Early-life tobacco smoke exposure and stroke risk: a prospective study of 341,783 and 352,737 UK Biobank participants.

INTRODUCTION: Stroke is a life-threatening condition that causes a major medical burden globally. The currently used methods for the prevention or prediction of stroke have certain limitations. Exposure to tobacco in early life, including smoking during adolescence and maternal smoking during pregnancy, can affect adolescent development and lead to several negative outcomes. However, the association between early-life tobacco exposure and stroke is not known. METHODS: In this prospective cohort study, for the analyses involving exposure to maternal smoking during pregnancy and age of smoking initiation, we included 304,984 and 342,893 participants, respectively., respectively from the UK Biobank. Cox proportional hazard regression model and subgroup analyses were performed to investigate the association between early-life tobacco exposure and stroke. Mediation analyses were performed to identify the mediating role of biological aging in the association between early tobacco exposure and stroke. RESULTS: Compared with participants whose mothers did not smoke during pregnancy, participants whose mothers smoked during pregnancy showed an 11% increased risk of stroke (HR: 1.11, 95% CI: 1.05-1.18, P < 0.001). Compared with participants who never smoked, participants who smoked during adulthood, adolescence and childhood showed a 22%, 24%, and 38% increased risk of stroke during their adulthood, respectively. Mediation analysis indicated that early-life tobacco exposure can cause stroke by increasing biological aging. CONCLUSION: This study reveals that exposure to tobacco during early life is associated with an increased risk of experiencing a stroke, and increased biological aging can be the underlying mechanism.

Haploidentical transplant for paediatric patients with severe thalassaemia using post-transplant cyclophosphamide and methotrexate: A prospectively registered multicentre trial from the Bone Marrow Failure Working Group of Hunan Province, China.

Haploidentical transplantation strategies for patients with transfusion-dependent thalassaemia (TD-TM) remain to be investigated. In this study, 54 paediatric patients with TD-TM were treated with a novel approach using post-transplant cyclophosphamide (PTCy) and low-dose methotrexate (LD-MTX), following a myeloablative regimen. The incidence of neutrophil and platelet engraftment was 96.3% ± 2.6% and 94.4% ± 3.1% respectively. The cumulative incidence of grades II-III acute graft-versus-host disease (GVHD) was 13.8% ± 4.8% at 100 days. At three years, the cumulative incidence of chronic GVHD was 28.5% ± 8.5%. With a median follow-up of 520 days (132-1325 days), the overall survival (OS) and event-free survival (EFS) were 98.1% ± 1.8% and 90.7% ± 3.9% respectively. Compared with the low-dose cyclophosphamide (CTX) conditioning regimen (120 mg/kg), the high-CTX regimen (200 mg/kg) achieved a higher incidence of stable engraftment (100% vs 66.7% ± 15.7%, p = 0.003), a comparable incidence of grades II-III acute GVHD, a lower incidence of chronic GVHD (20.2% ± 8.3% vs 66.6% ± 19.2%, p = 0.011), and better overall survival (100% vs 88.9% ± 10.5%, p = 0.025) as well as EFS (95.6% ± 3.1% vs 66.7% ± 15.7%, p = 0.008). Our results using unmanipulated haploidentical grafts and PTCy with LD-MTX in TD-TM are encouraging. (chictr.org.cn ChiCTR1800017969).

Clinical characteristics, drug resistance and death risk factors of Burkholderia cepacia infection in hematopoietic stem cell transplant patients.

BACKGROUND: Burkholderia cepacia (BC) has been detected more and more in infected patients in recent years. However, as a high-risk population, the clinical characteristics and prognosis of BC infection in hematopoietic stem cell transplantation (HSCT) patients have not been reported. The purpose of this study is to obtain data that will help fill in the gaps in this field, provide evidence for reducing the mortality rate of BC infection in HSCT patients, and guide the use of antibiotics in the future. METHODS: Electronic medical records of patients with BC infection who underwent HSCT in Xiangya Hospital of Central South University from September 1, 2015 to August 31, 2021 were collected. At the same time, 1:1 case-control matching was conducted according to gender, age and disease type. Comparisons between patients with/without BC infection and respiratory failure were made respectively, and the sensitivity of BC to five clinically commonly used antibiotics was also evaluated. Univariate and multivariate analyses were performed to identify independent risk factors for death. RESULTS: The most common site of BC infection in HSCT patients was the lung (75%). Although BC infection rate (3.74%) and antibiotic resistance were not significant, it was closely associated with a higher risk of death (P = 0.022), which even further increased to 90.9% when combined with respiratory failure (P = 0.008). Procalcitonin > 10 µg/L (HR = 40.88, 95% CI 6.51-256.63, P = 0.000) and septic shock (HR = 4.08, 95% CI 1.02-16.33, P = 0.047) were two independent risk factors for death. CONCLUSION: HSCT patients with BC infection are in critical condition, and the management of respiratory infection should be especially strengthened to improve the prognosis of these patients.

[Peripheral blood stem cell transplantation from HLA-mismatched unrelated donor or haploidentical donor for the treatment of X-linked agammaglobulinemia].

Allogeneic stem cell transplantation (allo-SCT) is currently the only curative option for patients with X-linked agammaglobulinemia (XLA). In this study, patient 1 aged 4 years who underwent allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from HLA-mismatched unrelated donor; patient 2 aged 24 years (childhood onset) with primary cutaneous acral CD8+ T cell lymphoma who underwent allo-PBSCT from haploidentical relative donor. Both were treated by reduced toxicity myeloablative conditioning with post-transplantation cyclophosphamide (PTCy), anti-thymocyte globulin (ATG), methotrexate (MTX) and cyclosporine (CsA) for graft-versus-host-disease (GVHD) prophylaxis. In patient 1, neutrophil and platelet engraftment were observed on day 11 post-transplantation; the donor chimerism dropped on day 90 post-transplantation, and recovered on day 150 with donor lymphocyte infusion (DLI). In patient 2, neutrophil and platelet engraftment were observed on days 20 and 87 post-transplantation respectively, with complete donor chimerism on day 30 post-transplantation. The serum levels of IgG, IgM and IgA and the percentage of CD19+ B cells in peripheral blood of patients 1 and 2 returned to normal within 2 months and more than 1 year after transplantation respectively. There was no evidence of acute GVHD for the two patients. Patient 1 developed a limited type of skin chronic GVHD after DLI, which disappeared after anti-GVHD treatment. This is the first report of successful treatment for two XLA patients using PTCy with allo-PBSCT from HLA-mismatched unrelated donor or haploidentical donor, combining with improved conditioning, which expands the pool of eligible donors for patients with XLA.

Structure and Bioactivity of Intracellular and Extracellular Polysaccharides of Trametes lactinea Mycelium.

Trametes lactinea polysaccharides have a high medicinal value; however, we still know little about the structure and bioactivity of intracellular and extracellular polysaccharides in the mycelial liquid fermentation of T. lactinea. This study analyzed the structures of intracellular (IP-1, IP-2, and IP-3) and extracellular (EP-1 and EP-2) polysaccharide components isolated from T. lactinea liquid fermentation, as well as investigated their antioxidant, antibacterial, and immunomodulatory properties. The results showed that IP-3 was the only component with a triple-helix structure, while the other four components did not possess this structure. IP3 has a higher molecular weight, flavonoid, and total phenolic content compared to other components. Both intracellular and extracellular polysaccharide components exhibited strong scavenging abilities against ABTS and DPPH radicals. The components showed limited antibacterial effects against four types of bacteria (Staphylococcus aureus, Bacillus subtilis, Erwinia carotovora, and Escherichia coli), and were found to be non-toxic to RAW264.7 cells, even promoting cell proliferation. Furthermore, within a specific concentration range, all components enhanced the phagocytic activity of RAW264.7 cells, increased the secretion of NO, TNF-α, and IL-6, and demonstrated concentration-dependent effects, with IP-3 displaying the most potent immunomodulatory activity. This study shows a high potential for the development and utilization of polysaccharides derived from the liquid fermentation of T. lactinea mycelium.

Mechanistic analysis of the hardening process of the thorns on stems of Bougainvillea glabra "Elizabeth Angus".

Introduction: Bougainvillea glabra "Elizabeth Angus" is a thorny woody vine or shrub. However, the hard thorns are considered a deficiency in its ornamental value. Methods: To find the genes and pathways related to the hardening process of the thorns on the stems of B. glabra, the eukaryotic unreferenced transcriptome sequencing analysis was conducted to explore the 3 stages of the thorn-hardening process. Total RNA was extracted from thorns and stems, and transcriptome libraries were constructed and sequenced using unreferenced Illumina sequencing. Results: Gene function annotation was performed using various databases, resulting in 8937 co-annotated genes. The density distribution of Fragments Per Kilobase of transcript per Million mapped reads (FPKM) depicted the overall gene expression patterns. The study found that stage 2 as the period of highest gene expression activity during the thorns hardening process in B. glabra. Differential expression analysis revealed that during thorn-hardening, 1045 genes up-regulated and 391 genes down-regulated significantly in thorns at stage 2 compared to stage 1 (early stage of thorns formation). Meanwhile, 938 genes up-regulated and 784 genes down-regulated significantly in stems. At stage 3, as thorns became harder, 63 genes exhibited notable expression increase and 98 genes' expression decreased obviously within thorns, and 46 genes up-regulated and 29 genes down-regulated in stems, compared to stage 2. Phenylpropanoid biosynthesis was the key step in the hardening process of the thorns of B. glabra. The formation and hardening of thorns on the stem of B. glabra was a process in which lignin gradually accumulated in the thorns, and several genes were involved in this process. They include PAL (EC:4.3.1.24), CYP73A (EC:1.14.14.91), 4CL (EC:6.2.1.12), CCR (EC:1.2.1.44), CAD (EC:1.1.1.195) and POX (EC:1.11.1.7). Discussion: This transcriptome analysis offers insights into the molecular mechanisms underlying thorns development in this plant species.

Uniform graft-versus-host disease prophylaxis using post-transplantation cyclophosphamide, methotrexate, and cyclosporine following peripheral blood hematopoietic stem cell transplantation from matched and haploidentical donors for transfusion-dependent thalassemia: a retrospective report from the BMF-WG of Hunan province, China.

BACKGROUND: Although the survival of patients with transfusion-dependent thalassemia (TD-TM) is reportedly inferior after haploidentical transplantation, the heterogeneity of transplantation approaches in studies suggests the need to assess the effect of one given conditioning regimen on matched and haploidentical transplantation outcomes. OBJECTIVE: A novel PTCy-based approach for patients with TD-TM undergoing haploidentical HSCT was reported in our prior study. We aimed to retrospectively evaluate the real-world efficacy and safety of GvHD prophylaxis in patients with TD-TM after HSCT from matched donors and haploidentical donors (HIDs). STUDY DESIGN: This was a retrospective multicenter study. Of 238 patients with TD-TM who underwent HSCT, 160 underwent peripheral blood HSCT, using uniform GvHD prophylaxis with PTCy, methotrexate, and cyclosporine, at member centers of the Bone Marrow Failure Working Group of Hunan Province between 2019 and 2023. RESULTS: The median age of the cohort was 6 years (95% confidence interval [CI], 6-7 years) at transplantation. Of 160 donors, 99 (61.9%) were haploidentical family members, and the others were matched donors (13 matched siblings, 48 matched or mismatched unrelated donors). The engraftment rate was 98.8% (95% CI: 96.1%-97.7%). HSCT from HIDs had a lower risk of mixed chimerism (HR 0·078, p=0.022). Within 100 days after transplantation, 31 patients (19.6%, 95% CI: 14.0%-26.3%) had grade II-IV acute GvHD, 9 of whom had grade III-IV acute GvHD (5.7%, 95% CI: 2.9%-10.1%). HIDs were significantly associated with a higher risk of grade II-IV acute GvHD (HR 3.973, p = 0.009). Nineteen patients (11.9%, 95% CI: 7.6%-17.6%) developed late acute GvHD after a median of 516 days (95% CI: 407-709 days). Twenty-six patients (16.5%, 95% CI: 11.3%-22.8%) exhibited any one of the diagnostic, distinctive, or atypical features of chronic GvHD according to the 2014 NIH criteria after a median of 690 days (95% CI: 496-902 days). Among these, 7 had NIH-defined chronic GvHD, 14 had only one distinctive sign with no histological evidence, and 5 had only atypical chronic GvHD signs. Of the 26 patients, 5 were classified as having overlap syndrome. Of 21 patients who were classified as having NIH-defined and potential chronic GvHD, 3 had moderate chronic GvHD, whereas 1 had severe chronic GvHD. Logistic regression analyses identified that grade II-IV acute GvHD independently predicted subsequent chronic GVHD (HR 3.920, p=0.006). The rates of chronic GvHD were similar between the matched and HID groups. Thalassemia-free survival (TFS) and event-free survival (EFS) were 97.5% (95% CI: 94.2%-99.2%) and 90.6% (95% CI: 85.4%-94.4%), respectively, after a median of 690 days (95% CI: 496-902 days). TFS rates were similar between the matched and HID groups (p = 0.549). The EFS rate was significantly higher in the matched group than in the HID group (p = 0.033). CONCLUSIONS: Our study suggests that when PTCy-based uniform GVHD prophylaxis is administered, HSCT from matched donors and HIDs results in a low incidence of severe GVHD and treatment-related mortality with satisfactory survival.

[3D interactive clipping technology in medical image processing].

The aim of this paper is to study the methods of 3D visualization and the 3D interactive clipping of CT/MRI image sequence in arbitrary orientation based on the Visualization Toolkit (VTK). A new method for 3D CT/MRI reconstructed image clipping is presented, which can clip 3D object and 3D space of medical image sequence to observe the inner structure using 3D widget for manipulating an infinite plane. Experiment results show that the proposed method can implement 3D interactive clipping of medical image effectively and get satisfied results with good quality in short time.

Alternative Transplantation With Post-Transplantation Cyclophosphamide in Aplastic Anemia: A Retrospective Report From the BMF-WG of Hunan Province, China.

Although the possibility of first-line hematopoietic cell transplantation (HCT) from alternative donors in severe aplastic anemia (SAA) patients has been suggested recently, transplantation strategies are still being investigated. We established a novel post-transplantation cyclophosphamide-based HCT protocol for patients with SAA in prior studies. We explores the effectiveness and safety of this HCT approach either as first-line or as salvage treatment in SAA patients. Outcomes of 71 consecutive young patients, who received HCT from unrelated or haploidentical donors, were retrospectively analyzed. According to their treatment before transplantation, the patients were classified into treatment-naive (TN) and relapsed or refractory (R/R) patients. The R/R patients were designated as such when a patient did not respond to previous immunosuppressive therapy or relapsed. We administered an antithymocyte globulin (ATG)-free, total body irradiation (TBI)-free conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine, all in an intravenous formula. We used a thorough post-transplantation prophylaxis regimen for GVHD, including post-transplantation cyclophosphamide (PTCy) and short-term methotrexate and long-term cyclosporine A. The median age of the cohort was 16 (95% confidence interval, 12-20) years at transplantation. Most patients (61 of 71) received HCT from haploidentical donors, and the others received HCT from unrelated donors. TN patients (n = 38) were younger and had a shorter time-to-transplant and lower HCT-specific comorbidity index than patients with R/R diseases (n = 33). The frequencies of graft failure, grade II-IV acute graft-versus-host disease (GVHD), and moderate-severe chronic GVHD were similar, at 5.3% versus 6.5% (P = .057), 8.3% versus 0% (P = .109), and 5.7% versus 0% (P = .199) between R/R and TN patients. With a median 42-month follow-up, the frequencies of overall survival (OS) and event-free survival (EFS) were higher in the TN group than in the R/R group (100% versus 84.8% [P = .013] and 86.8% versus 75.8% [P = .255], respectively). All patients who achieved successful engraftment showed full donor chimerism. Four patients, all in the R/R group, suffered from donor-type aplasia; of these, 2 died, 1 was salvaged with another transplantation, and the final one was still receiving transfusion at the last follow-up. Currently, 93.9% (62 of 66) of the patients are alive more than 12 months after transplantation; of these 93.5% (58 of 62) no longer receive immunosuppression, including 91.7% (33 of 34) of the TN group and 89.3% (25 of 28) in the R/R group. This novel TBI-free and ATG-free HCT protocol using a reduced-intensity conditioning regimen followed by modified PTCy achieved promising engraftment, minimal GVHD risk, and encouraging OS and EFS. Our study suggests that unrelated or haploidentical HCT with PTCy can be used as a first-line treatment for young patients with SAA. Nevertheless, further efforts are needed to explore possibilities for older patients and patients with a poor performance status.

A Pan-Cancer Analysis of Clinical Prognosis and Immune Infiltration of CKS1B in Human Tumors.

Although more and more evidence supports CDC28 protein kinase subunit 1B (CKS1B) is involved significantly in the development of human cancers, most of the researches have focused on a single disease, and pan-cancer studies conducted from a holistic perspective of different tumor sources have not been reported yet. Here, for the first time, we investigated the potential oncogenic and prognostic role of CKS1B across 33 tumors based on public databases and further verified it in a small scale by RNA sequencing or quantitative real-time PCR. CKS1B was generally highly expressed in a majority of tumors and had a notable correlation with the prognosis of patients, but its prognostic significance in different tumors was not exactly the same. In addition, CKS1B expression was also closely related to the infiltration of cancer-associated fibroblasts in tumors such as breast invasive carcinoma, kidney chromophobe, lung adenocarcinoma, and tumor-infiltrating lymphocytes in tumors such as glioblastoma multiforme, bladder urothelial carcinoma, and brain lower grade glioma. Moreover, reduced CKS1B methylation was observed in certain tumors, for example, adrenocortical carcinoma. Cell cycle and kinase activity regulation and PI3K-Akt signaling pathway were found to be involved in the functional mechanism of CKS1B. In conclusion, our first pan-cancer analysis of CKS1B contributes to a better overall understanding of CKS1B and may provide a new target for future cancer therapy.

Haploidentical Peripheral Stem Cell Transplantation for Young Patients with Severe Aplastic Anemia Using Post-Transplantation Cyclophosphamide and Methotrexate.

Severe aplastic anemia (SAA) is a serious bone marrow failure disorder that is often cured with hematopoietic stem cell transplantation (HSCT). The absence of a matched related donor is common, however, and thus novel approaches are needed to safely expand the donor pool to include alternative donors, especially haploidentical related donors, for patients with SAA. This study aimed to explore a novel approach to HSCT for patients with SAA without an available HLA-identical sibling or a matched unrelated donor, termed haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), using a conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine (CBF) and a graft-versus-host disease (GVHD) prophylaxis regimen with post-transplantation cyclophosphamide (PTCy), low-dose methotrexate (LD-MTX), and calcineurin inhibitors. This prospectively designed nonrandomized study included 29 patients with SAA who underwent haplo-PBSCT between November 2017 and May 2020. The median patient age was 17 years (range, 14 to 30 years), and the median time to neutrophil recovery was 13 days (range, 13 to 15 days). There was 1 primary graft failure (GF) in the group receiving PTCy at a dose of 50 mg/kg and no GFs in the group receiving PTCy at a dose of 100 mg/kg. The median duration of follow-up was 736 days (95% confidence interval, 512 to 879 days). The estimated 1-year overall survival and disease-free survival were 91.7 ± 5.7% and 89.7 ± 5.7%, respectively. Only 1 of the 27 patients developed grade II acute GVHD. Four patients developed limited and mild chronic GVHD, involving only the skin or/and oral mucosa. Haplo-PBSCT following CBF and followed by PTCy and LD-MTX represents a novel approach for safely expanding the donor pool to include alternative donors for young patients with SAA.

Viburnumfocesides A - D, 1-O-isovaleroylated iridoid 11-O-alloside derivatives from Viburnum foetidum var. ceanothoides.

Viburnumfocesides A - D, four undescribed 1-O-isovaleroylated iridoid 11-O-allosides modified with (Z / E)-p-coumaric acid, were isolated from the aqueous EtOH extract of the twigs of Viburnum foetidum var. ceanothoides, together with seven known natural products. Their structures were identified on the basis of the spectroscopic data interpretation and chemical derivation studies. Cell-based estrogen biosynthesis assays indicated that viburnumfoceside D (4), (2S,3R)-2,3-dihydro-3-hydroxymethyl-7-methoxy-2-(4-hydroxy-3-methoxyphenyl)-5-benzofuranpropanol-3a-O-α-L-rhamnopyranoside (8), and (-)-eriodictyol (11) inhibit estrogen biosynthesis with IC50 values of 5.8, 1.5, and 1.1 µM, respectively, in human ovarian granulosa-like KGN cells via decreasing the expression level of aromatase.