Delaying age at first sexual intercourse provides protection against oral cavity cancer: a mendelian randomization study.

Aim: To investigate whether age at first sexual intercourse could lead to any changes in the risk of oral cavity cancer. Methods: A two-sample mendelian randomization was conducted using genetic variants associated with age at first sexual intercourse in UK biobank as instrumental variables. Summary data of Northern American from a previous genome-wide association study aimed at oral cavity cancer was served as outcome. Three analytical methods: inverse variance-weighted, mendelian randomization Egger, and weighted median were used to perform the analysis, among which inverse variance-weighted was set as the primary method. Robustness of the results was assessed through Cochran Q test, mendelian randomization Egger intercept tests, MR PRESSO, leave one out analysis and funnel plot. Results: The primary analysis provided substantial evidence of a positive causal relationship age at first sexual intercourse and the risk of oral cavity cancer (p = 0.0002), while a delayed age at first sexual intercourse would lead to a decreased risk of suffering oral cavity cancer (ß = -1.013). The secondary outcomes confirmed the results (all ß < 0) and all assessments supported the robustness, too (all p > 0.05). Conclusion: The study demonstrates that a delayed sexual debut would provide protection against OCC, thus education on delaying sexual intercourse should be recommended.

Development and validation of a novel prognostic nomogram for advanced diffuse large B cell lymphoma.

Advanced diffuse large B cell lymphoma (DLBCL) is a common malignant tumor with aggressive clinical features and poor prognosis. At present, there is lack of effective prognostic tool for patients with advanced (stage III/IV) DLBCL. The aim of this study is to identify prognostic indicators that affect survival and response and establish the first survival prediction nomogram for advanced DLBCL. A total of 402 patients with advanced DLBCL were enrolled in this study. COX multivariate analysis was used to obtain independent prognostic factors. The independent prognostic factors were included in the nomogram, and the nomogram to predict the performance of the model was established by R rms package, C-index (consistency index), AUC curve and calibration curve. The training and validation cohorts included 281 and 121 patients. In the training cohort, multivariate analysis showed that Ki-67 (70% (high expression) vs ≤ 70% (low expression), p < 0.001), LDH (lactate dehydrogenase) (elevated vs normal, p = 0.05), FER (ferritin) (elevated vs normal, p < 0.001), and ß2-microglobulin (elevated vs normal, p < 0.001) were independent predictors and the nomogram was constructed. The nomogram showed that there was a significant difference in OS among the low-risk, intermediate-risk and high-risk groups, with 5-year survival rates of 81.6%, 44% and 6%, respectively. The C-index of the nomogram in the training group was 0.76. The internal validation of the training group showed good consistency. In the internal validation cohort of the training group, the AUC was 0.828, and similar results were obtained in the validation group, with a C-index of 0.74 and an AUC of 0.803. The proposed nomogram provided a valuable individualized risk assessment of OS in advanced DLBCL patients.

Application of CMV-IVIg as prophylaxis against cytomegalovirus reactivation in allogeneic hematopoietic stem cell transplantation patients.

Cytomegalovirus (CMV) reactivation remains one of the major and life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Yet, there is still a lack of safe and effective ways to prevent CMV reactivation in allo-HSCT patients. Here, we retrospectively analyzed a cohort of patients who underwent HSCT at our transplant center between 2018 and 2022 to evaluate the efficacy of prophylactic CMV-specific intravenous immunoglobulin (CMV-IVIg) against CMV reactivation. After Propensity Score Matching, the CMV reactivation rate was significantly decreased in the CMV-IVIg group (HR, 2.952; 95% CI,1.492-5.841; P = .002) compared with the control group. Additionally, the time duration of CMV reactivation (P = .001) and bacterial infection rate (P = .013) were significantly lower in the CMV-IVIg group. Moreover, prophylactic CMV-IVIg was more effective in CMV seropositive patients who received ATG as part of GVHD prevention (HR, 8.225; 95% CI,1.809-37.39; P = .006). In conclusion, CMV-IVIg is considered an effective and safe way to prevent CMV reactivation in HSCT recipients, which may be related to the acceleration of immune reconstitution in the early stage after transplantation.

Novel Synthesis Approach for Natural Tea Polyphenol-Integrated Hydroxyapatite.

Hydroxyapatite (HAP) has garnered considerable interest in biomedical engineering for its diverse applications. Yet, the synthesis of HAP integrated with functional natural organic components remains an area ripe for exploration. This study innovatively utilizes the versatile properties of tea polyphenol (TP) to synthesize HAP nanomaterials with superior crystallinity and distinct morphologies, notably rod-like structures, via a chemical deposition process in a nitrogen atmosphere. This method ensures an enhanced integration of TP, as confirmed by thermogravimetric (TGA) analysis and a variety of microscopy techniques, which also reveal the dependence of TP content and crystallinity on the synthesis method employed. The research significantly impacts the field by demonstrating how synthesis conditions can alter material properties. It leads the way in employing TP-modified nano-HAP particles for biomedical applications. The findings of this study are crucial as they open avenues for the future development of tailored HAP nanomaterials, aiming at specific medical applications and advancements in nanotechnology.

pH-Responsive Carrier-Free Polyphenol Nanoparticles Assembled by Oxidative Polymerization with Enhanced Stability and Antioxidant Activity for Improved Bioaccessibility.

Encapsulation of plant polyphenols with micro-/nano-carriers for enhanced bioavailability has been well documented, but the preparation of these carriers and subsequent loading of polyphenols is a multiple process, which is generally complicated with potentially unexpected negative effects on the bioactivity of the polyphenols. Here, we reported a convenient method to assemble carrier-free polyphenol nanoparticles (NPs) based on oxidative coupling polymerization. The effectiveness was assessed with five different polyphenols including pyrocatechol (PY), catechin (CA), epigallocatechin gallate (EGCG), tannic acid (TA), and proanthocyanidin (PC). The structural characteristics of these assembled nanoparticles (PY NPs, CA NPs, EG NPs, TA NPs, and PC NPs) were systematically analyzed with dynamic light scattering (DLS), transmission electron microscopy (TEM), UV-visible spectroscopy, and Fourier transform infrared spectroscopy (FTIR). All NPs were colloidally stable with varying NaCl concentrations from 0 to 300 mM, were acid-resistant and alkali-intolerant, and were suitable for oral administration. An array of antioxidant assays further confirmed the superior antioxidant capabilities of NPs over Trolox and polyphenol monomers, indicating that the oxidative polymerization of polyphenols did not compromise the polyphenol activity of NPs. The in vitro simulated digestion studies validated that these responsive NPs were actually gastrointestinal pH-responsive and applicable to the gastrointestinal physiological environment. The bioaccessibility assessments by using a static in vitro digestion model revealed that better results were achieved with NPs than polyphenol monomers, with TA NPs showing about 1.5-fold higher bioaccessibility than other polyphenol nanoparticles. The present study with five polyphenols demonstrated that the oxidative polymerization of polyphenols provides an effective platform to assemble various carrier-free NPs with enhanced antioxidant activity, favorable stability, and improved bioaccessibility, which could be used promisingly as a functional food ingredient in food matrices or as oral drug delivery candidates for helping to manage human health or treating various gastrointestinal disorders in both the pharmaceutical and nutritional fields.

Influences of carboxymethyl chitosan upon stabilization and gelation of O/W Pickering emulsions in the presence of inorganic salts.

The objective of this study was to investigate the effects of carboxymethyl chitosan (CMCS) on the stabilization and gelation of oil-in-water (O/W) Pickering emulsions (PEs) with polyphenol-amino acid particles in the presence of inorganic salts. The results revealed that the CMCS-induced depletion interactions contributed to improving the emulsification ability and interfacial adsorption efficiency of polyphenol-amino acid particles as well as constructing the network structures in the continuous phase. These relevant changes collectively resulted in elevating stability, viscosity and moduli of PEs. The additional effects of different inorganic salts with varying additions were further investigated, and the addition-dependent phenomena were observed. At low additions of inorganic salts, the occurrence of the chelation of inorganic salts with CMCS consolidated the constructed network structure, favorable to the gelation of PEs. With increasing additions, this chelation effect became stronger which compromised the CMCS-induced depletion, gradually leading to destabilization of PEs. In terms of ion species, the more pronounced effect on emulsion stability was achieved with calcium ions than with potassium and iron ions. This study expects to provide a new perspective on the extending application of cationic CMCS for improving the stability of O/W PEs in the food industry.

MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation.

CDK4/6 inhibitors (CDK4/6i) show anticancer activity in certain human malignancies, such as breast cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Here, we demonstrate that MYC amplification confers resistance to CDK4/6i in bladder, prostate and breast cancer cells. Mechanistically, MYC binds to the promoter of the E3 ubiquitin ligase KLHL42 and enhances its transcription, leading to RB1 deficiency by inducing both phosphorylated and total pRB1 ubiquitination and degradation. We identify a compound that degrades MYC, A80.2HCl, which induces MYC degradation at nanomolar concentrations, restores pRB1 protein levels and re-establish sensitivity of MYC high-expressing cancer cells to CDK4/6i. The combination of CDK4/6i and A80.2HCl result in marked regression in tumor growth in vivo. Altogether, these results reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the utilization of the MYC degrading molecule A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i.

Collagen Scaffolds Functionalized by Cu2+-Chelated EGCG Nanoparticles with Anti-Inflammatory, Anti-Oxidation, Vascularization, and Anti-Bacterial Activities for Accelerating Wound Healing.

Skin injury is a common health problem worldwide, and the highly complex healing process poses critical challenges for its management. Therefore, wound dressings with salutary effects are urgently needed for wound care. However, traditional wound dressing with a single function often fails to meet the needs of wound repair, and the integration of multiple functions has been required for wound repair. Herein, Cu2+-chelated epigallocatechin gallate nanoparticles (EAC NPs), with radical scavenging, inflammation relieving, bacteria restraining, and vascularization accelerating capacities, are adopted to functionalize collagen scaffold, aiming to promote wound healing. Radical scavenging experiments verify that EAC NPs could efficiently scavenge radicals. Additionally, EAC NPs could effectively remove Escherichia coli and Staphylococcus aureus. H2O2 stimuli-responsive EAC NPs show slow and sustained release properties of Cu2+. Furthermore, EAC NPs exhibit protective effects against H2O2-induced oxidative-stress damage and anti-inflammatory activity in vivo. Physicochemical characterizations show that the introduction of EAC NPs does not disrupt the gelation behavior of collagen, and the composite scaffolds (CS) remain porous structure similar to collagen scaffold. Animal experiments demonstrate that CS could promote wound healing through improving the thickness of renascent epidermis and number of new vessels. CS with multiple salutary functions is a promising dressing for wound care.

Docosahexaenoic and Eicosapentaenoic Acids Promote the Accumulation of Browning-Related Myokines via Calcium Signaling in Insulin-Resistant Mice.

BACKGROUND: Myokines have a prominent effect on improving insulin resistance (IR) by inducing browning of white adipose tissue (WAT). Although docosahexaenoic acids (DHA) and eicosapentaenoic acids (EPA) play roles in improving IR and stimulating browning, whether they mediate myokines directly remains unknown. OBJECTIVE: This study aims to investigate the effects of DHA and EPA on browning-related myokines under IR and clarify the mechanism via Ca2+ signaling. METHODS: The expression and secretion levels of myokines in IR mice and IR myotubes were detected after DHA/EPA treatment. The crosstalk between myotubes and adipocytes was evaluated through a method in which IR adipocytes were treated with the culture medium supernatant of myotubes treated with DHA/EPA. The expression of browning markers in the WAT of IR mice and adipocytes was determined. A calcium chelator was used to determine whether DHA and EPA regulate myokine production through a calcium ion-dependent pathway. RESULTS: In vivo experiments: 3:1 and 1:3 DHA/EPA promoted the mRNA levels of Irisin, IL-6, IL-15, and FGF21 in skeletal muscle, stimulated WAT browning, reduced lipid accumulation; 3:1 DHA/EPA upregulated the serum concentration of Irisin; 1:3 DHA/EPA upregulated the serum concentrations of Irisin, IL-6, and FGF21. In vitro experiments: the levels of Irisin and IL-6 in C2C12 myotubes and their medium supernatant were significantly elevated in the 3:1 and 1:3 groups and the upregulation of browning markers and reduction in fat accumulation were observed in adipocytes treated with the medium supernatant of C2C12 myotubes in the 3:1 and 1:3 groups. However, the above phenomena disappeared when Ca2+ signaling was inhibited. CONCLUSIONS: Treatment with DHA and EPA at composition ratios of 3:1 and 1:3 induces browning of WAT in IR mice, which is likely related to the promotion of the accumulation of myokines, especially Irisin and IL-6, via Ca2+ signaling.

Inhaled immunoantimicrobials for the treatment of chronic obstructive pulmonary disease.

Effective therapeutic modalities and drug administration strategies for the treatment of chronic obstructive pulmonary disease (COPD) exacerbations are lacking. Here, mucus and biofilm dual-penetrating immunoantimicrobials (IMAMs) are developed for bridging antibacterial therapy and pro-resolving immunotherapy of COPD. IMAMs are constructed from ceftazidime (CAZ)-encapsulated hollow mesoporous silica nanoparticles (HMSNs) gated with a charge/conformation-transformable polypeptide. The polypeptide adopts a negatively charged, random-coiled conformation, masking the pores of HMSNs to prevent antibiotic leakage and allowing the nebulized IMAMs to efficiently penetrate the bronchial mucus and biofilm. Inside the acidic biofilm, the polypeptide transforms into a cationic and rigid α helix, enhancing biofilm retention and unmasking the pores to release CAZ. Meanwhile, the polypeptide is conditionally activated to disrupt bacterial membranes and scavenge bacterial DNA, functioning as an adjuvant of CAZ to eradicate lung-colonizing bacteria and inhibiting Toll-like receptor 9 activation to foster inflammation resolution. This immunoantibacterial strategy may shift the current paradigm of COPD management.

Responses of composition and metabolism of microbial communities during the remediation of black and odorous water using bioaugmentation and aeration.

This study elucidated the effect patterns of aeration and bioaugmentation on indigenous microbial communities, metabolites, and metabolic pathways in the remediation of black and odorous water. This is crucial for the precise formulation and targeted development of effective microbial consortia, as well as for tracking and forecasting the bioremediation of black and odorous water. The results confirmed that combining bioaugmentation with aeration markedly enhanced the degradation of COD, NH4+-N, and TN and the conversion of Fe and Mn. Aeration significantly increased the relative abundance of Flavobacterium and Diaphorobacter, and the positive interbacterial interaction in the effective microbial consortia EM31 gave the constituent strain Klebsiella and Bacillus a dominant niche in the bioaugmentation. Furthermore, bioaugmentation improved the capacity of the indigenous microbial consortia to utilize basic carbon source, particularly the utilization of L-glycerol, I-erythritol, glucose-1-phosphate, and the catabolism of cysteine and methionine. Moreover, during the remediation of black and odorous water by aeration and bioaugmentation, Glucosinolate biosynthesis (map00966), Steroid hormone biosynthesis (map00140), Folate biosynthesis (map00790), One carbon pool by folate (map00670), and Tyrosine metabolism (map00350) were identified as key functional metabolic pathways in microbial communities.

Exploring BODIPY derivatives as sonosensitizers for anticancer sonodynamic therapy.

Sonodynamic therapy (SDT) is an emerging non-invasive and effective therapeutic modality for cancer treatment bearing benefit of deep tissue-penetration in comparison to photo-inspired therapy. However, exploring novel sonosensitizers with high sonosensitivity and desirable biosafety remains a significant challenge. Although boron dipyrromethene (BODIPY) dyes have been widely used in biomedical filed, no BODIPY-based sonosensitizers have been reported yet. Herein, we synthesized four BODIPY dyes (BDP1-BDP4) and investigated their potential applications in SDT. BDP4 exhibited superb sonosensitivity and high SDT efficiency against cancer cells and tumors in tumor-bearing mice. The types of the generated reactive oxygen species, cavitation effect, and cell apoptosis were investigated to figure out the sonodynamic therapeutic mechanisms of BDP4. This work for the first time demonstrates the potential of BODIPY dyes as novel sonosensitizers for SDT, which may pave an avenue for developing more efficient and safer sonosensitizers in future.

Molecular dynamics study of the corrosion protection improvement of superhydrophobic dodecyltrimethoxysilane film on mild steel.

Recently, superhydrophobic surfaces have received increasing interest in metal corrosion protection due to their excellent waterproofing characteristics. However, little attention has been paid to the related anti-corrosion mechanism at the molecular level. In this work, the protection behaviors provided by the superhydrophobic dodecyltrimethoxysilane for mild steel were first explored using molecular dynamics (MD) simulation in terms of silane absorption orientations and water cluster wetting behaviors. The results show that the conformations of dodecyltrihydroxysilane (DTHS) on the Fe substrate are greatly dependent on the solvent environment. Typically, the DTHS molecule adopts a "standing" orientation with the hydrophilic head attached to the Fe surface and the hydrophobic tail remaining in the polar phase, which is conducting to generate a good repulsive effect on the water droplet. Based on this, the diffusion performance of corrosive species in the superhydrophobic DTHS film was further investigated. The computational results indicate that the corrosive species are confined to specific regions of the film, which results in a decreased diffusion coefficient. Additionally, the weak movement of DTHS molecules also increases the transport resistance of the corrosive medium through the superhydrophobic DTHS film, thereby improving the corrosion protection of the underlying metal substrate. The results obtained in this work will deepen our understanding of the anticorrosion mechanism of superhydrophobic silane films.

Tea polyphenol carrier-enhanced dexamethasone nanomedicines for inflammation-targeted treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by synovial inflammation, cartilage damage and bone erosion. In the progression of RA, the inflammatory mediators including ROS, NO, TNF-α, and IL-6 play important roles in the aggravation of inflammation. Hence, reducing the generation and release of inflammatory mediators is of great importance. However, the high dose and frequent administration of clinical anti-inflammatory drugs such as glucocorticoids (GCs) usually lead to severe side effects. The development of nanotechnology provides a promising strategy to overcome these issues. Here, polyphenol-based nanoparticles with inherent anti-oxidative and anti-inflammatory activities were developed and used as a kind of nanocarrier to deliver dexamethasone (Dex). The in vitro experiments confirmed that the nanoparticles and drugs could act synergistically for suppressing inflammatory mediators in the LPS/INF-γ-induced inflammatory cell model. After intravenous administration, the Dex-loaded nanoparticles with good biosafety showed effective accumulation in inflamed joints and improved therapeutic efficacy by inducing anesis of synovial inflammation and cartilage destruction over free Dex in a collagen-induced arthritis (CIA) mouse model. The results demonstrated that polyphenol-based nanoparticles with therapeutic functions may serve as an innovative platform to synergize with chemotherapeutic agents for enhanced treatment of inflammatory diseases.

Pedicle Subtraction Osteotomy Versus Multilevel Anterior Lumbar Interbody Fusion and Lateral Lumbar Interbody Fusion in the Treatment of Adult Spinal Deformity: Trends, Outcomes, and Cost.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The aim of this study was to compare the outcomes of pedicle subtraction osteotomy (PSO) with multilevel anterior lumbar interbody fusion (ALIF) and lateral lumbar interbody fusion (LLIF) in posterior long-segment fusion. BACKGROUND: PSO and ALIF/LLIF are 2 techniques used to restore lumbar lordosis and correct sagittal alignment, with each holding its unique advantages and disadvantages. As there are situations where both techniques can be employed, it is important to compare the risks and benefits of both. PATIENTS AND METHODS: Patients aged 18 years or older who underwent PSO or multilevel ALIF/LLIF with posterior fusion of 7-12 levels and pelvic fixation were identified. 1:1 propensity score was used to match PSO and ALIF/LLIF cohorts for age, sex, and relevant comorbidities, including smoking status. Logistic regression was used to compare medical and surgical outcomes. Trends and costs were generated for both groups as well. RESULTS: ALIF/LLIF utilization in posterior long fusion has been steadily increasing since 2010, whereas PSO utilization has significantly dropped since 2017. PSO was associated with an increased risk of durotomy (P < 0.001) and neurological injury (P = 0.018). ALIF/LLIF was associated with increased rates of postoperative radiculopathy (P = 0.005). Patients who underwent PSO had higher rates of pseudarthrosis within 1 and 2 years (P = 0.015; P = 0.010), 1-year hardware failure (P = 0.028), and 2-year reinsertion of instrumentation (P = 0.009). Reoperation rates for both approaches were not statistically different at any time point throughout the 5-year period. In addition, there were no significant differences in both procedural and 90-day postoperative costs. CONCLUSIONS: PSO was associated with higher rates of surgical complications compared with anterior approaches. However, there was no significant difference in overall reoperation rates. Spine surgeons should select the optimal technique for a given patient and the type of lordotic correction required.

Mobile health supported multi-domain recovery trajectories after major arthroplasty or spine surgery: a pilot feasibility and usability study.

BACKGROUND: Recovery after surgery intersects physical, psychological, and social domains. In this study we aim to assess the feasibility and usability of a mobile health application called PositiveTrends to track recovery in these domains amongst participants undergoing hip, knee arthroplasty or spine surgery. Our secondary aim was to generate procedure-specific, recovery trajectories within the pain and medication, psycho-social and patient-reported outcomes domain. METHODS: Prospective, observational study in participants greater than eighteen years of age. Data was collected prior to and up to one hundred and eighty days after completion of surgery within the three domains using PositiveTrends. Feasibility was assessed using participant response rates from the PositiveTrends app. Usability was assessed quantitatively using the System Usability Scale. Heat maps and effect plots were used to visualize multi-domain recovery trajectories. Generalized linear mixed effects models were used to estimate the change in the outcomes over time. RESULTS: Forty-two participants were enrolled over a four-month recruitment period. Proportion of app responses was highest for participants who underwent spine surgery (median = 78, range = 36-100), followed by those who underwent knee arthroplasty (median = 72, range = 12-100), and hip arthroplasty (median = 62, range = 12-98). System Usability Scale mean score was 82 ± 16 at 180 days postoperatively. Function improved by 8 and 6.4 points per month after hip and knee arthroplasty, respectively. In spine participants, the Oswestry Disability Index decreased by 1.4 points per month. Mood improved in all three cohorts, however stress levels remained elevated in spine participants. Pain decreased by 0.16 (95% Confidence Interval: 0.13-0.20, p < 0.001), 0.25 (95% CI: 0.21-0.28, p < 0.001) and 0.14 (95% CI: 0.12-0.15, p < 0.001) points per month in hip, knee, and spine cohorts respectively. There was a 10.9-to-40.3-fold increase in the probability of using no medication for each month postoperatively. CONCLUSIONS: In this study, we demonstrate the feasibility and usability of PositiveTrends, which can map and track multi-domain recovery trajectories after major arthroplasty or spine surgery.

Impact of genetic patterns on sorafenib efficacy in patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation: a multi-center, cohort study.

Sorafenib therapy improves overall survival (OS) in patients with FLT3 internal tandem duplication (ITD) acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation. We explored the efficacy of sorafenib therapy in this population with different concomitant genetic patterns. In this multi-center, cohort study, we enrolled patients with FLT3-ITD AML undergoing allogenic hematopoietic cell transplantation. Patients with sorafenib maintenance post-transplantation for at least four weeks were allocated to the sorafenib group, and otherwise to the control group. Endpoints were OS, disease-free survival, and relapse for the whole cohort and OS for genetic pattern subgroups. Among 613 patients enrolled, 275 were in the sorafenib and 338 the control group. Median follow-up was 36.5 (interquartile range (IQR), 25.2-44.7) months post-transplantation. The 3-year OS post-transplantation was 79.6% (95% confidential interval (CI) 74.8%-84.6%) and 65.2% (95% CI 60.3%-70.6%) (Hazard ratio (HR) 0.50, 95% CI 0.37-0.69; P < 0.0001) in both groups. Sorafenib maintenance post-transplantation improved OS in the favorable (HR 0.33, 95% CI 0.14-0.77; P = 0.011) and adverse (HR 0.56, 95% CI 0.33-0.93; P = 0.026) ELN 2017 risk subgroups. Patients with mutated NPM1, DNMT3A, co-occurring NPM1/DNMT3A, "activated signaling" and "DNA methylation" genes benefited in OS from sorafenib maintenance, while those carrying CEBPA, "tumor suppressors" and "myeloid transcription factors" genes did not. Patients with FLT3-ITDhigh and FLT3-ITDlow AML both benefited in OS from sorafenib maintenance. Our results identify the response of genetic patterns to sorafenib maintenance, providing new viewpoints for the optimal use of sorafenib in FLT3-ITD AML in the transplantation setting.

Chimeric antigen receptor-immune cells against solid tumors: Structures, mechanisms, recent advances, and future developments.

ABSTRACT: The advent of chimeric antigen receptor (CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies. However, their success in treating solid tumors has been limited. CAR-natural killer (NK) cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex (MHC), which means they are more likely to become an "off-the-shelf" product. Moreover, they can kill cancer cells via CAR-dependent/independent pathways and have limited toxicity. Macrophages are the most malleable immune cells in the body. These cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments (TMEs). Importantly, CAR-macrophages (CAR-Ms) have recently yielded exciting preclinical results in several solid tumors. Nevertheless, CAR-T, CAR-NK, and CAR-M all have their own advantages and limitations. In this review, we systematically discuss the current status, progress, and the major hurdles of CAR-T cells, CAR-NK cells, and CAR-M as they relate to five aspects: CAR structure, therapeutic mechanisms, the latest research progress, current challenges and solutions, and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.

Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Our open-label, multicentre, randomised, phase 3 trial showed that sorafenib maintenance after haematopoietic stem-cell transplantation (HSCT) improved overall survival and reduced relapse for patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic HSCT. Here, we present a post-hoc analysis on the 5-year follow-up data of this trial. METHODS: This phase 3 trial, done in seven hospitals in China, included patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT, who were aged 18-60 years, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days after transplantation. Patients were randomly assigned (1:1) to receive sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days after transplantation. Randomisation was done with permuted blocks (block size four) via an interactive web-based system. Investigators and participants were not masked to group assignment. The primary endpoint was the 1-year cumulative incidence of relapse, which was reported previously. For this updated analysis, the 5-year endpoints were overall survival; cumulative incidence of relapse; non-relapse mortality; leukaemia-free survival; graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); cumulative incidence of chronic GVHD; and late effects in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02474290, and is complete. FINDINGS: Between June 20, 2015, and July 21, 2018, 202 patients were randomly assigned to sorafenib maintenance (n=100) or non-maintenance (n=102). Median follow-up was 60·4 months (IQR 16·7-73·3). Extended follow-up showed improved overall survival (72·0% [95% CI 62·1-79·7] vs 55·9% [45·7-64·9]; hazard ratio [HR] 0·55, 95% CI 0·34-0·88; p=0·011), leukaemia-free survival (70·0% [60·0-78·0] vs 49·0% [39·0-58·3]; 0·47, 0·30-0·73; p=0·0007), and GRFS (58·0% [47·7-67·0] vs 39·2% [29·8-48·5]; 0·56, 0·38-0·83; p=0·0030), lower cumulative incidence of relapse (15·0% [8·8-22·7] vs 36·3% [27·0-45·6]; 0·33, 0·18-0·60; p=0·0003), and no increase in non-relapse mortality (15·0% [8·8-22·7] vs 14·7% [8·6-22·3]; 0·79, 0·39-1·62; p=0·98) for patients in the sorafenib group compared with those in the control group. The 5-year cumulative incidence of chronic GVHD (54·0% [43·7-63·2] vs 51·0% [40·8-60·3]; 0·82, 0·56-1·19; p=0·73) did not differ significantly between the two groups and we did not find substantial differences in late effects between the two groups. There were no treatment-related deaths. INTERPRETATION: With extended follow-up, sorafenib maintenance after transplantation is associated with improved long-term survival and reduced relapse rates compared with non-maintenance, further supporting this strategy as a standard of care for patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT. FUNDING: None. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Abnormal balance control mechanisms during dynamic reaching forward and quiet standing in patients with anterior cruciate ligament reconstruction.

Purpose: Postural instability and decreased balance control ability have been observed in patients after anterior cruciate ligament (ACL) reconstruction. Herein, we examined the abnormal balance control mechanisms of these patients during dynamic reaching forward and quiet standing, providing a quantitative index for rehabilitation assessment. Methods: We enrolled ACL reconstruction patients 6-8 months after surgery, and 14 gender- and age-matched healthy volunteers. The IKDC and Lysholm were applied in each patient after ACL reconstruction. All participants conducted the quiet standing and reaching forward (RF) tests at the specified locations on force plates. The ground reaction force, center of pressure (COP), and kinematics signals were recorded. The maximal reach distance (MRD), speed of RF, length of COP, peak speed of COP in anterior-posterior direction (AP-COP), and weight bearing ratio (WBR) of the affected limb were calculated in the RF test. The COP speed, COP amplitude, frequency components of COP and WBR were extracted during quiet standing. Results: We observed that the speed of RF in the patients after ACL reconstruction was significantly lower than that of controls (p < 0.05). The COP length during RF was positively correlated with the Lysholm scale in the affected limb of patients (r = 0.604, p < 0.05). The peak of AP-COP speed during RF in the affected limb of patients was significantly lower than that of the healthy controls (p < 0.05), and positively correlated with the IKDC scale (r = 0.651, p < 0.05). WBR on the affected limb of patients during RF were significantly lower than that of controls (p < 0.05). The mean (r = -0.633, p < 0.05) and peak (r = -0.643, p < 0.05) speeds of COP during quiet standing were negatively correlated with the IKDC scale value. The amplitude of AP-COP on the contralateral side of patients was significantly higher than that of controls during quiet standing (p < 0.05). Conclusion: Patients after ACL reconstruction performed decreased postural control capacity, especially in dynamic balance, and were accompanied by deficiencies in proprioception. The COP length, peak speed of COP during RF and COP speed during quiet standing could be considered as quantitative index of balance function assessment after ACL reconstruction.