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Background: N-hexane, with its metabolite 2,5-hexanedine (HD), is an industrial hazardous material. Chronic hexane exposure causes segmental demyelination in the peripheral nerves, and high-dose intoxication may also affect central nervous system. Demyelinating conditions are difficult to treat and stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising novel strategy. Our previous study found that BMSCs promoted motor function recovery in rats modeling hexane neurotoxicity. This work aimed to explore the underlying mechanisms and focused on the changes in spinal cord. Methods: Sprague Dawley rats were intoxicated with HD (400 mg/kg/day, i.p, for 5 weeks). A bolus of BMSCs (5 × 107 cells/kg) was injected via tail vein. Demyelination and remyelination of the spinal cord before and after BMSC treatment were examined microscopically. Cultured oligodendrocyte progenitor cells (OPCs) were incubated with HD ± BMSC-derived conditional medium (BMSC-CM). OPC differentiation was studied by immunostaining and morphometric analysis. The expressional changes of Hes1, a transcription factor negatively regulating OPC-differentiation, were studied. The upstream Notch1 and TNFα/RelB pathways were studied, and some key signaling molecules were measured. The correlation between neurotrophin NGF and TNFα was also investigated. Statistical significance was evaluated using one-way ANOVA and performed using SPSS 13.0. Results: The demyelinating damage by HD and remyelination by BMSCs were evidenced by electron microscopy, LFB staining and NG2/MBP immunohistochemistry. In vitro cultured OPCs showed more differentiation after incubation with BMSC-CM. Hes1 expression was found to be significantly increased by HD and decreased by BMSC or BMSC-CM. The change of Hes1 was found, however, independent of Notch1 activation, but dependent on TNFα/RelB signaling. HD was found to increase TNFα, RelB and Hes1 expression, and BMSCs were found to have the opposite effect. Addition of recombinant TNFα to OPCs or RelB overexpression similarly caused upregulation of Hes1 expression. The secretion of NGF by BMSC and activation of NGF receptor was found important for suppression of TNFα production in OPCs. Conclusions: Our findings demonstrated that BMSCs promote remyelination in the spinal cord of HD-exposed rats via TNFα/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease. [ABSTRACT FROM AUTHOR]

• Detection and quantification of EAs, PAs, and TAs was developed by LC-MS/MS. • Sample preparation based on QuEChERS method was developed. • The method was validated and applied to 134 forage grasses. • There are marked differences in frequency of contamination among herbage species. • The frequency of contamination varies significantly between different regions. The toxic alkaloids in forage grass present a serious health hazard to humans and livestock, especially ergot alkaloids (EAs), pyrrolizidine alkaloids (PAs) and tropane alkaloids (TAs). Hence, there is a need for a simultaneous method that allows these dangerous plant toxins to be determined. A simple and effective method was developed to determine fifteen toxic alkaloids (EAs, PAs and TAs) in forage grass using the QuEChERS method and liquid chromatography tandem mass spectrometry (LC-MS/MS). The developed method was validated with average recoveries ranging from 63.10 to 102.10%, and relative standard deviations lower than or equal to 6.39% were obtained. Good linearity over the concentration range of 10-600 µg/kg dry matter (DM) was observed for the target alkaloids. The determination coefficients R2 calculated for each of the matrix calibration curves were greater than 0.99. The limits of detection and quantification were 5 µg/kg DM and 10 µg/kg DM, respectively. The reproducibility of the method was verified in three laboratories: all of the mean recoveries of 15 alkaloids were higher than 60%, and the relative standard deviations in alkaloids between laboratories were all less than 14.24%. The proposed method was applied to analyse 134 forage grass samples from the meadow steppe of Inner Mongolia to monitor toxic alkaloids. A significant difference in the frequency of contamination was found between different herbage species and different regions. [ABSTRACT FROM AUTHOR]

Vascular smooth muscle cell (VSMC) phenotypic switch plays an essential role in the pathogenesis of hypertension. Mitochondrial dynamics, such as mitochondrial fission, can also contribute to VSMC phenotypic switch. Whether mitochondrial fission act as a novel target for anti-hypertensive drug development remains unknown. In the present study, we confirmed that angiotensin II (AngII) rapidly and continuously induced mitochondrial fission in VSMCs. We also detected the phosphorylation status of dynamin-related protein-1 (Drp1), a key protein involved in mitochondrial fission, at Ser616 site; and observed Drp1 mitochondrial translocation in VSMCs or arteries of AngII-induced hypertensive mice. The Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) dramatically reversed AngII-induced Drp1 phosphorylation, mitochondrial fission, and reactive oxidative species generation. Treatment with Mdivi-1 (20 mg/kg/every other day) significantly attenuated AngII-induced hypertension (22 mmHg), arterial remodeling, and cardiac hypertrophy, in part by preventing VSMC phenotypic switch. In addition, Mdivi-1 treatment was not associated with liver or renal functional injury. Collectively, these results indicate that Mdivi-1 inhibited mitochondrial fission, recovered mitochondrial activity, and prevented AngII-induced VSMC phenotypic switch, resulting in reduced hypertension. [Display omitted] • Mitochondria fission is an integrated part in AngII-triggered VSMCs phenotypic switch. • AngII promotes Drp1 phosphorylation at Ser616, and Drp1 mitochondrial translocation. • Mdivi-1 supplementation inhibited AngII-induced VSMCs phenotypic switch, then attenuation hypertension. [ABSTRACT FROM AUTHOR]

Abstract: Culture of human hepatocarcinoma cells in three-dimensional structure or spheroid represents a unique opportunity to recapitulate aspects of cell homeostasis and to better reflect the characteristics of native hepatic tumor. In this paper, human hepatocarcinoma SMMC-7721 cells were encapsulated in alginate-poly-l-lysine-alginate (APA) microcapsules and the behavior of the cells in the restricted three-dimensional culture system was investigated. The cells were polygonal-shaped, proliferating with high viability, and formed a single multicellular spheroid in microcapsule. During the assembly of the aggregate in microcapsule, cytoskeletal reorganization and repolorization was occurred, which was absent in cells cultured in monolayer. The in vivo-like cytoarchitecture was confirmed by the phalloidin–FITC labeling of F-actin filaments. The trabecular structure revealed by scanning electron microscope (SEM), and the bile canaliculus with multiple microvilli and tight junctions revealed by transmission electron microscope (TEM) was found in microencapsulated cells, which exhibited the ultrastructural characteristics of native hepatic tissue. It suggested that microcapsule culture provides an in vivo-like model which can be used for the study of the interactions of cell–cell and cell–microenvironment, and the mechanisms of invasion, metastasis and multicellular drug resistance of tumor cells. [Copyright &y& Elsevier]

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]

Both epidemiological investigation and animal experiments demonstrated that pre-/postnatal exposure to perfluorooctane sulfonic acid (PFOS) could induce neurodevelopmental disorders. Previous studies showed that astrocyte was involved in PFOS-induced neurotoxicity, while little information is available. In the present study, the role of astrocyte-derived calmodulin-dependent protein kinase II (CaMKII)-phosphorylated discs large homolog 1 (DLG1) signaling in PFOS eliciting cytotoxicity in neuron was explored with primary cultured hippocampal astrocyte and neuron. The application of PFOS showed a decreased cell viability, synapse length and glutamate transporter 1 (GLT-1) expression, but an increased CaMKII, DLG1 and cyclic AMP response element binding protein (CREB) expression in primary cultured astrocyte. With 2-(2-hydroxyethylamino)-6-aminohexylcarbamic acid tert-butyl ester-9-isopropylpurine (CK59), the CaMKII inhibitor, the disturbed cell viability and molecules induced by PFOS could be alleviated (CREB expression was excluded) in astrocytes. The cytotoxic effect of neuron exposed to astrocyte conditional medium collected from PFOS (PFOS-ACM) pretreated with CK59 was also decreased. These results indicated that PFOS mediated GLT-1 expression through astrocyte-derived CaMKII-DLG signaling, which might be associated with injuries on neurons. The present study gave an insight in further exploration of mechanism in PFOS-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Background: Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (allo‐HSCT) with ABO major incompatibility is characterized by transfusion dependent anemia. No standard treatment existed for PRCA following allo‐HSCT yet. Study Design and Methods: We conducted a retrospective study, and reported our experience with the use of avatrombopag and lower dose rituximab to treat five patients with PRCA subsequent to major ABO‐incompatible allo‐HSCT. Results: Five cases of PRCA were identified from 72 patients who underwent allo‐HSCT with major or bidirectional ABO mismatch. Cumulative incidence at Day +60 was 6.9% (5/72) at our center. All donor and recipient blood groups were A+ and O+, respectively. In the first three cases we reported, patients received erythropoietin, plasma exchange, and donor lymphocyte infusion, but none of them had any effect. After 4 weeks of treatment with low dose rituximab (100 mg/week) combined with avatrombopag (40 mg/day), favorable outcomes were obtained. According to the aforementioned experience, Cases 4 and 5 were administered low‐dose rituximab and avatrombopag in 3 months after transplantation, and erythroid response was observed on 3 weeks after treatment. Our patients tolerated low‐dose rituximab and avatrombopag well and experienced rapid efficacy, with a median duration of 3 weeks. Furthermore, no severe infection or thrombocytosis necessitated a dose adjustment. Conclusion: Low‐dose rituximab and avatrombopag may be an effective treatment for patients with PRCA after major ABO‐incompatible allo‐HSCT. The patients should be treated at least 90 days post transplantation if conventional erythropoietin therapy fails. [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]

A single injection of 12 mg pegfilgrastim was used to mobilize peripheral blood progenitor cells (PBPCs) from healthy donors in some studies. The purpose of this study was to determine if 6 mg of pegfilgrastim was effective and safe for mobilizing CD34+ cells in donors for allogeneic hematopoietic stem cell transplantation. We conducted a retrospective case-matched design. A single dosage of 6 mg pegfilgrastim was used to mobilize PBPCs from 60 healthy donors. Granulocyte colony-stimulating factor (G-CSF, 10 μg/kg) was administered daily to the matched donors. Leukapheresis was scheduled to commence on day 4 of the mobilization regimen. The median yielded CD34+ cell in the pegfilgrastim group was higher than those in the G-CSF group, at 5.06 × 106/kg recipient weight. The 73.3% of donors mobilized with pegfilgrastim yielded >4 × 106 cells/kg CD34+ cells in a single apheresis procedure when compared to the 33.3% of donors mobilized with G-CSF (P < 0.001). The myeloid-derived suppressor cells (MDSC) proportion in the pegfilgrastim group was significantly higher than that in the G-CSF group (P < 0.001). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was higher in the G-CSF group than that in the pegfilgrastim group (26.7% vs. 11.7%), without statistical difference. In comparison to the G-CSF group, the pegfilgrastim group had a reduced median pain intensity numerical rating scale score (1 vs. 2). A single 6 mg dosage of pegfilgrastim is effective and safe for allogeneic PBPCs collection from healthy donors. Pegfilgrastim may decrease the incidence of aGVHD by boosting MDSCs, which need further investigation. [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]

Background and Purpose: Hydrogen sulfide donors can block the cardiovascular injury of hyperhomocysteinemia. H2 S also lowers serum homocysteine in rats with mild hyperhomocysteinemia, but the pharmacological mechanism is unknown. The present study investigated the mechanism(s) involved.Experimental Approach: ApoE-knockout mice were fed a Paigen diet and L-methionine in drinking water for 16 weeks to create a mouse model of atherosclerosis with hyperhomocysteinemia. H2 S donors (NaHS and GYY4137) were administered by intraperitoneal injection. We also assayed the H2 S produced (by methylene blue assay and mito-HS [H2 S fluorescence probe]), cystathionine γ lyase (CSE) mRNA and protein expression, and CSE sulfhydration and nitrosylation and its activity.Key Results: H2 S donor treatment significantly lowered atherosclerotic plaque area, macrophage infiltration, and serum homocysteine level in the mouse model of atherosclerosis with co-existing hyperhomocysteinemia. mRNA and protein levels of CSE, a key enzyme catalyzing homocysteine trans-sulfuration, were down-regulated with hyperhomocysteinemia, and CSE catalytic activity was inhibited. All these effects were reversed with H2 S donor treatment. Hyperhomocysteinemia induced CSE nitrosylation, whereas H2 S sulfhydrated CSE at the same cysteine residues. Nitrosylated CSE decreased and sulfhydrated CSE increased its catalytic and binding activities towards L-homocysteine. Mutation of C252, C255, C307, and C310 residues in CSE abolished CSE nitrosylation or sulfhydration and prevented its binding to L-homocysteine.Conclusions and Implications: Sulfhydration or nitrosylation of CSE represents a yin/yang regulation of catalysis or binding to L-homocysteine. H2 S donor treatment enhanced CSE sulfhydration, thus lowering serum L-homocysteine, which contributed in part to the anti-atherosclerosis effects in ApoE-knockout mice with hyperhomocysteinemia. [ABSTRACT FROM AUTHOR]

An optimal strategy for mobilizing hematopoietic stem cells in poorly mobilizing patients with multiple myeloma (MM) and lymphoma has not yet been determined. We retrospectively analyzed the efficacy and safety of etoposide combined with cytarabine (etoposide 75 mg/m2, daily d1∼2; Ara-C 300 mg/m2, every 12 h d1∼2), plus pegfilgrastim (6 mg d6) in 32 patients with MM or lymphoma, among whom 53.1% were defined as "proven poor mobilizers." This approach resulted in adequate mobilization (≥2.0 × 106 CD34+ cells/kg) in 93.8% of patients and optimal mobilization (≥5.0 × 106 CD34+ cells/kg) in 71.9% of patients. A total of 100% of patients with MM reached at least 5 × 106 CD34+ cells/kg collected, the amount required for double autologous stem cell transplant. In total, 88.2% of patients with lymphoma reached at least 2 × 106 CD34+ cells/kg collected, the amount required for a single autologous stem cell transplant. This was achieved with a single leukapheresis in 78.1% of cases. A median peak number of 42.0/μL circulating CD34+ cells and a median number of blood CD34+ cells counts in 6.7 × 106/L were collected among 30 successful mobilizers. Approximately 6.3% of patients required plerixafor rescue, which was successful. Nine (28.1%) of the 32 patients suffered grade 2∼3 infections, and 50% required platelet transfusions. We conclude that chemo-mobilization with etoposide, Ara-C and pegfilgrastim in poorly mobilizing patients with MM or lymphoma is very effective and has acceptable toxicity. [ABSTRACT FROM AUTHOR]

The transcription factor interferon regulatory factor 8 (IRF8), as a member of the IRF family, is essential for myeloid cell differentiation. However, the precise role of IRF8 in the pathogenesis of acute myeloid leukemia (AML) remains unknown. By using multivariate analysis, we discovered that high IRF8 expression was an independent poor predictor of overall survival (OS) in AML patients from our clinical follow-up study. The proliferation of three AML cell lines was significantly inhibited by shRNA-mediated knockdown of IRF8, owing to cell cycle S-phase arrest. Furthermore, we demonstrated that knocking down IRF8 could suppress the expression of CyclinA and CyclinB1, resulting in a shift in cell cycle distribution. Loss of IRF8 in AML cells decreased the expression of STAT3 and phosphor-STAT3 (pSTAT3), which are key factors in JAK/STAT signal pathway and are important for AML progression. Using a xenograft mouse model, we discovered the antiproliferative effect of losing IRF8 in vivo. In conclusion, this study found that IRF8 may play a prognostic factor and therapeutic target in AML. [ABSTRACT FROM AUTHOR]

Aims: Testis and sperm are particularly susceptible to inflammation and oxidative stress. Although hydrogen sulfide (H2S) has been considered an important biological signaling molecule in inflammatory and oxidative stress processes, its role in the male reproductive system was poorly understood. The aim of this study was to investigate the role of H2S in the regulation of male reproductive system. Results: We found that both subfertile and infertile patients, especially asthenospermic patients, exhibited decreased concentration of H2S in their seminal plasma and diminished expression of H2S-generating enzyme (cystathionine β-synthase [CBS]) in sperm. Supplying exogenous H2S to semen improved sperm motility of these asthenospermic patients. Furthermore, decreased sperm motility was observed in animal models with a defective in H2S generation such as lipopolysaccharide-treated mice, diabetic mice, and CBS-deficient mice. Our research showed that stress-induced reductions of endogenous H2S production and CBS expression are correlated with impaired spermatogenesis and a defective blood–testis barrier. Supplying exogenous H2S or overexpressing CBS could relieve the spermatogenic failure. This occurred primarily through the combination of anti-inflammatory and antioxidative effects. Innovation: These results provide the first indication that H2S is important for maintaining male fertility and protecting testicular function. Conclusion: H2S plays an important role in spermatogenic failure and testicular dysfunction mainly by its anti-inflammatory and antioxidative effects. Antioxid. Redox Signal. 28, 1447–1462. [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]

Chemotherapy-induced nausea and vomiting (CINV) is common in patients with lymphoma and multiple myeloma (MM) receiving high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Despite a standard triple antiemetic regimen of a neurokinin-1 (NK1) receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone is recommended, how to control the protracted CINV in ASCT setting remains an intractable problem. Here, we retrospectively analyze CINV data of 100 patients who received either SEAM (semustine, etoposide, cytarabine, melphalan) or MEL140-200 (high-dose melphalan) before ASCT, evaluate the efficacy and safety of multiple-day administration of fosaprepitant combined with tropisetron and olanzapine (FTO), and compare the results to those of patients who received a standard regimen of aprepitant, tropisetron, and dexamethasone (ATD). The overall rate of complete response (CR), defined as no emesis and no rescue therapy, is 70% in the FTO group compared to 36% in the ATD group. Although CR rates are comparable in the acute phase between the two groups, significantly more patients treated by FTO achieve CR in the delayed phase than those treated by ATD (74% vs. 38%, p < 0.001). Moreover, FTO treatment significantly reduced the percentage of patients who are unable to eat, as well as the requirement for rescue medications. Both regimens are well tolerated and most adverse events (AEs) were generally mild and transient. In conclusion, the antiemetic strategy containing multiple-day administration of fosaprepitant is safe and effective for preventing CINV in lymphoma and MM patients, particularly in the delayed phase. [ABSTRACT FROM AUTHOR]

In this study, the deep belief network (DBN) algorithm was used to identify the Wilm's tumor 1 (WT1) gene expression levels, and then, the role of WT1 expression in the classification of acute myeloid leukemia (AML) was explored. 121 AML patients diagnosed in the hospital from 2017.10 to 2019.10 were selected as the research subjects and set as the AML group. Another 9 non-leukemia patients were selected as the control group. The expression levels of WT1 in the two groups were compared, and DBN was used to classify the patients based on the WT1 expression levels. The real-time quantitative PCR was used to detect the abnormalities of FLT3, PML-RAR, and other molecular markers at different WT1 expression levels. The results showed that the expression of WT1 in AML patients was significantly higher than that in non-leukemia patients. The expression of WT1 in patients of M3 type was the highest, and that was the lowest in patients of the M5 type. The accuracy, precision, recall, and F1 indexes for WT1 expression identification using deep belief network were 94.06%, 93.82%, 93.59%, and 93.63%, respectively. In conclusion, deep learning technology is very sensitive in identifying the molecular biology markers in AML patients, which provides a reference for efficient and intelligent disease diagnosis. [ABSTRACT FROM AUTHOR]

Background: There is no consensus on the optimal secondary antifungal prophylaxis (SAP) regimen in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to evaluate the efficacy and safety of posaconazole oral suspension as secondary prophylaxis of invasive fungal disease (IFD) for allo-HSCT patients.Methods: We retrospectively reviewed clinical data from prior IFD patients who received posaconazole oral suspension as systemic antifungal prophylaxis between June 2016 and January 2021 and have a follow-up period of 1 year after HSCT. The clinical outcomes of patients with a prior history of IFD (n = 30) and those without (n = 93) were compared.Results: The 1-year cumulative incidence of prophylaxis failure was 58.3% in the group with prior history of IFD and 41.6% in the group without a prior history of IFD (p = 0.459). The cumulative incidence of proven, probable or possible IFD within 1 year after allo-HSCT was 23.1% in the group with prior history of IFD and 14.1% in the group without prior history of IFD (p = 0.230). There was no significant difference between the cumulative incidence of proven or probable IFD within 1-year after allo-HSCT in the group with a prior history of IFD and the group without (p = 0.807). Multivariate logistic regression revealed cytomegalovirus disease as risk factor for post-transplantation IFD occurrence in posaconazole oral suspension prophylaxis. There was not a significant difference in overall survival between the patients with IFD history and those without (P = 0.559).Conclusions: Our study support that allo-HSCT recipients with a prior history of IFD and normal GI absorption can choose posaconazole oral suspension as a safe and effective SAP option. [ABSTRACT FROM AUTHOR]

The majority of risk loci identified by genome-wide association studies (GWAS) are in non-coding regions, hampering their functional interpretation. Instead, transcriptome-wide association studies (TWAS) identify gene-trait associations, which can be used to prioritize candidate genes in disease-relevant tissue(s). Here, we aimed to systematically identify susceptibility genes for coronary artery disease (CAD) by TWAS. We trained prediction models of nine CAD-relevant tissues using EpiXcan based on two genetics-of-gene-expression panels, the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) and the Genotype-Tissue Expression (GTEx). Based on these prediction models, we imputed gene expression of respective tissues from individual-level genotype data on 37,997 CAD cases and 42,854 controls for the subsequent gene-trait association analysis. Transcriptome-wide significant association (i.e. P < 3.85e−6) was observed for 114 genes. Of these, 96 resided within previously identified GWAS risk loci and 18 were novel. Stepwise analyses were performed to study their plausibility, biological function, and pathogenicity in CAD, including analyses for colocalization, damaging mutations, pathway enrichment, phenome-wide associations with human data and expression-traits correlations using mouse data. Finally, CRISPR/Cas9-based gene knockdown of two newly identified TWAS genes, RGS19 and KPTN, in a human hepatocyte cell line resulted in reduced secretion of APOB100 and lipids in the cell culture medium. Our CAD TWAS work (i) prioritized candidate causal genes at known GWAS loci, (ii) identified 18 novel genes to be associated with CAD, and iii) suggested potential tissues and pathways of action for these TWAS CAD genes. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes and axonopathy is its main pathological feature. Previous studies suggested an advantage of taurine against diabetes. However, there are few reports which study the effect of taurine against axonopathy. In this study, we confirmed that taurine significantly decreased blood glucose level, mitigated insulin resistance and improved dysfunctional nerve conduction in diabetic rats. Taurine corrected damaged axonal morphology of sciatic nerve in diabetic rats and induced axon outgrowth of Dorsal root ganglion (DRG) neurons exposed to high glucose. Taurine up-regulated phosphorylation levels of PI3K, Akt, and mTOR in sciatic nerve of diabetic rats and DRG neurons exposed to high glucose. However, Akt and mTOR inhibitors (MK-2206 and Rapamycin) blocked the effect of taurine on improving axonal damage. These results indicate that taurine ameliorates axonal damage in sciatic nerve of diabetic rats by activating PI3K/Akt/mTOR signal pathway. Our findings provide taurine as a potential candidate for axonopathy and a new evidence for elucidating protective mechanism of taurine on DPN. [ABSTRACT FROM AUTHOR]

Type 2 Diabetes causes learning and memory deficits that might be mediated by hippocampus neuron apoptosis. Studies found that taurine might improve cognitive deficits under diabetic condition because of its ability to prevent hippocampus neuron apoptosis. However, the effect and mechanism is not clear. In this study, we explore the effect and mechanism of taurine on inhibiting hippocampus neuron apoptosis. Sixty male Sprague–Dawley rats were randomly divided into control, T2D, taurine treatment (giving 0.5%, 1%, and 2% taurine in drinking water) groups. Streptozotocin was used to establish the diabetes model. HT-22 cell (hippocampus neurons line) was used for in vitro experiments. Morris Water Maze test was used to check the learning and memory ability, TUNEL assay was used to measure apoptosis and nerve growth factor (NGF); Akt/Bad pathway relevant protein was detected by western blot. Taurine improved learning and memory ability and significantly decreased apoptosis of the hippocampus neurons in T2D rats. Moreover, taurine supplement also inhibited high glucose-induced apoptosis in HT-22 cell in vitro. Mechanistically, taurine increased the expression of NGF, phosphorylation of Trka, Akt, and Bad, as well as reduced cytochrome c release from mitochondria to cytosol. However, beneficial effects of taurine were blocked in the presence of anti-NGF antibody or Akt inhibitor. Taurine could inhibit hippocampus neuron apoptosis via NGF-Akt/Bad pathway. These results provide some clues that taurine might be efficient and feasible candidate for improvement of learning and memory ability in T2D rats. [ABSTRACT FROM AUTHOR]

Protein S-nitrosylation plays an important role in the progression of cardiovascular diseases. eNOS can be S-nitrosylated in endothelial cells, and this modification reversibly attenuates enzyme activity. Under physiological conditions, eNOS directly interacts with β‑catenin. However, whether and how eNOS S-nitrosylation regulates the β‑catenin signal pathway and participates in endothelial dysfunction remains unknown. Here, we show that OxLDL induces the S-nitrosylation of eNOS, which enhances the interaction between eNOS and β‑catenin, transcriptional activity of β‑catenin, cell migration and adhesion molecule expression in endothelial cells. In addition, these effects are partially abolished after eNOS is mutated at Cys94 and Cys99, but not Cys441, in endothelial cells. Furthermore, OxLDL increases iNOS expression. The specific iNOS inhibitor 1400 W decreases eNOS S-nitrosylation and the association of eNOS and β‑catenin, thereby blocking the β‑catenin signal pathway to alleviate OxLDL-induced endothelial dysfunction. Taken together, OxLDL induces eNOS S-nitrosylation at Cys94 and Cys99 via an iNOS-dependent manner, which may increase β‑catenin activation and trigger endothelial injury. This study describes a novel mechanism of endothelial dysfunction. • OxLDL increases the association of eNOS with β‑catenin. • OxLDL can induce S-nitrosylation of eNOS at Cys94 and Cys99 and this effect is dependent on iNOS. • S-nitrosylation of eNOS at Cys94 and Cys99 contributes to OxLDL-induced endothelial dysfunction. • S-nitrosylation of eNOS at Cys94 and Cys99 is essential for eNOS binding to β‑catenin in OxLDL-treated endothelial cells. [ABSTRACT FROM AUTHOR]

Perfluorooctane sulfonate (PFOS) is one of the perfluorinated compounds (PFCs), and has been used in industrial and consumer products. It has already been shown that PFOS could be detected in the environmental media and biological species including humans, due to its resistance to environmental degradation. PFOS is known to induce a series of adverse impacts on human health, e.g., as a potential neurotoxic substance. Recent studies suggest that astrocytes act as the mediator in PFOS-induced neurotoxicity; however, the underlying molecular mechanism needs further investigation. Under the physiological condition, astrocytes play an important role in maintaining brain functions through releasing and up-taking of neurotransmitters between astrocytes and neurons. In the present study, astrocytes-derived d -serine was shown to be involved in PFOS-induced apoptosis and death in the rat primary hippocampal neurons. Significant alterations in d -serine were found in astrocytes, mediated by the molecules in d -serine synthesis (serine racemase), metabolism (d -amino acid oxidase) and delivery (calcium, vacuolar type H+-ATPase, alanine–serine–cysteine transporter and connexin 43 hemichannels). Meanwhile, the N -methyl- d -aspartate receptor (NMDAR) subunits (NR1, NR2 A and NR2B) gene and protein expressions were significantly increased in the hippocampal neurons exposed to the PFOS-activated astrocytes-conditional medium (ACM). Further, the adverse effects of PFOS could be attenuated by the fluorocitrate (an inhibitor for d -serine up-taken by the glial cells) application. Our data indicated that astrocytes-derived d -serine was involved in PFOS-induced neurotoxicity through the NMDARs in the rat primary hippocampal neurons. [ABSTRACT FROM AUTHOR]

We aimed to investigate the effects of bone marrow mesenchymal stem cell conditioned medium (BMSC-CM) in preventing 2,5-hexanedione (HD)-induced damage to motoneurons, and examined the molecular mechanisms that mediate these effects. VSC4.1 cells were exposed to 25 mM HD for 24 h followed by incubation with DMEM for 24 h. HD-treated cells were incubated with BMSC-CM at varied concentrations. Incubation with BMSC-CM ameliorated the decreased cell viability and reduced LDH release from cells exposed to HD. BMSC-CM suppressed the elevated number of autophagic vacuoles, cells with LC3 puncta, increased LC3-II/LC3-I ratio, and decreased p62 caused by HD exposure. BMSC-CM elevated NGF and p-TrkA expressions in HD-treated cells. Administration of NGF inhibited autophagy, an effect that was similar to that observed after BMSC-CM treatment; this effect was abolished by the addition of NGF-neutralizing antibodies. BMSC-CM or NGF elevated p-protein kinase B (Akt) and p-mammalian target of rapamycin (mTOR) in HD-exposed cells, which was interrupted by TrkA inhibitor, K252a and mTOR inhibitor, rapamycin. BMSC-CM prevented HD-induced autophagic cell damage in VSC4.1 cells. The neuroprotective effect of BMSC-CM appeared to be at least partly associated with its ability to trigger the NGF-phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

2,5-hexanedione (2,5-HD) is the main active metabolite of n-hexane and induces apoptosis in nerve tissue, however, the mechanism of which remains unclear. In the present study, neuropathic animal models were successfully constructed in rats by injecting 100, 200 and 400 mg/kg 2,5-HD intraperitoneally for 5 weeks. Rats exposed to 2,5-HD exhibited progressive gait abnormalities and slower motor neural response in a dose-dependent manner. TUNEL analysis and immunofluorescence dual labeling revealed that the spinal cord of the 2,5-HD treated rats underwent significantly more apoptosis in the cells of spinal cord than that of the control group. The neuron apoptosis index in spinal cord was 4.1%, 6.7%, 9.8% respectively in rats exposed to 100, 200 and 400 mg/kg 2,5-HD, compared with 1.1% in the control group (p < 0.05). Biochemical analysis showed that 2,5-HD exposure downregulated NGF expression in the spinal cord of the intoxicated rats; inhibited the phosphorylation of Akt and Bad, two key players in PI3K/Akt pathway downstream of NGF; increased the dimerization of Bad with Bcl-xL in the mitochondrial fraction, followed by the release of cytochrome c and activation of caspase-3 in the spinal cord of rats. In vitro study showed that the NGF expression decreased significantly in VSC4.1 cells dosed with 5.0, 10.0 mM 2,5-HD in comparison with the control group. It was also found that NGF supplement repressed the induced apoptosis, and increased p-Akt and p-Bad level in 2,5-HD treated VSC4.1 cells, which could be antagonized by PI3K kinase (the upstream member of Akt) inhibitor LY294002. Taken together, our experimental results indicate that 2,5-HD may induce apoptosis in the spinal cord of rats via downregulating NGF expression and subsequently repressing PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Perfluorooctane sulfonate (PFOS) is a potential neurotoxicant reported by epidemiological investigations and experimental studies, while the underlying mechanisms are still unclear. Astrocytes not only support for the construction of neurons, but also conduct neuronal functions through glutamate-glutamine cycle in astrocyte-neuron crosstalk. In the present study, the effect of PFOS exposure on rat primary hippocampal neurons or cortex astrocytes was evaluated. Then the role of the astrocytes in PFOS-induced toxic effect on neurons was explored with astrocyte-neuron co-culture system. Exposure of rat primary hippocampal neurons to PFOS has led to oxidation-antioxidation imbalance, increased apoptosis and abnormal autophagy. The adverse effect of PFOS on rat primary cortex astrocytes manifested in the form of altered extracellular glutamate and glutamine concentrations, decreased glutamine synthase activity, as well as decreased gene expression of glutamine synthase, glutamate transporters and glutamine transporters in the glutamate-glutamine cycle. Especially, the alleviation of PFOS-inhibited neurite outgrowth in neurons could be observed in astrocyte-neuron co-culture system, though the ability of astrocytes in fostering neurite outgrowth was affected by PFOS. These results indicated that both astrocytes and neurons might be the targets of PFOS-induced neurotoxicity, and astrocytes could protect against PFOS-inhibited neurite outgrowth in primary cultured neurons. Our research might render some information in explaining the mechanisms of PFOS-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Relapse and graft-versus-host disease (GVHD) are the important complications influencing mortality for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). GVHD prophylaxis based on post-transplant cyclophosphamide (PTCy) or antithymocyte globulin (ATG) is widely used in haploidentical HSCT (haplo-HSCT). We developed a modified intensified conditioning regimen including fludarabine (Flu) and investigated the effect of ATG-PTCy combination on transplant outcomes in high-risk AML and MDS compared with those patients who received only ATG as GVHD prophylaxis. A total of 80 patients with high-risk AML and MDS were divided into two groups and assigned to one-to-one pairing. The modified ATG-PTCy group had more infused mononuclear cells, CD34-positive cells and CD3-positive cells than those in the ATG group (P < 0.05). The amount of platelet transfusion was higher in the ATG group than the modified ATG-PTCy group [2 (range, 1–6) U vs 2 (range, 1–5) U, P = 0.005]. The median of platelet recovery was better in the modified ATG-PTCy group than in the ATG group (12 days vs 13 days, P = 0.041). The infection rates of bacteria, fungi and virus at 100 days after transplantation were similar in both groups. Compared with the ATG group, individuals who received the modified ATG-PTCy regimen had higher 2-year GVHD- and relapse-free survival(GRFS) [60.0% (95%CI, 44.9–75.1%) vs 34.8% (95%CI, 19.9–49.7%), P = 0.028]; lower 180-day incidence of II-IV acute GVHD (aGVHD) [15.0% (95%CI, 4.0–26.0%) vs 39.8% (95%CI, 23.9–55.7%), P = 0.029]; lower 1-year incidence of moderate to severe chronic GVHD (cGVHD) [2.9% (95%CI, 2.0–3.8%) vs 19.6% (95%CI, 5.3–33.9%), P = 0.039]; and without an increase in the 2-year cumulative incidence of relapse (CIR) [19.5% (95%CI, 6.6–32.4%) vs 30.4% (95%CI, 15.3–45.5%), P = 0.291]. High-dose stem cells can promote blood cell implantation. The modified ATG-PTCy combination was associated with decreased risk of aGVHD and cGVHD, no increased risk of recurrence, and improved GRFS. It represents an effective strategy for high risk AML and MDS. [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]

• We provide a recommendation for the treatment of multi-hit MM. • Lenalidomide has an advantage in improving the early ORR of multi-hit MM. • Tandem-ASCT can further prolong the long-term survival rate of multi-hit MM. • We analyzed factors affecting survival of MM with and without ASCT by univariate and multivariate analyses. In order to investigate the efficacy of lenalidomide, bortezomib and dexamethasone (VRD) induction chemotherapy regimen combined with tandem autologous stem cell transplantation (ASCT) in treating multi-hit multiple myeloma (MM), we analyzed 252 cases of newly diagnosed MM treated with the bortezomib-containing induction chemotherapy from June 2016 to June 2019. According to the fluorescence in situ hybridization (FISH) results on diagnosis, the patients were divided into multi-hit MM group (47 cases), single-hit MM group (81 cases), and standard-risk group (124 cases). Our analysis showed that R-ISS stageⅢ in transplantation group and R-ISS stageⅢ, multi-hit and VGPR or above was not achieved at the fourth cycle of chemotherapy in non-transplantation group were independent factors for poor prognosis by univariate and multivariate analyses. Moreover, the overall response rate (ORR) of VRD induction chemotherapy group was significantly higher than that of the non-VRD group in the single-hit and multi-hit groups (P = 0.021, P = 0.032); In terms of ASCT, tandem-ASCT can significantly improve the 2-year PFS (77.8 ± 3.9 %) and OS (83.3 ± 5.6 %) of multi-hit MM (P = 0.024, P = 0.037), while single-ASCT only has a limited effect on PFS (61.5 ± 3.0 %) and OS (71.9 ± 4.5 %) (P = 0.115, P = 0.155). [ABSTRACT FROM AUTHOR]

Background: Both all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) have proven to be very effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL). Methods: In this study, 73 newly diagnosed APL subjects were treated with an ATRA and As2O3 combination treatment in remission induction and post remission therapy. Tumor burden was examined with PCR of the PML-RAR fusion transcripts, and side effects were evaluated by means of clinical examination. Results: The results showed that ATRA/As2O3 combination therapy yielded a CR rate of 94.5% (69/73) with a shorter time to enter CR (median: 27 days; range: 21-43 days). Four cases failed to enter CR; three of these died of cerebral hemorrhage and disseminated intravascular coagulation (DIC) within 72 hours of starting induction therapy, one older patient died of severe pulmonary infection. The early death rate was 5.5% (4/73). All 69 cases that obtained CR remained in good clinical remission after a follow-up of 35-74 months (median: 52 months).The drug toxicity profile with the use of As2O3 showed mainly hepatotoxicity. Liver dysfunction was slight in most cases. There were no severe side effects in long term follow-up. Conclusion: We conclude that APL patients may benefit from the use of the combination of ATRA and As2O3 in either remission induction or consolidation/maintenance. [ABSTRACT FROM AUTHOR]

Abstract: Cell microencapsulation is a promising therapeutic strategy to many diseases; however, the metabolic characteristics of microencapsulated cells and also the optimum microcapsule additives that meet the criteria for long-term functional immunoisolated transplantation have rarely been taken into consideration hitherto. In this work, the optimized amino acid supplements and several chemically defined compounds were applied to cultivation of the microencapsulated CHO cells. The results show that the optimized medium significantly enhances cell survival and, particularly, endostatin secretion of encapsulated CHO cells over a time period of 8 weeks. Furthermore, long-term in vitro stability of alginate–poly-l-lysine–alginate (APA) microcapsules underwent no changes, which indicated that this optimized medium might be feasible to maintain high viability of microencapsulated cell for short periods of time before implantation. [Copyright &y& Elsevier]