Targeting nucleolin improves sensitivity to chemotherapy in acute lymphoblastic leukemia.

PURPOSE: Most patients with acute lymphoblastic leukemia (ALL) are treated with chemotherapy as primary care. Although the treatment response is usually positive, resistance and relapse often occur via unknown mechanisms. The purpose of this study was to identify factors associated with chemotherapy resistance in ALL. Here, we present clinical and experimental evidence that overexpression of nucleolin (NCL), a multifunctional nucleolar protein, is linked to drug resistance in ALL. METHODS: NCL mRNA and protein levels were compared between cell lines and patient samples using qRT-PCR and immunoblotting. NCL mRNA levels were compared between patients of different disease stages from our clinic patients' specimens and publicly available ALL patient datasets. Cells and patient-derived xenograft mouse experiments were performed to assess the effect of NCL inhibition on ALL chemotherapy effectiveness. RESULTS: Analysis of patient specimens, and publicly available RNA-sequencing datasets revealed a strong correlation between the abundance of NCL and disease relapse or poor survival in B-ALL. Altering NCL expression results in changes in drug sensitivity in ALL cell lines. High levels of NCL upregulated components of the ATP-binding cassette transporters via activation of the ERK pathway, resulting in a decrease in drug accumulation inside the cells. Targeting NCL with AS1411, an NCL-binding oligonucleotide aptamer, significantly increased the sensitivity of ALL cell lines and cells/patient-derived ALL xenograft mice to chemotherapeutic drugs and prolonged mouse survival. CONCLUSION: Our results highlight NCL as a prognostic marker in B-ALL and a potential therapeutic target to combat chemotherapy resistance in ALL.

Lineage-mosaic and mutation-patched spike proteins for broad-spectrum COVID-19 vaccine.

SARS-CoV-2 spread in humans results in continuous emergence of new variants, highlighting the need for vaccines with broad-spectrum antigenic coverage. Using inter-lineage chimera and mutation-patch strategies, we engineered a recombinant monomeric spike variant (STFK1628x) that contains key regions and residues across multiple SAR-CoV-2 variants. STFK1628x demonstrated high immunogenicity and mutually complementary antigenicity to its prototypic form (STFK). In hamsters, a bivalent vaccine composed of STFK and STFK1628x elicited high titers of broad-spectrum neutralizing antibodies to 19 circulating SARS-CoV-2 variants, including Omicron sublineages BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.75, and BA.4/5. Furthermore, this vaccine conferred robust protection against intranasal challenges by either SARS-CoV-2 ancestral strain or immune-evasive Beta and Omicron BA.1. Strikingly, vaccination with the bivalent vaccine in hamsters effectively blocked within-cage virus transmission of ancestral SARS-CoV-2, Beta variant, and Omicron BA.1 to unvaccinated sentinels. Thus, our study provided insight and antigen candidates for the development of next-generation COVID-19 vaccines.

Effects of Taurine on Serum Indexes of Broilers with Chronic Heat Stress.

The aim of this study was to investigate the effects of taurine on tissue injury, protein metabolism, and basal metabolism of broilers after chronic heat stress by detecting serum physiological and biochemical indices. In the test, 240 AA + broilers at 7 days of age were randomly divided into five groups: the normal temperature control group (24 ± 2 °C) in group C, the heat stress control group (34 ± 2 °C) in HS group, and the LTau, MTau, and HTau groups in heat under stress conditions, 0.5, 2, and 8 g/L taurine were added to the drinking water, and each group was repeated three times. After 2 weeks of feeding at normal temperature, heat stress began. The test period was 4 weeks. Blood was collected at 6 h, 12 h, 7 d, 14 d, 21 d, and 28 d after heat stress, and serum was separated. The results showed that compared with the HS group, the MTau group had significantly higher total serum protein content (P < 0.05), while the other groups were not significantly different (P > 0.05). The MTau and HTau groups had significantly lower serum uric acid levels than the HS group (P < 0.05). At 7d and 14d, the LTau, MTau, and HTau groups all showed significantly increased T3 and T4 concentrations (P < 0.05). There was no significant difference between the groups thereafter (P > 0.05). Compared with HS group, the MTau group contained significantly reduced serum CK activity, LDH activity, AST activity, and ALT activity (P < 0.05). In conclusion, the effects of taurine on tissue damage, protein metabolism, and basal metabolism of broilers after chronic heat stress were studied by measuring serum physiological and biochemical indices. To provide a theoretical basis for the application of taurine in acute heat-stressed broilers.

Antioxidant Effect of Taurine on Chronic Heat-Stressed Broilers.

The purpose of this study was to investigate the effects of taurine on blood indices of broilers with chronic heat stress and to provide theoretical basis for the application of taurine in the anti-chronic heat stress of broilers. In the test, 240 AA + broilers at 7 days of age were randomly divided into five groups: the normal temperature control group (24 ± 2 °C) in group C, the heat stress control group (34 ± 2 °C) in HS group, and the LTau, MTau, and HTau groups in heat under stress conditions, 0.5 g/L, 2 g/L, and 8 g/L taurine, were added to the drinking water, and each group was repeated three times. After 2 weeks of feeding at normal temperature, heat stress began. The test period was 4 weeks. Blood was collected at 6 h, 12 h, 7 d, 14 d, 21 d, and 28 d after heat stress, and serum was separated. The results showed that compared with the HS group, MTau significantly increased the total serum protein content (P < 0.05), but the other groups were not significantly different (P > 0.05). The MTau and HTau groups contained significantly lowered serum uric acid levels than the HS group (P < 0.05). At 7d and 14d, the LTau, MTau, and HTau groups all exhibited significantly increased T3 and T4 concentrations (P < 0.05). There was no significant difference between the groups at other times (P > 0.05). Compared with the HS group, the MTau group contained significantly reduced serum CK activity, LDH activity, AST activity, and ALT activity (P < 0.05). Compared with the LTau, MTau, and HTau groups, serum MDA content was significantly increased in the heat-stressed broilers (P < 0.05). MTau group contained significantly increased T-AOC, SOD, CAT, and GSH-PX levels (P < 0.05). The other groups were not significantly different (P > 0.05). Compared with group C, serum HSP60 and HSP70 levels were significantly elevated in the HS group (P < 0.05). Compared with the HS group, the LTau and MTau groups contained significantly increased serum HSP60 and HSP70 concentrations (P < 0.05), but the other groups were not significantly different (P > 0.05). In conclusion, taurine can alleviate the symptoms of chronic heat stress of broilers, regulate the metabolism of the body, and improve the antioxidant activity of the body.

Cost-effectiveness analysis of axicabtagene ciloleucel vs. salvage chemotherapy for relapsed or refractory adult diffuse large B-cell lymphoma in China.

PURPOSE: Axicabtagene ciloleucel (Axi-Cel, 2 × 106 CAR-T cells/kg, single intravenous injection) is a chimeric antigen receptor cell immunotherapy that exhibits favorable clinical efficacy and safety in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). However, this treatment is expensive in China. This study aimed to evaluate the cost-effectiveness of Axi-Cel versus salvage chemotherapy for the treatment of R/R DLBCL from the perspective of the Chinese healthcare system. METHODS: A decision analysis model containing a short-term decision tree and long-term semi-Markov partitioned survival model was developed. The time horizon was 40 years and the period from 10 to 40 years was included in sensitivity analysis. The model was developed based on data from the ZUMA-1 and SCHOLAR-1 trials. Life years, quality-adjusted life years (QALYs), overall costs, and the incremental cost-effectiveness ratio (ICER) were estimated at a willingness to pay (WTP) threshold of US $31,320 per QALY, which is three times the gross domestic product per capita. RESULTS: The base case analysis revealed that treatment with Axi-Cel is associated with an increased overall cost of US $175,380 and improved effectiveness of 3.43 LYs and 2.61 QALYs compared to salvage chemotherapy, leading to an ICER of US $51,190 per LY and US $67,250 per QALY. The developed model is sensitive to the discount rate, utility of progression-free survival (PFS), and cost of Axi-Cel. The ICER of Axi-Cel was greater than the WTP threshold in the sensitivity and scenario analyses. To achieve cost-effectiveness, the price of Axi-Cel must be reduced by 59.19% to US $71,000. CONCLUSION: At its current price, Axi-Cel is not likely to be a cost-effective option compared to salvage chemotherapy for adult patients with R/R DLBCL.

Genomic heterogeneity contributed to different prognosis between adult and pediatric acute lymphoblastic.

The prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to that in children. Hence, ALL remains challenging to cure in the adult population. Aberrant genetic alterations have been observed in ALL, although the patterns of differential gene alterations in adult and pediatric ALL have not been comprehensively determined on a genome-wide scale. We investigated the biologic differences in genomic profiles between adults (n = 64) and children (n = 54) with ALL and relationship between genomic heterogeneity and prognosis. The 2 populations showed similar common mutation types but an increased prevalence of genetic alterations in adult ALL. The median numbers of gene mutations were 17 (range: 1-53) and 4.5 (range: 1-19) per sample in adult and pediatric ALL, respectively (p < 0.001). An increased number of gene mutations and age were significantly correlated (R2  = 0.5853, p < 0.001). We identified 122 and 53 driver genes in adult and pediatric ALL samples, respectively. IKZF1, IDH1, and TTN mutations were significantly enriched in adult patients with ALL. KRAS, ARID1A, and CREBBP mutations were significantly enriched in pediatric patients with ALL (p < 0.05). The incidence of relapse was 40.0% and 9.6% in adult and pediatric patients with ALL, respectively (p = 0.003). The overall survival and relapse-free survival of adult patients with ALL were poorer than those of pediatric patients with ALL (p = 0.002 and p < 0.001, respectively). This genomic landscape enhances the understanding of the biologic differences in ALL between the 2 populations and provides insight for developing therapeutic approaches.

A recombinant spike protein subunit vaccine confers protective immunity against SARS-CoV-2 infection and transmission in hamsters.

Multiple safe and effective vaccines that elicit immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary to respond to the ongoing coronavirus disease 2019 (COVID-19) pandemic. Here, we developed a protein subunit vaccine composed of spike ectodomain protein (StriFK) plus a nitrogen bisphosphonate-modified zinc-aluminum hybrid adjuvant (FH002C). StriFK-FH002C generated substantially higher neutralizing antibody titers in mice, hamsters, and cynomolgus monkeys than those observed in plasma isolated from COVID-19 convalescent individuals. StriFK-FH002C also induced both TH1- and TH2-polarized helper T cell responses in mice. In hamsters, StriFK-FH002C immunization protected animals against SARS-CoV-2 challenge, as shown by the absence of virus-induced weight loss, fewer symptoms of disease, and reduced lung pathology. Vaccination of hamsters with StriFK-FH002C also reduced within-cage virus transmission to unvaccinated, cohoused hamsters. In summary, StriFK-FH002C represents an effective, protein subunit-based SARS-CoV-2 vaccine candidate.

Neural differentiation of bone marrow mesenchymal stem cells with human brain-derived neurotrophic factor gene-modified in functionalized self-assembling peptide hydrogel in vitro.

OBJECTIVE: To investigate the biocompatibility and differentiation of human brain-derived neurotrophic factor (hBDNF) gene-modified bone marrow mesenchymal stem cells (hBDNF-rMSCs) in a functionalized self-assembling peptide hydrogel. METHODS: hBDNF was engineered in rMSCs using adenovirus vector and the enhanced green fluorescence protein (eGFP) was used as a reporter gene. Mesenchymal stem cell-specific surface markers (CD90, CD29, and CD45) were used for identifying rat-derived MSCs. Fluorescence microscope was used to detect the transfection of rMSCs. hBDNF-rMSCs and control cells (eGFP-rMSCs) were seeded in a functional self-assembling peptide hydrogel (RADA16-PRG hydrogel) and a control hydrogel (RADA16 hydrogel). Cells were divided into three groups (hBDNF-rMSCs + RADA16 hydrogel, hBDNF-rMSCs + RADA16-PRG hydrogel, and eGFP-rMSCs + RADA16-PRG hydrogel) and a control group (eGFP-rMSCs + RADA16 hydrogel). Cell growth, cell proliferation, expression of hBDNF-mRNA, the level of hBDNF, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP) protein were analyzed for each group. RESULTS: rMSCs were positive for CD90 and CD29 and negative for CD45, green fluorescence was strongly visible at 72 hours after transfection. Compared with control group, the expression of hBDNF-mRNA and levels of hBDNF protein in both hBDNF group were significantly increased (P < 0.01), the cell growth, cell proliferation, and levels of NSE and GFAP protein were significantly increased in three groups ( P < 0.01). Cell growth, cell proliferation, expression of hBDNF-mRNA, and levels of hBDNF, NSE, and GFAP protein in hBDNF-rMSCs + RADA16-PRG hydrogel group were significantly higher than that of hBDNF-rMSCs + RADA16 hydrogel group ( P < 0.01). CONCLUSION: Bone marrow MSCs can be induced into neural cells by the human brain-derived neurotrophic factor gene in a RADA16-PRG functionalized self-assembling peptide hydrogel.

Effect of curcumin on acute spinal cord injury in mice via inhibition of inflammation and TAK1 pathway.

BACKGROUND: Traumatic spinal cord injury (SCI) is damage to the spinal cord that results in damaged spinal cord function. As a natural compound, curcumin has recently been shown to have anti-inflammatory and strong antioxidant activities. To investigate the effect of curcumin against acute spinal cord injury (SCI), we explored its induced effects in SCI mice. Transforming growth factor (TGF)-activated kinase 1 (TAK1) is a member of the MAPKKK family and plays an essential role in TNF, IL-1, and Toll-like receptor (TLR) signaling pathways. METHODS: One hundred adult female KM mice were randomly divided into 5 groups (Control, Model, Test-L, Test-M, and Test-H). SCI was induced using the method described by Allen's. Motor function of the hindlimbs was evaluated on days 1, 7, 14, 21, and 28 after the injury using the motor rating test on the Basso mouse scale (BMS). 7 days after SCI, the levels of TNF-α, IL-1ß, and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA); the level of NO was evaluated by Griess assay; and Western blot was used to verify the levels of proteins in the TAK1 pathway. Expressions of GFAP positive cells in injured spinal cord were detected by immunohistochemical staining. RESULTS: The experiment showed that curcumin markedly inhibited SCI-induced production of inflammatory mediators, including TNF-α, IL-1ß, IL-6 (ELISA assay) and nitrite oxide (Griess method) in a concentration-dependent manner. Curcumin decreased the phosphorylation levels of TGF-ß-activated kinase 1 (TAK1) protein, leading to decreased phosphorylation levels of MKK6 and p38 MAPKs, key players in the microglia-mediated inflammatory response. Curcumin also significantly down-regulated the expression levels of the NF-κB upstream regulators IκB and IκB kinase (IKK). Additionally, behavior research showed that curcumin-treated mice showed significantly improved functional recovery compared to untreated mice (BMS assay). The expressions of GFAP increased in the injured spinal cord segments, which were decreased by Teat-M and Teat-H at 7d after SCI. CONCLUSIONS: Curcumin restores mice hind-limb function that has been reduced by SCI. This occurs by inhibition of TAK1/MKK6/p38MAPK via the TAK1 and NFκB pathways and inflammation. These results suggest the therapeutic potential for curcumin in the treatment of SCI.