Associations of granulocyte colony-stimulating factor with toxicities and efficacy of chimeric antigen receptor T-cell therapy in relapsed or refractory B-cell acute lymphoblastic leukemia.

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We present a retrospective study of 67 patients with R/R B-ALL who received anti-CD19 CAR T-cell therapy, 41 (61.2%) patients received G-CSF (G-CSF group), while 26 (38.8%) did not (non-G-CSF group). Patients had similar duration of grade 3-4 neutropenia between the two groups. The incidences of CRS and NEs were higher in G-CSF group, while no differences in severity were found. Further stratified analysis showed that the incidence and severity of CRS were not associated with G-CSF administration in patients with low bone marrow (BM) tumor burden. None of the patients with low BM tumor burden developed NEs. However, there was a significant increase in the incidence of CRS after G-CSF administration in patients with high BM tumor burden. The duration of CRS in patients who used G-CSF was longer. There were no significant differences in response rates at 1 and 3 months after CAR T-cell infusion, as well as overall survival (OS) between the two groups. In conclusion, our results showed that G-CSF administration was not associated with the incidence or severity of CRS in patients with low BM tumor burden, but the incidence of CRS was higher after G-CSF administration in patients with high BM tumor burden. The duration of CRS was prolonged in G-CSF group. G-CSF administration was not associated with the efficacy of CAR T-cell therapy.

A novel remediation strategy of mixed calcium peroxide and degrading bacteria for polycyclic aromatic hydrocarbon contaminated water.

Polycyclic aromatic hydrocarbons (PAHs) are a class of toxic organic pollutants commonly detected in the aqueous phase. Traditional biodegradation is inefficient and advanced oxidation technologies are expensive. In the current study, a novel strategy was developed using calcium peroxide (CP) and PAH-degrading bacteria (PDB) to effectively augment PAH degradation by 28.62-59.22%. The PDB consisted of the genera Acinetobacter, Stenotrophomonas, and Comamonas. Applying the response surface model (RSM), the most appropriate parameters were identified, and the predictive degradation rates of phenanthrene (Phe), pyrene (Pyr), and ΣPAHs were 98%, 76%, and 84%, respectively. The constructed mixed system could reduce 90% of Phe and more than 60% of ΣPAHs and will perform better at pH 5-7 and lower salinity. Because PAHs tend to bind to dissolved organic matter (DOM) with larger molecular weights, humic acid (HA) had a larger negative effect on the PAH-degradation efficiency of the CP-PDB mixed system than fulvic acid (FA). The proposed PAH-degradation pathways in the mixed system were based on the detection of intermediates at different times. The investigation constructed and optimized a novel environmental PAH-degradation strategy. The synergistic application of PDB and oxidation was extended for organic contaminant degradation in aqueous environments.

A Factor-Free Hydrogel with ROS Scavenging and Responsive Degradation for Enhanced Diabetic Bone Healing.

In view of the increased levels of reactive oxygen species (ROS) that disturb the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), the repair of diabetic bone defects remains a great challenge. Herein, a factor-free hydrogel is reported with ROS scavenging and responsive degradation properties for enhanced diabetic bone healing. These hydrogels contain ROS-cleavable thioketal (TK) linkers and ultraviolet (UV)-responsive norbornene (NB) groups conjugated with 8-arm PEG macromers, which are formed via UV crosslinking-mediated gelation. Upon reacting with high levels of ROS in the bone defect microenvironment, ROS-cleavable TK linkers are destroyed, allowing the responsive degradation of hydrogels, which promotes the migration of BMSCs. Moreover, ROS levels are reduced through hydrogel-mediated ROS scavenging to reverse BMSC differentiation from adipogenic to osteogenic phenotype. As such, a favorable microenvironment is created after simultaneous ROS scavenging and hydrogel degradation, leading to the effective repair of bone defects in diabetic mouse models, even without the addition of growth factors. Thus, this study presents a responsive hydrogel platform that regulates ROS scavenging and stromal degradation in bone engineering.

Exploring sustainable food packaging: Nanocellulose composite films with enhanced mechanical strength, antibacterial performance, and biodegradability.

Food packaging films play a vital role in preserving and protecting food. However, due to their non-biodegradability, conventional packaging materials have led to significant environmental pollution. To overcome this hurdle, we have developed safe, innovative, sustainable and biodegradable packaging materials that can effectively extend the shelf life of food. In this study, two types of cellulose materials cellulose nanofibers (CNF) and carboxymethyl cellulose (CMC) with complementary roles were combined to prepare nanocellulose composite films with high transparency (90.3 %) of a certain thickness (30 ± 0.019 µm) by solution casting method, and their mechanical properties were further optimized by the addition of plasticizer-glycerol (Gly) and cross-linking agent-glutaraldehyde (GA), so as to maintain the strong tensile strength (≈112.60 MPa) and better malleability (4.12 %). In addition, we loaded the natural active agent tea polyphenols (TPs) with different concentrations to study the inhibition effect on E.coli and S.aureus and to simulate food packaging. Finally, we also found that the synthesized nanocellulose composite films can also achieve rapid degradation in a short time through soil burial, water flushing and immersion. The excellent performance demonstrated in this study provides reference value for further replacing petroleum-based materials with biomass materials in the field of food packaging.

Osteocalcin has a muscle-protective effect during weight loss in men without metabolic syndrome: a multicenter, prospective, observational study.

Objective: Weight reduction often accompanies muscle loss. Existing studies highlight the involvement of osteocalcin (OC) in energy metabolism and its potential to prevent age-related muscle loss. Nevertheless, these studies predominantly involve individuals with hyperglycemia, yielding conflicting research outcomes. This study investigated the protective role of OC against muscle loss during weight reduction in individuals without metabolic syndrome (MetS). Measures: We enrolled 130 overweight or obese individuals without MetS in a 4-month high-protein, energy-restricted dietary weight management program conducted at two clinic centers. Body composition and laboratory tests were assessed both before and after weight loss. Correlation and regression analysis were made between the changes in metabolic indicators and muscle mass during weight loss. Results: Following weight loss, there was a decrease in body mass index (BMI), percentage of body fat (PBF), visceral fat area (VFA), fasting insulin (FINS), homeostasis model assessment insulin resistance (HOMA-IR), glycated haemoglobin (HbA1c), and lipid profile, and increase in the percentage of skeletal muscle (PSM) and vitamin D. There was no change in osteocalcin (OC) during the intervention. Correlation analysis of the relative changes in all metabolic indicators revealed a positive correlation between OC and PSM (r=0.383, p=0.002). Multiple linear regression analysis found that OC has a significant protective effect on muscles during weight loss in males after adjusting for confounding factors (ß=0.089, p=0.017). Conclusion: High-protein, energy-restricted diets demonstrate efficacy in enhancing metabolic indicators within the weight-loss population. Furthermore, OC exhibits a protective effect on muscle mass during weight reduction in individuals without MetS, with this effect being particularly evident in males.

The diagnostic/prognostic roles and biological function of the IFIT family members in acute myeloid leukemia.

BACKGROUND: The Interferon-induced protein with tetratricopeptide repeat (IFIT) family, IFIT1/2/3/5, play an important role in different tumors progression. However, the prognosis significance and biological role of IFIT family members in acute myeloid leukemia (AML) remains unclear. METHODS: We obtained the gene expression data and clinical information of 173 AML patients from The Cancer Genome Atlas (TCGA) database. Several databases were used in our study, including GEPIA, MethSurv, STRING, GSCA and GeneMANIA database. RESULTS: The mRNA expression of IFIT1/2/3/5 was elevated in AML patients and had a high ability to distinguish AML from controls based on the receiver operating characteristic (ROC) curve (AUC > 0.9). Kaplan-Meier survival analysis showed that higher levels of IFIT2/3/5 expression predict poor prognosis in AML patients. Besides, the DNA methylation analysis suggested that 7 CpG sites of IFIT2, 4 CpG sites of IFIT3 and 10 CpG sites of IFIT5 were significantly associated with the prognosis of AML patients. In addition, IFIT2/3/5 expression was significantly positively associated with the immune cell infiltration and immune checkpoint expression, such as CTLA4, PDCD1, LAG3, and TIGIT. Finally, drug sensitivity analysis revealed that AML patients with high expression of IFIT2/3/5 were resistant to multiple drugs, but sensitive to dasatinib. CONCLUSION: IFIT family genes might serve as biomarkers for diagnosis, prognosis and drug sensitivity in AML patients. The activation or blocking of IFIT-related signaling pathways may provide novel insights into immunotherapy for patients with AML.

Tri-ponderal mass index as a screening tool for obesity prediction in children aged 6-9 years.

Objective: This study aimed to evaluate the efficiency of tri-ponderal mass index (TMI) in determining obesity in Chinese children aged 6-9 years, using the criteria of percentage of body fat (PBF) and body mass index z-scores (BMI-Z). Methods: The cross-sectional study included 5365 children, aged 6-9 years, who participated in the project survey "Group prevention and treatment of obesity among students and school health promotion in Shanghai" from September 2007 to September 2009. Height, weight, waist circumference, body mass index (BMI), TMI, waist-to-height ratio (WHtR), and PBF were recorded. Statistical analyses including Kolmogorov-Smirnov test, chi-square test, receiver operating characteristics curve, and kappa chi-square test were performed. Results: TMI for both sexes was relatively constant with increasing age, and statistically significant differences were not observed at some ages (P > 0.05 at 6, 7, 8, and 9 years). WHtR showed subtle changes, while BMI and PBF increased significantly with age in boys and girls (P < 0.01). Using BMI-Z criteria as the measure of general obesity, the results indicated that TMI cutoff values for 6-9 years were 14.60 kg/m3 for boys and 14.84 kg/m3 for girls (P < 0.001). Analysis of the agreement between TMI and BMI-Z showed that the kappa statistic was 0.826 in boys and 0.709 in girls (P < 0.001). Conclusion: TMI, as a constant tool, holds great potential as an alternative screening method for identifying children aged 6-9 years who may be at risk of obesity at an early stage.

Developing Strategies to Improve the Efficacy of CAR-T Therapy for Acute Myeloid Leukemia.

OPINION STATEMENT: Acute myeloid leukemia (AML) is a fatal blood malignancy. With the development of immunotherapy, particularly chimeric antigen receptor T cells (CAR-T), the treatment of AML has undergone a significant change. Despite its advantages, CAR-T still faces a number of limitations and challenges while treating AML. Finding novel targets, altering the structure of CAR to increase efficacy while lowering side effects, and using double-target CAR and logic circuits are typical examples of key to answer these problems. With the advancement of gene editing technology, gene editing of tumor cells or normal cells to create therapeutic effects has grown in popularity. Additionally, the combination of multiple drugs is routinely used to address some of the obstacles and difficulties associated with CAR-T therapy. The review's primary goal was to summarize recent strategies and developments of CAR-T therapy for AML.

Hip circumference has independent association with the risk of hyperuricemia in middle-aged but not in older male patients with type 2 diabetes mellitus.

BACKGROUND: Obesity and type 2 diabetes mellitus (T2DM) are risk factors for hyperuricemia. However, which anthropometric indices can better predict incident hyperuricemia in patients with T2DM remains inconsistent. This study aimed to examine the associations between hyperuricemia and different anthropometric indices in middle-aged and older male patients with T2DM. METHODS: In this retrospective study, a total of 1447 middle-aged (45-65 years, n = 791) and older (≥ 65 years, n = 656) male patients with T2DM were collected from December 2015 to January 2020 at Shanghai Xinhua Hospital. Hyperuricemia was defined as a serum uric acid level above 7.0 mg/dL. Weight, height, waist circumference (WC) and hip circumference (HC) were measured by trained nurses at visit. RESULTS: The median uric acid level of subjects was 5.6 (interquartile ranges: 4.7-6.7) mg/dl, and 279 (19.3%) were hyperuricemia, with 146 (18.5%) in the middle-aged group, and 133 (20.3%) in the older group. After adjusting for age, duration of T2DM, fasting plasma glucose and insulin, homeostasis model assessment-ß, aspartate aminotransferase, triglycerides, high-density lipoprotein cholesterol and estimated glomerular filtration rate, body mass index (BMI), WC, HC, and waist-to-height ratio (WHtR) were associated with a higher risk of hyperuricemia in both middle-aged and older group (P < 0.05). After further adjusting for BMI and WC, HC still showed a positive relationship with the risk of hyperuricemia (Odds Ratio = 1.51, 95% confidence intervals: 1.06-2.14) in the middle-aged group, but such relationship was not found in the older group. Moreover, according to receiver operating characteristic analysis, the optimal cutoff value was 101.3 cm of HC for hyperuricemia screening in the middle-aged male patients with T2DM. CONCLUSION: In middle-aged male patients with T2DM, more attention should be paid to HC with the cutoff value of 101.3 cm in clinical practice for early recognition of individuals with a high risk of hyperuricemia for targeted guidance on disease prevention, such as community screening.

Claudin18.2 bispecific T cell engager armed oncolytic virus enhances antitumor effects against pancreatic cancer.

Bispecific T cell engagers (BiTEs) represent a promising immunotherapy, but their efficacy against immunologically cold tumors such as pancreatic ductal adenocarcinoma remains unclear. Oncolytic viruses (OVs) can transform the immunosuppressive tumor microenvironment into the active state and also serve as transgene vectors to selectively express the desired genes in tumor cells. This study aimed to investigate whether the therapeutic benefits of tumor-targeting Claudin18.2 BiTE can be augmented by combining cancer selectively and immune-potentiating effects of OVs. Claudin18.2/CD3 BiTE was inserted into herpes simplex virus type 1 (HSV-1) to construct an OV-BiTE. Its expression and function were assessed using reporter cells and peripheral blood mononuclear cell (PBMC) co-culture assays. Intratumoral application of OV-BiTE restrained tumor growth and prolonged mouse survival compared with the unarmed OV in xenograft models and syngeneic mice bearing CLDN18.2-expressing KPC or Pan02 pancreatic cancer cells. Flow cytometry of tumor-infiltrating immune cells suggested both OV-BiTE and the unarmed OV remodeled the tumor microenvironment by increasing CD4+ T cell infiltration and decreasing regulatory T cells. OV-BiTE further reprogrammed macrophages to a more pro-inflammatory antitumor state, and OV-BiTE-induced macrophages exhibited greater cytotoxicity on the co-cultured tumor cell. This dual cytotoxic and immunomodulatory approach warrants further development for pancreatic cancer before clinical investigation.

CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells.

Chimeric antigen receptor (CAR)-T cells have not made significant progress in the treatment of acute myeloid leukemia (AML) in earlyclinical studies. This lack of progress could be attributed in part to the immunosuppressive microenvironment of AML, such as monocyte-like myeloid-derived suppressor cells (M-MDSCs) and alternatively activated macrophages (M2 cells), which can inhibit the antitumor activity of CAR-T cells. Furthermore, AML cells are usually heterogeneous, and single-target CAR-T cells may not be able to eliminate all AML cells, leading to disease relapse. CD123 and NKG2D ligands (NKG2DLs) are commonly used targets for CAR-T therapy of AML, and M-MDSCs and M2 cells express both antigens. We developed dual-targeted CAR-T (123NL CAR-T) cells targeting CD123 and NKG2DL by various structural optimization screens. Our study reveals that 123NL CAR-T cells eradicate AML cells and selectively target immunosuppressive cells. A highly compact marker/suicide gene, RQR8, which binds targeting epitopes of CD34 and CD20 antigens, was also incorporated in front of the CAR structure. The binding of Rituximab to RQR8 leads to the elimination of 123NL CAR-T cells and cessation of their cytotoxicity. In conclusion, we successfully developed dual effects of 123NL CAR-T cells against tumor cells and immunosuppressive cells, which can avoid target escape and resist the effects of immunosuppressive microenvironment.

OX40L-Armed Oncolytic Virus Boosts T-cell Response and Remodels Tumor Microenvironment for Pancreatic Cancer Treatment.

Rationale: The resistance of pancreatic ductal adenocarcinoma (PDAC) to immunotherapies is caused by the immunosuppressive tumor microenvironment (TME) and dense extracellular matrix. Currently, the efficacy of an isolated strategy targeting stromal desmoplasia or immune cells has been met with limited success in the treatment of pancreatic cancer. Oncolytic virus (OV) therapy can remodel the TME and damage tumor cells either by directly killing them or by enhancing the anti-tumor immune response, which holds promise for the treatment of PDAC. This study aimed to investigate the therapeutic effect of OX40L-armed OV on PDAC and to elucidate the underlying mechanisms. Methods: Murine OX40L was inserted into herpes simplex virus-1 (HSV-1) to construct OV-mOX40L. Its expression and function were assessed using reporter cells, cytopathic effect, and immunogenic cell death assays. The efficacy of OV-mOX40L was then evaluated in a KPC syngeneic mouse model. Tumor-infiltrating immune and stromal cells were analyzed using flow cytometry and single-cell RNA sequencing to gain insight into the mechanisms of oncolytic virotherapy. Results: OV-mOX40L treatment delayed tumor growth in KPC tumor-bearing C57BL/6 mice. It also boosted the tumor-infiltrating CD4+ T cell response, mitigated cytotoxic T lymphocyte (CTL) exhaustion, and reduced the number of regulatory T cells. The treatment of OV-mOX40L reprogrammed macrophages and neutrophils to a more pro-inflammatory anti-tumor state. In addition, the number of myofibroblastic cancer-associated fibroblasts (CAF) was reduced after treatment. Based on single-cell sequencing analysis, OV-mOX40L, in combination with anti-IL6 and anti-PD-1, significantly extended the lifespan of PDAC mice. Conclusion: OV-mOX40L converted the immunosuppressive tumor immune microenvironment to a more activated state, remodeled the stromal matrix, and enhanced T cell response. OV-mOX40L significantly prolonged the survival of PDAC mice, either as a monotherapy or in combination with synergistic antibodies. Thus, this study provides a multimodal therapeutic strategy for pancreatic cancer treatment.

Role of chemokines in T-cell acute lymphoblastic Leukemia: From pathogenesis to therapeutic options.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous and aggressive subtype of hematologic malignancy, with limited therapeutic options due to the complexity of its pathogenesis. Although high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation have improved outcomes for T-ALL patients, there remains an urgent need for novel treatments in cases of refractory or relapsed disease. Recent research has demonstrated the potential of targeted therapies aimed at specific molecular pathways to improve patient outcomes. Chemokine-related signals, both upstream and downstream, modulate the composition of distinct tumor microenvironments, thereby regulating a multitude of intricate cellular processes such as proliferation, migration, invasion and homing. Furthermore, the progress in research has made significant contributions to precision medicine by targeting chemokine-related pathways. This review article summarizes the crucial roles of chemokines and their receptors in T-ALL pathogenesis. Moreover, it explores the advantages and disadvantages of current and potential therapeutic options that target chemokine axes, including small molecule antagonists, monoclonal antibodies, and chimeric antigen receptor T-cells.

Epstein‒Barr virus-associated cellular immunotherapy.

Epstein‒Barr virus (EBV) is a human herpes virus that is saliva-transmissible and universally asymptomatic. It has been confirmed that more than 90% of the population is latently infected with EBV for life. EBV can cause a variety of related cancers, such as nasopharyngeal carcinoma, diffuse large B-cell lymphoma, and Burkitt lymphoma. Currently, many clinical studies have demonstrated that EBV-specific cytotoxic T lymphocytes and other cell therapies can be safely and effectively transfused to prevent and treat some diseases caused by EBV. This review will mainly focus on discussing EBV-specific cytotoxic T lymphocytes and will touch on therapeutic EBV vaccines and chimeric antigen receptor T-cell therapy briefly.

Properties and composition of the spent electrolyte for premium circulation mediated by Al-air batteries.

Al-air batteries can serve as a bridge for high-quality cyclic utilization of aluminum resources. However, limited insights into the spent electrolyte are challenging to accurately adjust the recovery process to obtain premium Al-containing products. Herein, the properties and composition of the spent electrolyte were explored through experiments and theoretical calculations. The results demonstrate that the viscosity of the spent electrolyte increased with the rise in discharge current density, time and temperature under highly alkaline conditions, while the ionic conductivity and causticity obviously decreased. Al(OH)4- was the prime and balanced aluminate species when the battery was discharged at 25 °C and coexisted with a bit of [Al2O(OH)6]2-, [Al2O2(OH)6]4- and Al(OH)63- ions. Especially, the characteristics of the spent electrolyte were mainly dominated by the discharge time and temperature when the current density was continuously increased. There was only Al(OH)4- in the electrolyte at a higher discharge temperature. The DFT results also reveal that the polynuclear aluminate ions were produced by the interaction between the mononuclear aluminate ion Al(OH)4- and OH-. This work manifests a profound insight into the spent electrolyte from Al-air batteries for the efficient recycling of aluminum resources.

Bicistronic CAR-T cells targeting CD123 and CLL1 for AML to reduce the risk of antigen escape.

PURPOSE: Acute myeloid leukemia (AML) is a highly heterogeneous neoplastic disease with a poor prognosis that relapses even after its treatment with chimeric antigen receptor (CAR)-T cells targeting a single antigen. CD123 and CLL1 are expressed in most AML blasts and leukemia stem cells, and their low expression in normal hematopoietic stem cells makes them ideal targets for CAR-T. In this study, we tested the hypothesis that a new bicistronic CAR targeting CD123 and CLL1 can enhance antigenic coverage and prevent antigen escape and subsequent recurrence of AML. METHODS: CD123 and CLL1 expressions were evaluated on AML cell lines and blasts. Then, in addition to concentrating on CD123 and CLL1, we introduced the marker/suicide gene RQR8 with a bicistronic CAR. Xenograft models of disseminated AML and in vitro coculture models were used to assess the anti-leukemia efficacy of CAR-T cells. The hematopoietic toxicity of CAR-T cells was evaluated in vitro by colony cell formation assays. It was demonstrated in vitro that the combination of rituximab and NK cells caused RQR8-mediated clearance of 123CL CAR-T cells. RESULTS: We have successfully established bicistronic 123CL CAR-T cells that can target CD123 and CLL1. 123CL CAR-T cells effectively cleared AML cell lines and blasts. They also demonstrated appreciable anti-AML activity in animal transplant models. Moreover, 123CL CAR-T cells can be eliminated in an emergency by a natural safety switch and don't target hematopoietic stem cells. CONCLUSIONS: The bicistronic CAR-T cells targeting CD123 and CLL1 may be a useful and secure method for treating AML.

Targeted CD7 CAR T-cells for treatment of T-Lymphocyte leukemia and lymphoma and acute myeloid leukemia: recent advances.

The high expression of CD7 targets in T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoma has attracted considerable attention from researchers. However, because CD7 chimeric antigen receptor (CAR) T-cells undergo fratricide, CD7 CAR T-cells develop an exhaustion phenotype that impairs the effect of CAR T-cells. There have been significant breakthroughs in CD7-targeted CAR T-cell therapy in the past few years. The advent of gene editing, protein blockers, and other approaches has effectively overcome the adverse effects of conventional methods of CD7 CAR T-cells. This review, in conjunction with recent advances in the 64th annual meeting of the American Society of Hematology (ASH), provides a summary of the meaningful achievements in CD7 CAR T-cell generations and clinical trials over the last few years.