PML/RARαisoforms exhibit a negative association with thrombotic events. The thrombotic events of APL can predict the subsequent survival of thrombosis. The findings of our study have the potential to facilitate early detection of thrombosis and enhance the prognosis for individuals with APL who develop thrombosis. Further validation of our findings will be essential through future prospective or multicenter studies.

Plerixafor-based mobilization and mononuclear cell counts in graft increased the risk of engraftment syndrome after autologous hematopoietic stem cell transplantation.

Engraftment syndrome (ES) is one of the most common complications in the early phase after autologous hematopoietic stem cell transplantation (ASCT), and we aimed to evaluate the incidence and risk factors for ES patients receiving ASCT in the era of plerixafor-based mobilization. A total of 294 were enrolled, and 16.0% (n = 47) experienced ES after ASCT. The main clinical manifestations were fever (100%), diarrhea (78.7%), skin rash (23.4%), and hypoxemia/pulmonary edema (12.8%). Plerixafor-based mobilization was associated with higher counts of CD3+ cells, CD4+ cells, and CD8+ cells in grafts. In univariate analysis of the total cohort, age ≥60 years, receiving ASCT at complete remission (CR), higher number of mononuclear cell (MNC), CD3+ cell counts, CD4+ cells as well as CD8+ cells transfused and plerixafor-based mobilization were associated with ES after ASCT. Multivariate analysis showed that age ≥60 years (P = .0014), receiving ASCT at CR (P = .002), and higher number of MNC transfused (P = .026) were associated with ES in total cohort. In plasma cell disease subgroup, age ≥60 years (P = .013), plerixafor-based mobilization (P = .036), and receiving ASCT at CR (P = .002) were associated with ES. Patients with more risk factors had a higher risk of ES. The 1-year probabilities of relapse, non-relapse mortality, and survival were comparable between patients with and without ES. Thus, plerixafor-based mobilization may influence the composition of T lymphocytes in grafts and increase the risk of ES, particularly in patients with plasma cell disease.

Clinical manifestations, prognostic factors, and outcomes of adenovirus pneumonia after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Severe pneumonia is one of the most important causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adenovirus (ADV) is a significant cause of severe viral pneumonia after allo-HSCT, and we aimed to identify the clinical manifestations, prognostic factors, and outcomes of ADV pneumonia after allo-HSCT. METHODS: Twenty-nine patients who underwent allo-HSCT at the Peking University Institute of Hematology and who experienced ADV pneumonia after allo-HSCT were enrolled in this study. The Kaplan-Meier method was used to estimate the probability of overall survival (OS). Potential prognostic factors for 100-day OS after ADV pneumonia were evaluated through univariate and multivariate Cox regression analyses. RESULTS: The incidence rate of ADV pneumonia after allo-HSCT was approximately 0.71%. The median time from allo-HSCT to the occurrence of ADV pneumonia was 99 days (range 17-609 days). The most common clinical manifestations were fever (86.2%), cough (34.5%) and dyspnea (31.0%). The 100-day probabilities of ADV-related mortality and OS were 40.4% (95% CI 21.1%-59.7%) and 40.5% (95% CI 25.2%-64.9%), respectively. Patients with low-level ADV DNAemia had lower ADV-related mortality and better OS than did those with high-level (≥ 106 copies/ml in plasma) ADV DNAemia. According to the multivariate analysis, high-level ADV DNAemia was the only risk factor for intensive care unit admission, invasive mechanical ventilation, ADV-related mortality, and OS after ADV pneumonia. CONCLUSIONS: We first reported the prognostic factors and confirmed the poor outcomes of patients with ADV pneumonia after allo-HSCT. Patients with high-level ADV DNAemia should receive immediate and intensive therapy.

Surface-active agent enhanced FRET effect Cu-doped NH2-MIL-88(Fe) for highly sensitive detection of 3-nitro-L-tyrosine.

In this study, Cu-doped NH2-MIL-88(Fe) metal-organic frameworks (MOF) were synthesized via a one-step method. Characterization techniques such as XPS, XRD and FTIR confirmed the successful incorporation of Cu2+ into NH2-MIL-88(Fe), naming this MOF as NH2-MIL-88(Fe)@Cu2+. This MOF was employed to develop a highly sensitive fluorescence sensing platform for detecting 3-nitro-L-tyrosine(3-NT). The potential for fluorescence resonance energy transfer (FRET) was suggested by the spectral overlap between NH2-MIL-88(Fe)@Cu2+'s emission and 3-NT's UV absorption. To augment this effect, cationic surfactant hexadecyltrimethylammonium bromide (CTAB), which self-assembled into nanostructured microspheres above its critical micelle concentration, was utilized. The charged surface of these microspheres, formed by the self-assembly of CTAB, is bound to the MOF surface through electrostatic force and simultaneously attracts 3-NT. Adjusting the solution's pH strengthened the interaction between NH2-MIL-88(Fe)@Cu2+ and 3-NT, thereby enhancing their mutual FRET interaction. Experimental results indicated that CTAB's introduction markedly improved the FRET effects, potentially converting a weak FRET into a strong one and enhancing detection sensitivity and accuracy. Under optimal conditions, NH2-MIL-88(Fe)@Cu2+ detected 3-NT within 0-30 µM range, with a limit of detection (LOD, S/N = 3) of 41.1 nM. Finally, the applicability of the sensor is tested by calibrating measurements in fetal bovine serum samples, achieving good performance in terms of sensitivity, selectivity and reproducibility. This research provides a method for efficient and highly sensitive 3-NT detection and insights into the FRET effect between MOF and target molecules, likely advancing related fields and inspiring future fluorescence sensor designs.

Dissolved organic matter, calcium ion and extracellular polymeric substances on living associated bacteria of Microcystis colony are crucial for unicellular Microcystis to efficiently form colonies.

Microcystis typically forms colonies under natural conditions, which contributes to occurrence and prevalence of algal blooms. The colonies consist of Microcystis and associated bacteria (AB), embedded in extracellular polymeric substances (EPS). Previous studies indicate that AB can induce Microcystis to form colonies, however the efficiency is generally low and results in a uniform morphotype. In this study, by using filtrated natural water, several AB strains induced unicellular M. aeruginosa to form colonies resembling several Microcystis morphotypes. The mechanisms were investigated with Methylobacterium sp. Z5. Ca2+ was necessary for Z5 to induce Microcystis to form colonies, while dissolved organic matters (DOM) facilitated AB to agglomerate Microcystis to form large colonies. EPS of living Z5, mainly the aromatic protein components, played a key role in colony induction. Z5 initially aggregated Microcystis via the bridging effects of Ca2+ and DOM, followed by the induction of EPS synthesis and secretion in Microcystis. In this process, the colony forming mode shifted from cell adhesion to a combination of cell adhesion and cell division. Intriguingly, Z5 drove the genomic rearrangement of Microcystis by upregulating some transposase genes. This study unveiled a novel mechanism about Microcystis colony formation and identified a new driver of Microcystis genomic evolution.

Mini-dose methotrexate combined with methylprednisolone for the initial treatment of acute GVHD: a multicentre, randomized trial.

BACKGROUND: There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. RESULTS: The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. CONCLUSIONS: In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (NCT04960644).

Bioaccumulation, trophic transfer and risk assessment of polycyclic musk in marine food webs of the Bohai Sea.

Galaxolide (HHCB) and tonalide (AHTN) are dominant musks added to personal care products. However, the accumulate and trophic transfer of SMs through the marine food chain are unclear. In this study, organisms were collected from three bays in Bohai Sea to investigate the bioaccumulation, trophic transfer, and health risk of SMs. The HHCB and AHTN concentrations in the muscles range from 2.75 to 365.40 µg/g lw and 1.04-4.94 µg/g lw, respectively. The median HHCB concentrations in muscles were the highest in Bohai Bay, followed by Laizhou Bay and Liaodong Bay, consistent with the HHCB concentrations in sediments. The different fish tissues from Bohai Bay were analyzed, and the HHCB and AHTN concentrations followed the heart > liver > gill > muscles. The trophic magnification factors (TMF) were lower than 1 and the health risk assessment showed no adverse health effects. The results provide insights into the bioaccumulation and trophic transfer behavior of SMs in marine environments.

Characterization of the Dynamic Behavior of Multinanobubble System under Shock Wave Influence.

Shockwave-induced changes in nanobubbles cause cavitation erosion and membrane damage but can also be applied to biocarrier transport. Currently, research focuses on single nanobubbles; however, in reality, nanobubbles usually appear as a multibubble system. Therefore, this study proposes a method based on cutting and replicating to construct a multibubble model. This method can be widely applied to molecular dynamics (MD) models and enhance the customization capabilities of MD models. The dynamic behavior of a multinanobubble system with different numbers and arrangements of nanobubbles is investigated with the MD method under the influence of shock waves in a liquid argon system. The study also explores the range of influence between nanobubbles. The results show that in the case of two nanobubbles, when the distance between the bubbles is constant, the smaller the angle between the direction of the shock wave and the line connecting the bubbles, the greater is the influence between nanobubbles, and the moment of collapse of the nanobubbles farther away from the shock wave is slower. When three nanobubbles are arranged with a right offset, after the first bubble collapses, the effect on the other two bubbles is similar to the changes in bubbles when the angle of arrangement is 30° or 60°. Under a different arrangement, the change of shock wave velocity on the nanobubble size only affects its collapse time and contraction collapse rate. When the shock wave with a radian of about 2.87 or greater than 2.87 touches the bubbles, the collapse of the second nanobubble will not be affected.

Evaluating the clinical utility of semi-quantitative luciferase immunosorbent assay using Treponema pallidum antigens in syphilis diagnosis and treatment monitoring.

To assess the clinical applicability of a semi-quantitative luciferase immunosorbent assay (LISA) for detecting antibodies against Treponema pallidum antigens TP0171 (TP15), TP0435 (TP17), and TP0574 (TP47) in diagnosing and monitoring syphilis. LISA for detection of anti-TP15, TP17, and TP47 antibodies were developed and evaluated for syphilis diagnosis using 261 serum samples (161 syphilis, 100 non-syphilis). Ninety serial serum samples from 6 syphilis rabbit models (3 treated, 3 untreated) and 110 paired serum samples from 55 syphilis patients were used to assess treatment effects by utilizing TRUST as a reference. Compared to TPPA, LISA-TP15, LISA-TP17, and LISA-TP47 showed a sensitivity of 91.9%, 96.9%, and 98.8%, specificity of 99%, 99%, and 98%, and AUC of 0.971, 0.992, and 0.995, respectively, in diagnosing syphilis. Strong correlations (rs = 0.89-0.93) with TPPA were observed. In serial serum samples from rabbit models, significant differences in the relative light unit (RLU) were observed between the treatment and control group for LISA-TP17 (days 31-51) and LISA-TP47 (day 41). In paired serum samples from syphilis patients, TRUST titres and the RLU of LISA-TP15, LISA-TP17, and LISA-TP47 decreased post-treatment (P < .001). When TRUST titres decreased by 0, 2, 4, or ≥8-folds, the RLU decreased by 17.53%, 31.34%, 48.62%, and 72.79% for LISA-TP15; 8.84%, 17.00%, 28.37%, and 50.57% for LISA-TP17; 22.25%, 29.79%, 51.75%, and 70.28% for LISA-TP47, respectively. Semi-quantitative LISA performs well for syphilis diagnosis while LISA-TP17 is more effective for monitoring syphilis treatment in rabbit models and clinical patients.

Biomechanics of the lower limb in patients with mild knee osteoarthritis during the sit-to-stand task.

BACKGROUND: Knee osteoarthritis (KOA) is a prevalent and debilitating condition that markedly affects the sit-to-stand (STS) activity of patients, a prerequisite for daily activities. Biomechanical recognition of movements in patients with mild KOA is currently attracting attention. However, limited studies have been conducted solely on the observed differences in sagittal plane movement and muscle activation. AIM: This study aimed to identify three-dimensional biomechanical and muscle activation characteristics of the STS activity in patients with mild KOA. METHODS: A cross-sectional study was conducted to observe the differences between patients with mild KOA and a control group (CG). It was conducted to observe the differences in muscle activation, including root mean square (RMS%) and integrated electromyography (items), kinematic parameters like range of motion (ROM) and maximum angular velocity, as well as dynamic parameters such as joint moment and vertical ground reaction force (vGRF). RESULTS: Patients with mild KOA had a higher body mass index and longer task duration. In the sagittal plane, patients with KOA showed an increased ROM of the pelvic region, reduced ROM of the hip-knee-ankle joint, and diminished maximum angular velocity of the knee-ankle joint. Furthermore, patients with KOA displayed increased knee-ankle joint ROM in the coronal plane and decreased ankle joint ROM in the horizontal plane. Integrated vGRF was higher in both lower limbs, whereas the vGRF of the affected side was lower. Furthermore, patients showed a decreased peak adduction moment (PADM) and increased peak external rotation moment in the knee joint and smaller PADM and peak internal rotation moment in the ankle joint. The affected side exhibited decreased RMS% and iEMG values of the gluteus medius, vastus medialis, and vastus lateralis muscles, as well as a decreased RMS% of the rectus femoris muscle. Conversely, RMS% and iEMG values of the biceps femoris, lateral gastrocnemius, and medial gastrocnemius muscles were higher. CONCLUSION: The unbalanced activation characteristics of the anterior and posterior muscle groups, combined with changes in joint moment in the three-dimensional plane of the affected joint, may pose a potential risk of injury to the irritated articular cartilage.

Deep-learning-based image super-resolution of an end-expandable optical fiber probe for application in esophageal cancer diagnostics.

Significance: Endoscopic screening for esophageal cancer (EC) may enable early cancer diagnosis and treatment. While optical microendoscopic technology has shown promise in improving specificity, the limited field of view (<1 mm) significantly reduces the ability to survey large areas efficiently in EC screening. Aim: To improve the efficiency of endoscopic screening, we propose a novel concept of end-expandable endoscopic optical fiber probe for larger field of visualization and for the first time evaluate a deep-learning-based image super-resolution (DL-SR) method to overcome the issue of limited sampling capability. Approach: To demonstrate feasibility of the end-expandable optical fiber probe, DL-SR was applied on simulated low-resolution microendoscopic images to generate super-resolved (SR) ones. Varying the degradation model of image data acquisition, we identified the optimal parameters for optical fiber probe prototyping. The proposed screening method was validated with a human pathology reading study. Results: For various degradation parameters considered, the DL-SR method demonstrated different levels of improvement of traditional measures of image quality. The endoscopists' interpretations of the SR images were comparable to those performed on the high-resolution ones. Conclusions: This work suggests avenues for development of DL-SR-enabled sparse image reconstruction to improve high-yield EC screening and similar clinical applications.

Haploidentical hematopoietic stem cell transplantation with busulfan, cyclophosphamide, and fludarabine conditioning for X-linked adrenal cerebral leukodystrophy.

OBJECTIVE: We investigated the safety and efficacy of haploidentical stem cell transplantation (SCT) in pediatric patients with X-linked adrenoleukodystrophy (ALD). METHODS: A retrospective analysis of transplantation data from 29 cases of ALD, treated between December 2014 and April 2022, was conducted. Neurologic function scores (NFS) were assessed. The conditioning regimen was busulfan 9.6 mg/kg, cyclophosphamide 200 mg/kg, and fludarabine 90 mg/m2 (BFC). Graft-versus-host disease prophylaxis consisted of anti-human thymocyte globulin, cyclosporine A, mycophenolate mofetil, and short course of methotrexate. RESULTS: Among the 29 cases, 14 cases (NFS = 0) were asymptomatic, and 15 (NFS ≥ 1) were symptomatic. The median age at SCT was 8 years (range: 4-16 years); the median follow-up time was 1058 days (range: 398-3092 days); 28 cases were father donors and 1 case was a grandfather donor. Hematopoietic reconstitution was successful in all patients, and all of them achieved complete donor chimerism at the time of engraftment. The leading cause of death was still primary disease progression (n = 4). Survival free of major functional disabilities was 100% in asymptomatic patients versus 66.67% in the symptomatic group (p = .018). CONCLUSION: BFC regimen used in haploidentical SCT was administered safely without major transplant-related complications even in symptomatic patients, and neurological symptoms were stabilized after SCT.

Dynamic role of CUL4B in radiation-induced intestinal injury-regeneration.

CUL4B, a crucial scaffolding protein in the largest E3 ubiquitin ligase complex CRL4B, is involved in a broad range of physiological and pathological processes. While previous research has shown that CUL4B participates in maintaining intestinal homeostasis and function, its involvement in facilitating intestinal recovery following ionizing radiation (IR) damage has not been fully elucidated. Here, we utilized in vivo and in vitro models to decipher the role of CUL4B in intestinal repair after IR-injury. Our findings demonstrated that prior to radiation exposure, CUL4B inhibited the ubiquitination modification of PSME3, which led to the accumulation of PSME3 and subsequent negative regulation of p53-mediated apoptosis. In contrast, after radiation, CUL4B dissociated from PSME3 and translocated into the nucleus at phosphorylated histones H2A (γH2AX) foci, thereby impeding DNA damage repair and augmenting p53-mediated apoptosis through inhibition of BRCA1 phosphorylation and RAD51. Our study elucidated the dynamic role of CUL4B in the repair of radiation-induced intestinal damage and uncovered novel molecular mechanisms underlying the repair process, suggesting a potential therapeutic strategy of intestinal damage after radiation therapy for cancers.

CAR-T Therapy Followed by Hematopoietic Stem Cell Transplantation Can Improve Survival in Children Relapsed/Refractory Philadelphia Chromosome-positive B-cell Acute Lymphoblastic Leukemia.

BACKGROUND: Philadelphia chromosome (Ph)-positive B-cell acute lymphoblastic leukemia (ALL) has a high complete remission (CR) rate, but relapse and prolonged measurable residual disease remain serious problems. We sought to describe the CR rate measurable residual disease negative rate and address the results and safety of pediatric patients who underwent after receiving chimeric antigen receptor (CAR) specific for CD19 (CAR-19) followed by hematopoietic stem cell transplantation (HSCT) for the treatment of Ph-positive ALL. METHODS: A descriptive study was conducted at Peking University People's Hospital from September 2013 to January 2021. 13 patients with relapsed/refractory Ph-positive B-ALL who received CAR-T therapy followed by allo-HSCT were included. We concentrated on the overall patient survival and CR rate. RESULTS: The median time between CAR-T therapy and allo-HSCT was 58 days. Among all the patients, the CR rate was 100%, the flow cytometry negativity rate was 84.62%, and the BCR-ABL negativity rate was 53.85% at 1 month after CAR-T infusion. All the patients achieved a major molecular response in 6 months after HSCT. After a median follow-up of 45 months, the 3-year OS rate was 66.7%, and the 3-year DFS rate was 61.5%. The 3-year OS rate of patients with BCR-ABL-positive pre-HSCT was significantly lower than that in the BCR-ABL-negative group (40.0% vs. 85.7%, P=0.042). Also, the same trend was observed for the 3-year DFS rate but did not differ significantly (40.0% vs. 75.0%, P=0.233). CONCLUSIONS: CAR-T therapy followed by allo-HSCT can be a safe and effective treatment for Ph-positive B-ALL pediatric patients.

High dimensional proteomic mapping of bone marrow immune characteristics in immune thrombocytopenia.

To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia (ITP), this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight (CyTOF). Thirty-six patients with ITP and nine healthy volunteers were enrolled in the study. As soluble immunomodulatory molecules, more sCD25 and sGalectin-9 were detected in ITP patients. On the cell surface, co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells. In contrast, co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets. Taking a platelet count of 30×109 L-1 as the cutoff value, ITP patients with high and low platelet counts showed different T cell immune profiles. Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions, respectively, and participate in the pathogenesis of ITP. In conclusion, the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP. They may offer novel targets to develop personalized immunotherapies.

The impact of low-velocity shock waves on the dynamic behaviour characteristics of nanobubbles.

Low-velocity shock wave-induced contraction and expansion of nanobubbles can be applied to biocarriers and microfluidic systems. Although experiments have been conducted to study the application effects, the dynamic behavior characteristics of nanobubbles remain unexplored. In this work, we utilize molecular dynamics (MD) simulations to investigate the dynamic behavior characteristics of nanobubbles influenced by low-velocity shock waves in a liquid argon system. The DBSCAN (Density-Based Spatial Clustering of Applications with Noise) machine learning method is used to calculate the equivalent radius of nanobubbles. Two statistical methods are then utilized to predict the time series changes in the equivalent radius of nanobubbles without rebound shock waves. The piston velocity is analyzed using the bisection method to obtain the critical impact states of the nanobubble. The results show that at the low velocity shock wave (piston velocity of 0.1 km s-1), the shock wave pressure is small, the non-vacuum nanobubbles contract and expand in a circular shape, and the gas particles inside the bubble are not dispersed. In contrast, the vacuum nanobubbles collapse directly. As the shock wave rebounds upon impact, it triggers periodic contraction and expansion of the nanobubbles. The predictions indicate that the equivalent radius will vary within a small range according to the pre-predicted values in the absence of the rebound shock wave. Nanobubbles are present in four critical impact states: dispersed gaps, multiple smaller bubbles, two split bubbles, and a concave bubble.