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In order to prepare metallographic samples that accurately characterize the true state of the analyzed samples and evaluate the microstructure of the coating precisely, taking nano-zirconia coating as the research object, metallographic samples were prepared by using different inlaying methods. The influence of different grinding and polishing process parameters on the microstructure evaluation of the coatings based on orthogonal tests was investigated, and the results were verified by measuring the porosity of coatings through the nano-CT method. Results showed that the method of vacuum cold inlay could significantly reduce the phenomenon of coating particle detachment. The factors affecting the porosity of the coating in order of magnitude were the number of revolutions of the grinding disc during rough grinding, the number of fixture revolutions during rough grinding, the polishing time during rough polishing and the pressure during grinding and rough polishing. The optimized parameters for the grinding and polishing process were 15 N pressure for grinding and rough polishing, 200 r/min for the grinding disc during rough grinding, 50 r/min for the fixture during rough grinding, and 9 min for rough polishing. The porosity of the coating under this process was 4.26%, which significantly reduced the phenomenon of shedding of coating particles and allowed the preparation of metallographic samples that reflected the true microstructure of the coating, thereby achieving the goal of accurately evaluating the performance of the coating. The results obtained by the nano-CT method were consistent with the present method.

Background: Acute myeloid leukaemia (AML) comprises a group of heterogeneous and aggressive haematological malignancies with unsatisfactory prognoses and limited treatment options. Treatments targeting B-cell lymphoma-2 (BCL-2) with venetoclax have been approved for patients with AML, and venetoclax-based drug combinations are becoming the standard of care for older patients unfit for intensive chemotherapy. However, the therapeutic duration of either single or combination strategies is limited, and the development of resistance seems inevitable. Therefore, more effective combination regimens are urgently needed. Methods: The efficacy of combination therapy with NL101, a SAHA-bendamustine hybrid, and venetoclax was evaluated in preclinical models of AML including established cell lines, primary blasts from patients, and animal models. RNA-sequencing and immunoblotting were used to explore the underlying mechanism. Results: NL101 significantly potentiated the activity of venetoclax in AML cell lines, as evidenced by the enhanced decrease in viability and induction of apoptosis. Mechanistically, the addition of NL101 to venetoclax decreased the stability of the antiapoptotic protein myeloid cell leukaemia-1 (MCL-1) by inhibiting ERK, thereby facilitating the release of BIM and triggering mitochondrial apoptosis. Moreover, the strong synergy between NL101 and venetoclax also relied on the downregulation of c-Myc via PI3K/Akt/GSK3β signalling. The combination of NL101 and venetoclax synergistically eliminated primary blasts from 10 AML patients and reduced the leukaemia burden in an MV4-11 cell-derived xenograft model. Conclusions: Our results encourage the pursuit of clinical trials of combined treatment with NL101 and venetoclax and provide a novel venetoclax-incorporating therapeutic strategy for AML. [ABSTRACT FROM AUTHOR]

Summary: A chemotherapy‐based mobilization regimen in patients who mobilize poorly, based on etoposide, cytarabine and pegfilgrastim (EAP), has recently been introduced. The aim of this prospective study was to investigate the efficacy and safety of the EAP regimen in patients with poorly mobilizing multiple myeloma (MM) or lymphoma. This single‐arm clinical trial was performed at eight public hospitals in China and was registered as a clinical trial (NCT05510089). The inclusion criteria were; (1) diagnosis of MM or lymphoma, (2) defined as a 'poor mobilizer' and (3) aged 18–75 years. The EAP regimen consisted of etoposide 75 mg/m2/day on days 1–2, cytarabine 300 mg/m2 every 12 h on days 1–2 and pegfilgrastim 6 mg on day 6. The primary endpoint of the study was the ratio of patients achieving adequate mobilization (≥2.0 × 106 CD34+ cells/kg). From 1 September 2022 to 15 August 2023, a total of 58 patients were enrolled, 53 (91.4%) achieved adequate mobilization, while 41 (70.7%) achieved optimal mobilization with a median number of cumulative collected CD34+ cells was 9.2 (range 2.1–92.7) × 106/kg and the median number of apheresis per patient of 1.2. The median time from administration of the EAP regimen to the first apheresis was 12 days. Approximately 8.6% of patients required plerixa for rescue, which was successful. Twelve (20.7%) of the 58 patients suffered grade 2–3 infections, while 25 (43.1%) required platelet transfusions. The duration of neutrophil and platelet engraftment was 11 days. In conclusion, these results suggest that the EAP mobilization regimen might be a promising option for poorly mobilizing patients with MM or lymphoma. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy (DN) is a common neurological complication caused by diabetes mellitus (DM). Axonal degeneration is generally accepted to be the major pathological change in peripheral DN. Taurine has been evidenced to be neuroprotective in various aspects, but its effect on spinal cord axon injury (SCAI) in DN remains barely reported. This study showed that taurine significantly ameliorated axonal damage of spinal cord (SC), based on morphological and functional analyses, in a rat model of DN induced by streptozotocin (STZ). Taurine was also found to induce neurite outgrowth in cultured cerebral cortex neurons with high glucose exposure. Moreover, taurine up-regulated the expression of nerve growth factor (NGF) and neurite outgrowth relative protein GAP-43 in rat DN model and cultured cortical neurons/VSC4.1 cells. Besides, taurine increased the activating phosphorylation signals of TrkA, Akt, and mTOR. Mechanistically, the neuroprotection by taurine was related to the NGF–pAKT–mTOR axis, because either NGF-neutralizing antibody or Akt or mTOR inhibitors was found to attenuate its beneficial effects. Together, our results demonstrated that taurine promotes spinal cord axon repair in a model of SCAI in STZ-induced diabetic rats, mechanistically associating with the NGF-dependent activation of Akt/mTOR pathway. [ABSTRACT FROM AUTHOR]

Post-transplantation cyclophosphamide (PTCy) can reduce the incidence of graft versus host disease (GVHD) and this intervention is often applied on adults with hematologic malignancy. However, the high relapse rate hinders the development of the intervention and data of PTCy used on children with hematologic malignancy remains limited. In order to overcome issue of high relapse rate in PTCy treatment, we used fludarabine (Flu), enhanced dose of cytarabine (Ara-C, 9 g/m2), busulfan (Bu), Cy, anti-thymocyte globulin (ATG) combined with PTCy for an intensified conditioning regimen. A total of 22 children with acute leukemia received intensified PTCy conditioning regimen (PTCy intensified group). We matched with 18 children who received modified Bu-Cy and ATG conditioning regimen in the same period (ATG group). The two-year cumulative incidences of grade II–IV acute GVHD was significantly lower in PTCy intensified group (13.6 ± 7.7% vs 38.9 ± 11.5%, P = 0.048). Two-year GVHD-free relapse free survival (GRFS) in PTCy seems to be better among the increment group despite not being significant (63.3 ± 10.3% vs 35.4 ± 11.9%, P = 0.092). The positive rate of minimal residual disease after transplantation was significantly lower than that before transplantation (20.0% vs 2.5%, P = 0.029). In conclusion, ATG and PTCy combined with Flu-based increased intensity conditioning regimen is effective for acute leukemia in children. It could reduce GVHD rate significantly and potentially improve GRFS. [ABSTRACT FROM AUTHOR]

Objective: Mounting evidence has linked microbiome and metabolome to systemic autoimmunity and cardiovascular diseases (CVDs). Takayasu arteritis (TAK) is a rare disease that shares features of immune‐related inflammatory diseases and CVDs, about which there is relatively limited information. This study was undertaken to characterize gut microbial dysbiosis and its crosstalk with phenotypes in TAK. Methods: To address the discriminatory signatures, we performed shotgun sequencing of fecal metagenome across a discovery cohort (n = 97) and an independent validation cohort (n = 75) including TAK patients, healthy controls, and controls with Behçet's disease (BD). Interrogation of untargeted metabolomics and lipidomics profiling of plasma and fecal samples were also used to refine features mediating associations between microorganisms and TAK phenotypes. Results: A combined model of bacterial species, including unclassified Escherichia, Veillonella parvula, Streptococcus parasanguinis, Dorea formicigenerans, Bifidobacterium adolescentis, Lachnospiraceae bacterium 7 1 58FAA, Escherichia coli, Streptococcus salivarius, Klebsiella pneumoniae, Bifidobacterium longum, and Lachnospiraceae Bacterium 5 1 63FAA, distinguished TAK patients from controls with areas under the curve (AUCs) of 87.8%, 85.9%, 81.1%, and 71.1% in training, test, and validation sets including healthy or BD controls, respectively. Diagnostic species were directly or indirectly (via metabolites or lipids) correlated with TAK phenotypes of vascular involvement, inflammation, discharge medication, and prognosis. External validation against publicly metagenomic studies (n = 184) on hypertension, atrial fibrillation, and healthy controls, confirmed the diagnostic accuracy of the model for TAK. Conclusion: This study first identifies the discriminatory gut microbes in TAK. Dysbiotic microbes are also linked to TAK phenotypes directly or indirectly via metabolic and lipid modules. Further explorations of the microbiome–metagenome interface in TAK subtype prediction and pathogenesis are suggested. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported a strong association between gut microbiome and hypertension; yet, the exact bacterial species associated with the disease development and progression have not yet been detected. This study aimed to investigate whether opportunistic pathogen Klebsiella pneumoniae is a causal factor for hypertension pathogenesis, and explore the potential mechanisms.Methods: The enrichment of Klebsiella pneumoniae in the gut of patients with hypertension was validated by meta-analysis based on 3 independent cohorts. Klebsiella pneumoniae was inoculated into germ-free mice, antibiotic pretreated and conventional mice.Results: Klebsiella pneumoniae led to higher blood pressure, slight cardiac hypertrophy, and enhanced contractility of resistant arteries in recipient mice. Moreover, Klebsiella pneumoniae induced pathological damages, deficiency of tight junction proteins and transcriptional shifts. Metabolic alterations, especially the depletion of stearoylethanolamide, were observed upon Klebsiella pneumoniae administration. In addition, renal transcriptome dysfunction with significant upregulation of genes related to hypertension pathogenesis was observed in Klebsiella pneumoniae treated mice.Conclusions: These results provide evidence that the enrichment of Klebsiella pneumoniae acts as a direct contributor to blood pressure elevation and hypertension pathogenesis, and Klebsiella pneumoniae induced intestinal damages, fecal metabolic changes, and renal shifts may be integrated mediators. [ABSTRACT FROM AUTHOR]

Treatment of resistant or recurrent acute lymphoblastic leukemia (ALL) remains a challenge. It was previously demonstrated that the adhesion molecule integrin α4, referred to hereafter as α4, mediates the cell adhesion-mediated drug resistance (CAM-DR) of B-cell ALL by binding to vascular cell adhesion molecule-1 (VCAM-1) on bone marrow stroma. In addition, it was previously observed that the blockade of α4 with natalizumab or inhibition using the small molecule antagonist TBC3486 sensitized relapsed ALL cells to chemotherapy. However, α4-targeted therapy is not clinically available for the treatment of leukemia to date. In the present study, the use of a novel non-peptidic small molecule integrin α4 antagonist, AVA4746, as a potential new approach to combat drug-resistant B-ALL was explored. An in vitro co-culture = model of primary B-ALL cells and an in vivo xenograft model of patient-derived B-ALL cells were utilized for evaluation of AVA4746. VLA-4 conformation activation, cell adhesion/de-adhesion, endothelial tube formation, in vivo leukemia cell mobilization and survival assays were performed. AVA4746 exhibited high affinity for binding to B-ALL cells, where it also efficiently blocked ligand-binding to VCAM-1. In addition, AVA4746 caused the functional de-adhesion of primary B-ALL cells from VCAM-1. Inhibition of α4 using AVA4746 also prevented angiogenesis in vitro and when applied in combination with chemotherapy consisting of Vincristine, Dexamethasone and L-asparaginase, it prolonged the survival of ~33% of the mice in an in vivo xenograft model of B-ALL. These data implicate the potential of targeting the α4-VCAM-1 interaction using AVA4746 for the treatment of drug-resistant B-lineage ALL. [ABSTRACT FROM AUTHOR]

Granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells have become the preferred source of hematopoietic stem cells. We compared the effectiveness of G-CSF and pegylated G-CSF (peg-G-CSF) for hematopoietic stem cell mobilization in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) donors, and evaluated the transplant outcomes. We conducted a matched retrospective cohort study. Donors mobilized with peg-G-CSF (n = 70) and G-CSF (n = 70). 140 consecutive patients diagnosed with acute leukemia who underwent haplo-HSCT were included in this study. The findings revealed that the peg-G-CSF cohort exhibited significantly elevated myeloid-derived suppressor cells (MDSCs) levels in their grafts when compared to the G-CSF cohort (P < 0.001). The 100-day cumulative incidence (CI) of grade III-IV acute graft-versus-host disease (GVHD) and 1-year CI of moderate-to-severe chronic GVHD were 4.3% vs 14.3 % (P = 0.047) and 11.2% vs 27.4 % (P = 0.023), in the peg-G-CSF group and G-CSF group. Patients reveiving mobilized stem cell with peg-G-CSF had a significantly greater likelihood of 1-year GVHD-free relapse-free survival (GRFS) compared to patients reveiving mobilized stem cell with G-CSF (74.9% vs 37.9 %, P < 0.001). The higher graft MDSCs proportion was associated with lower grade II-IV aGVHD, cGVHD (P < 0.05) and higher GRFS in the univariate analysis (P < 0.05). Multivariate analysis showed that MDSCs proportion higher than 11.36 % (HR, 0.305; 95 % CI, 0.154-0.606; P = 0.001) and peg-G-CSF for stem cell mobilization (HR, 0.466; 95 % CI, 0.251-0.865; P = 0.016) were independent prognostic factors of GRFS. The superior survival rates observed in recipients of peg-G-CSF-mobilized cells are likely due to reduced acute GVHD, potentially mediated by the increased MDSCs within the grafts., Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

[Purpose] To determine the optimal Tuina rolling manipulation parameters for improving peripheral blood circulation and to observe the duration of these effects. [Participants and Methods] A total of 162 healthy males and 20 males with coronary heart disease were recruited, with a mean age of 29.5 ± 6.4 years. The change in blood flow was used as the observation index, and the best combination of parameters was selected using a cyclic orthogonal experiment. We observed changes in rolling manipulation across different time periods and groups. [Results] There were significant interactions between pressure, frequency and duration in the rolling manipulation. The combination mode of 4 kg, 120 repetitions/min and 10 min is the most effective to improve the average blood flow increase rate of popliteal artery. At 15 minutes after manipulation, different degrees of significant increase were observed, but 20 minutes after manipulation, the average blood flow rate returned to the premanipulation level. There was no difference in blood flow rate between healthy males and coronary heart disease patients. [Conclusion] An effective dynamic model of rolling manipulation was constructed. These results contradicted the idea that more pressure and longer continuous manipulation led to stronger effects. The effect of rolling manipulation on improving peripheral circulation can be maintained for 20 minutes., Competing Interests: There are no conflicts of interest related to this study to disclose., (2024©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Myeloid-derived suppressor cells (MDSC) are powerful immunomodulatory cells that play an important role in infectious and inflammatory disorders, but the correlation between graft MDSC amount and early transplant outcomes remains unknown in allogeneic hematopoietic stem cell transplantation. We collected data from 91 patients with acute leukemia undergoing haploidentical allogeneic hematopoietic stem cell transplantation. The grafts were analyzed in terms of CD34+ cells, CD3+ T cells and subpopulation, and MDSC (HLA-DR -/low CD33 + CD16 - ) by flow cytometry. The cutoff value of the MDSC proportion in the graft on the receiver operating curve was 8.89%, with a sensitivity of 0.833 and specificity of 0.852. Day +100 cumulative incidences of II-IV and III-IV acute graft-versus-host disease (aGVHD) in the low MDSC group were 73.5% and 38.8%, respectively, and that in the high MDSC group were 5.3% and 0%, with a significant difference in incidences of II-IV and III-IV aGVHD ( P <0.001). The overall survival, relapse-free survival, and GVHD-relapse-free survival (GRFS) at 1 year were 66.3% versus 80.5% ( P =0.043), 71.6% versus 71.7% ( P =0.248), and 22.1% versus 62.8% ( P <0.001), respectively. No significant difference in the cumulative incidence of relapse between the 2 groups was observed. Multivariate analysis revealed that higher MDSC proportions were associated with a lower risk of II-IV aGVHD. Graft MDSC proportion exceeding 8.89% was significantly associated with higher overall survival and GRFS. The prophylaxis of antithymocyte globulin+post-transplant cyclophosphamide and higher MDSC proportion in the graft were favorable factors for improving GRFS. In conclusion, graft MDSC proportion may be a significant predictor of aGVHD., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, whose known drug treatments are limited and expensive., Objective: This investigation aimed to investigate the therapeutic potential of anlotinib in B-cell acute lymphoblastic leukemia (B-ALL)., Methods: The B-ALL cell lines Nalm-6 and BALL-1 were used to verify the therapeutic potential of anlotinib in BALL. The cell activity was measured by Cell Counting Kit-8. Apoptosis was detected by Annexin V-FITC/PI double staining combined with flow cytometry. Afterward, the binding capacity of anlotinib to the critical protein was predicted by molecular docking, and the protein changes in the related pathways downstream of the target proteins were verified by western blot. Finally, the effect of anlotinib on the survival rate was verified in B-ALL nude mice., Results: Anlotinib inhibited the proliferation of the B-ALL cell lines, Nalm-6, and BALL-1, and promoted apoptosis. Molecular docking results showed that it had the potential binding ability to BTK. Western blot revealed that anlotinib was able to inhibit the phosphorylation of BTK, AKT, and mTOR, thereby inhibiting the proliferation of B-ALL cells. In addition, anlotinib suppressed weight loss and prolonged the survival time of mice., Conclusion: To summarize, anlotinib can inhibit the proliferation of B-ALL and promotes apoptosis by inhibiting the phosphorylation of BTK and AKT, and mTOR., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Patients underwent peroral endoscopic myotomy (POEM) for treating achalasia suffered with mild to moderate, sometimes even severe postoperative pain., Aim: To evaluate the efficacy of oxycodone on postoperative analgesia of patients undergoing PEOM., Material and Methods: In this prospective, double-blinded, randomized, controlled trial, patients with achalasia were recruited and received 0.08 mg/kg oxycodone or morphine 15 min before the end of the POEM procedure. The short-form McGill questionnaire (SF-MPQ) was used to measure the postoperative pain at 0, 2, 6, 24, and 48 h after surgery, which included the visual analogue scale (VAS), the present pain intensity (PPI) scale, and the pain rating index (PRI)., Results: A total of 73 patients were included, of whom 36 received oxycodone, and 37 received morphine. Compared with morphine, patients received oxycodone were associated with lower VAS in the first 24 h postoperatively (1.64 ±0.76 vs. 2.14 ±1.23, p = 0.042) as well as PPI at 2 h (1.11 ±0.40 vs. 2.22 ±0.89, p < 0.001), 6 h (1.42 ±0.55 vs. 2.08 ±0.92, p < 0.001) and 24 h (1.06 ±0.23 vs. 1.30 ±0.46, p = 0.006). Patients who received oxycodone experienced lower sensory McGill pain score than those who received morphine at 2, 6, 24, and 48 h after surgery (p < 0.05). Significantly lowered affective McGill pain score was observed in the oxycodone group at 0, 2, and 24 h postoperatively. Regarding the PRI, the sum of both sensory and affective McGill pain scores, patients with oxycodone therapy were associated with better scores postoperatively., Conclusions: Oxycodone appears to be superior to morphine in dealing with post-POEM pain, which has distinct visceral pain characteristics., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 Fundacja Videochirurgii.)