Development and validation of a random survival forest model for predicting long-term survival of early-stage young breast cancer patients based on the SEER database and an external validation cohort.

Young breast cancer (YBC) patients often face a poor prognosis, hence it's necessary to construct a model that can accurately predict their long-term survival in early stage. To realize this goal, we utilized data from the Surveillance, Epidemiology, and End Results (SEER) databases between January 2010 and December 2020, and meanwhile, enrolled an independent external cohort from Tianjin Medical University Cancer Institute and Hospital. The study aimed to develop and validate a prediction model constructed using the Random Survival Forest (RSF) machine learning algorithm. By applying the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, we pinpointed key prognostic factors for YBC patients, which were used to create a prediction model capable of forecasting the 3-year, 5-year, 7-year, and 10-year survival rates of YBC patients. The RSF model constructed in the study demonstrated exceptional performance, achieving C-index values of 0.920 in the training set, 0.789 in the internal validation set, and 0.701 in the external validation set, outperforming the Cox regression model. The model's calibration was confirmed by Brier scores at various time points, showcasing its excellent accuracy in prediction. Decision curve analysis (DCA) underscored the model's importance in clinical application, and the Shapley Additive Explanations (SHAP) plots highlighted the importance of key variables. The RSF model also proved valuable in risk stratification, which has effectively categorized patients based on their survival risks. In summary, this study has constructed a well-performed prediction model for the evaluation of prognostic factors influencing the long-term survival of early-stage YBC patients, which is significant in risk stratification when physicians handle YBC patients in clinical settings.

Overexpression of GPX2 gene regulates the development of porcine preadipocytes and skeletal muscle cells through MAPK signaling pathway.

Glutathione peroxidase 2 (GPX2) is a selenium-dependent enzyme and protects cells against oxidative damage. Recently, GPX2 has been identified as a candidate gene for backfat and feed efficiency in pigs. However, it is unclear whether GPX2 regulates the development of porcine preadipocytes and skeletal muscle cells. In this study, adenoviral gene transfer was used to overexpress GPX2. Our findings suggest that overexpression of GPX2 gene inhibited proliferation of porcine preadipocytes. And the process is accompanied by the reduction of the p-p38. GPX2 inhibited adipogenic differentiation and promoted lipid degradation, while ERK1/2 was reduced and p-p38 was increased. Proliferation of porcine skeletal muscle cells was induced after GPX2 overexpression, was accompanied by activation in JNK, ERK1/2, and p-p38. Overexpression methods confirmed that GPX2 has a promoting function in myoblastic differentiation. ERK1/2 pathway was activated and p38 was suppressed during the process. This study lays a foundation for the functional study of GPX2 and provides theoretical support for promoting subcutaneous fat reduction and muscle growth.

Clarification of the infection pattern of Xanthomonas citri subsp. citri on citrus fruit by artificial inoculation.

BACKGROUND: Citrus canker is a significant bacterial disease caused by Xanthomonas citri subsp. citri (Xcc) that severely impedes the healthy development of the citrus industry. Especially when citrus fruit is infected by Xcc, it will reduce or even lost its commercial value. However, due to the prolonged fruiting cycle and intricate structure, much less research progress had been made in canker disease on fruit than on leaf. In fact, limited understanding has been achieved on canker development and the response to Xcc infection in fruit. RESULTS: Herein, the progression of canker disease on sweet orange fruit was tracked in the field. Results indicated that typical lesions initially appear on the sepal, style residue, nectary disk, epicarp, and peduncle of young fruits after petal fall. The susceptibility of fruits to Xcc infection diminished as the fruit developed, with no new lesions forming at the ripening stage. The establishment of an efficient method for inoculating Xcc on fruit as well as the artificial inoculation throughout the fruit's developmental cycle clarified this infection pattern. Additionally, microscopic observations during the infection process revealed that Xcc invasion caused structural changes on the surface and cross-section of the fruit. CONCLUSIONS: An efficient system for inoculation on citrus fruit with Xcc was established, by which it can serve for the evaluation of citrus germplasm for canker disease resistance and systematic research on the interactions between Xcc and citrus fruits.

Role of umbilical cord mesenchymal stromal cells in skin rejuvenation.

Aging is the main cause of many degenerative diseases. The skin is the largest and the most intuitive organ that reflects the aging of the body. Under the interaction of endogenous and exogenous factors, there are cumulative changes in the structure, function, and appearance of the skin, which are characterized by decreased synthesis of collagen and elastin, increased wrinkles, relaxation, pigmentation, and other aging characteristics. skin aging is inevitable, but it can be delayed. The successful isolation of mesenchymal stromal cells (MSC) in 1991 has greatly promoted the progress of cell therapy in human diseases. The International Society for Cellular Therapy (ISCT) points out that the MSC is a kind of pluripotent progenitor cells that have self-renewal ability (limited) in vitro and the potential for mesenchymal cell differentiation. This review mainly introduces the role of perinatal umbilical cord-derived MSC(UC-MSC) in the field of skin rejuvenation. An in-depth and systematic understanding of the mechanism of UC-MSCs against skin aging is of great significance for the early realization of the clinical transformation of UC-MSCs. This paper summarized the characteristics of skin aging and summarized the mechanism of UC-MSCs in skin rejuvenation reported in recent years. In order to provide a reference for further research of UC-MSCs to delay skin aging.

ROS-responsive core-shell nano-inhibitor impedes pyruvate metabolism for reinforced photodynamic therapy and interrupted pre-metastatic niche formation.

The formation of pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor requires the communication between the tumor cells and the host environment. Pyruvate is a fundamental nutrient by which the tumor cells metabolically reshape the extracellular matrix in the lung to facilitate their own metastatic development. Here we report a combination regimen by integrating the photo-sensitizer and the mitochondrial pyruvate carrier (MPC) inhibitor in a dendritic polycarbonate core-hyaluronic acid shell nano-platform with multivalent reversible crosslinker embedded in it (DOH-NI+L) to reinforce photodynamic therapy (PDT) toward the primary tumor and interrupt PMN formation in the lung via impeding pyruvate uptake. We show that DOH-NI+L mediates tumor-specific MPC inhibitor liberation, inhibiting the aerobic respiration for facilitated PDT and restraining ATP generation for paralyzing cell invasion. Remarkably, DOH-NI+L is demonstrated to block the metabolic crosstalk of tumor cell-host environment by dampening pyruvate metabolism, provoking a series of metabolic responses and resulting in the pulmonary PMN interruption. Consequently, DOH-NI+L realizes a significant primary tumor inhibition and an efficient pulmonary metastasis prevention. Our research extends nano-based anti-metastatic strategies aiming at PMN intervention and such a dendritic core-shell nano-inhibitor provides an innovative paradigm to inhibit tumor growth and prevent metastasis efficiently. STATEMENT OF SIGNIFICANCE: In the progression of cancer metastasis, the formation of a pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor is one of the rate-limiting stages. The current nano-based anti-metastatic modalities mainly focus on targeted killing of tumor cells and specific inhibition of tumor cell invasion, while nanomedicine-mediated interruption of PMN formation has been rarely reported. Here we report a combination regimen by integrating a photo-sensitizer and an inhibitor of mitochondrial pyruvate carrier in a dendritic core-shell nano-platform with a reversible crosslinker embedded in it to reinforce PDT toward the primary tumor and interrupt PMN formation via impeding the uptake of pyruvate that is a fundamental nutrient facilitating aerobic respiration and PMN formation. Our research proposed a nano-based anti-metastatic strategy aiming at PMN intervention.

Genetically supported causality between gut microbiota and frailty: a two-sample Mendelian randomization study.

Background: A mounting body of evidence suggests a strong connection between gut microbiota and the risk of frailty. However, the question of causality remains unanswered. In this study, we employed a Mendelian randomization (MR) approach to assess potential causal relationships between gut microbiota and the risk of frailty. Materials and methods: Summary statistics for the gut microbiome were obtained from a genome wide association study (GWAS) meta-analysis of the MiBioGen consortium (N = 18,340). Summary statistics for frailty were obtained from a GWAS meta-analysis, including the UK Biobank and TwinGene (N = 175,226). Our primary analysis utilized the inverse variance weighted (IVW) method. To enhance the robustness of our results, we also applied weighted median methods, MR Egger regression, and MR pleiotropy residual sum and outlier test. Finally, we conducted reverse MR analysis to investigate the potential for reverse causality. Results: IVW method identified 7 bacterial taxa nominally associated with the risk of FI. Class Bacteroidia (p = 0.033) and genus Eubacterium ruminantium group (p = 0.028) were protective against FI. In addition, class Betaproteobacteria (p = 0.042), genus Allisonella (p = 0.012), genus Bifidobacterium (p = 0.013), genus Clostridium innocuum group (p = 0.036) and genus Eubacterium coprostanoligenes group (p = 0.003) were associated with a higher risk of FI. No pleiotropy or heterogeneity were found. Conclusion: The MR analysis indicates a causal relationship between specific gut microbiota and FI, offering new insights into the mechanisms underlying FI mediated by gut microbiota.

The discovery of a novel pyrrolo[2,3-b]pyridine as a selective CDK8 inhibitor offers a new approach against psoriasis.

Currently, the drugs used in clinical to treat psoriasis mainly broadly suppress cellular immunity. However, these drugs can only provide temporary and partial symptom relief, they do not cure the condition and may lead to recurrence or even serious toxic side effects. In this study, we describe the discovery of a novel potent CDK8 inhibitor as a treatment for psoriasis. Through structure-based design, compound 46 was identified as the most promising candidate, exhibiting a strong inhibitory effect on CDK8 (IC50 value of 57 nM) along with favourable inhibition against NF-κB. Additionally, it demonstrated a positive effect in an in vitro psoriasis model induced by TNF-α. Furthermore, this compound enhanced the thermal stability of CDK8 and exerted evident effects on the biological function of CDK8, and it had favourable selectivity across the CDK family and tyrosine kinase. This compound showed no obvious inhibitory effect on CYP450 enzyme. Further studies confirmed that compound 46 exhibited therapeutic effect on IMQ-induced psoriasis, alleviated the inflammatory response in mice, and enhanced the expression of Foxp3 and IL-10 in the dorsal skin in vivo. This discovery provides a new strategy for developing selective CDK8 inhibitors with anti-inflammatory activity for the treatment of psoriasis.

Improving the bacterial community, flavor, and safety properties of northeastern sauerkraut by inoculating autochthonous Levilactobacillus brevis.

The effect of Levilactobacillus brevis as a starter in northeastern sauerkraut fermentation is still unknown, and further evaluation is worthwhile. Hence, this study aimed to evaluate the effect of autochthonous L. brevis inoculation on the bacterial community succession and formation of flavor and harmful substances in sauerkrauts. Inoculation with L. brevis lowered the pH and increased the total acid content of sauerkrauts (P < 0.05). The nitrite content of the inoculated sauerkraut was significantly lower than that of control (P < 0.05). Moreover, the spoilage bacteria of the inoculated sauerkraut were decreased and nitrogen metabolism was improved. The contents of aldehydes, alcohols, esters, acids, and alkanes increased significantly (P < 0.05), and the sensory attributes such as aroma, sourness, and gloss were also improved. L. brevis was positively and negatively correlated with flavor metabolites and nitrite, respectively, which proved to be a potential starter culture to manufacture sauerkraut.

LncRNA FOXD2-AS1 promotes the growth, invasion and migration of OSCC cells by regulating the MiR-185-5p/PLOD1/Akt/mTOR pathway.

Although lncRNAs are recognized to contribute to the development of oral squamous-cell carcinoma (OSCC), their exact function in invasion and cell migration is not clear. In this research, we explored the molecular and cellular mechanisms of FOXD2-AS1 in OSCC. Prognostic and bioinformatics analyses were used to test for the differential expression of FOXD2-AS1-PLOD1. Following FOXD2-AS1 suppression or overexpression, changes in cell viability were measured using the CCK-8 test; changes in cell migration and invasion abilities were measured using the migration and the Transwell assay. The expression of associated genes and proteins was found using Western blot and RT-qPCR. Analysis of luciferase reporter genes was done to look for regulatory connections between various molecules. The FOXD2-AS1-PLOD1 pair, which was highly expressed in OSCC, was analyzed and experimentally verified to be closely related to the prognosis of OSCC, and a nomogram model and correction curve were constructed. The inhibition of FOXD2-AS1 resulted in the reduction of cell activity, migration, invasion ability and changes in genes related to invasion and migration. In vivo validation showed that inhibition of FOXD2-AS1 expression slowed tumor growth, and related proteins changed accordingly. The experiments verified that FOXD2-AS1 negatively regulated miR-185-5 p and that miR-185-5 p negatively regulated PLOD1. In addition, it was found that the expression of PLOD1, p-Akt and p-mTOR proteins in OSCC cells was reduced by the inhibition of FOXD2-AS1, and FOXD2-AS1 and PLOD1 were closely related to the Akt/mTOR pathway. Increased expression of FOXD2-AS1 promotes OSCC growth, invasion and migration, which is important in part by targeting miR-185-5 p/PLOD1/Akt/mTOR pathway activity.

Comparison of deep learning models to traditional Cox regression in predicting survival of colon cancer: Based on the SEER database.

BACKGROUND AND AIM: In this study, a deep learning algorithm was used to predict the survival rate of colon cancer (CC) patients, and compared its performance with traditional Cox regression. METHODS: In this population-based cohort study, we used the characteristics of patients diagnosed with CC between 2010 and 2015 from the Surveillance, Epidemiology and End Results (SEER) database. The population was randomized into a training set (n = 10 596, 70%) and a test set (n = 4536, 30%). Brier scores, area under the (AUC) receiver operating characteristic curve and calibration curves were used to compare the performance of the three most popular deep learning models, namely, artificial neural networks (ANN), deep neural networks (DNN), and long-short term memory (LSTM) neural networks with Cox proportional hazard (CPH) model. RESULTS: In the independent test set, the Brier values of ANN, DNN, LSTM and CPH were 0.155, 0.149, 0.148, and 0.170, respectively. The AUC values were 0.906 (95% confidence interval [CI] 0.897-0.916), 0.908 (95% CI 0.899-0.918), 0.910 (95% CI 0.901-0.919), and 0.793 (95% CI 0.769-0.816), respectively. Deep learning showed superior promising results than CPH in predicting CC specific survival. CONCLUSIONS: Deep learning showed potential advantages over traditional CPH models in terms of prognostic assessment and treatment recommendations. LSTM exhibited optimal predictive accuracy and has the ability to provide reliable information on individual survival and treatment recommendations for CC patients.

Association of blood pressure and outcomes differs upon cerebral perfusion post-thrombectomy in patients with acute ischemic stroke.

BACKGROUND: The relationship between post-endovascular thrombectomy (EVT) blood pressure (BP) and outcomes in patients with acute ischemic stroke (AIS) remains contentious. We aimed to explore whether this association differs with different cerebral perfusion statuses post-EVT. METHODS: In a multicenter observational study of patients with AIS with large vessel occlusion who underwent EVT, we enrolled those who accepted CT perfusion (CTP) imaging within 24 hours post-EVT. We recorded post-EVT systolic (SBP) and diastolic BP. Patients were stratified into favorable perfusion and unfavorable perfusion groups based on the hypoperfusion intensity ratio (HIR) on CTP. The primary outcome was good functional outcome (90-day modified Rankin Scale score of ≤3). Secondary outcomes included early neurological deterioration, infarct size growth, and symptomatic intracranial hemorrhage. RESULTS: Of the 415 patients studied (mean age 62 years, 75% male), 233 (56%) achieved good functional outcomes. Logistic regression showed that post-EVT HIR and 24-hour mean SBP were significantly associated with functional outcomes. Among the 326 (79%) patients with favorable perfusion, SBP <140 mmHg was associated with a higher percentage of good functional outcomes compared with SBP ≥140 mmHg (68% vs 52%; aOR 1.70 (95% CI 1.00 to 2.89), P=0.04). However, no significant difference was observed between SBP and functional outcomes in the unfavorable perfusion group. There was also no discernible difference between SBP and secondary outcomes across the different perfusion groups. CONCLUSIONS: In patients with favorable perfusion post-EVT, SBP <140 mmHg was associated with good functional outcomes, which underscores the need for further investigations with larger sample sizes or a more individualized BP management strategy. CLINICAL TRIAL REGISTRATION: ChiCTR1900022154.

Panchromatic Light-Harvesting Three-Dimensional Metal Covalent Organic Frameworks for Boosting Photocatalysis.

Constructing artificial photocatalysts with panchromatic solar energy utilization remains an appealing challenge. Herein, two complementary photosensitizers, [Ru(bpy)3]2+ (bpy = 2,2'-bipyridine) and porphyrin dyes, have been cosensitized in metal covalent organic frameworks (MCOFs), resulting in the MCOFs with strong light absorption covering the full visible spectrum. Under panchromatic light irradiation, the cosensitized MCOFs exhibited remarkable photocatalytic H2 evolution with an optimum rate of up to 33.02 mmol g-1 h-1. Even when exposed to deep-red light (λ = 700 ± 10 nm), a commendable H2 production (0.79 mmol g-1 h-1) was still obtained. Theoretical calculation demonstrated that the [Ru(bpy)3]2+ and porphyrin modules in our MCOFs have a synergistic effect to trigger an interesting dual-channel photosensitization pathway for efficient light-harvesting and energy conversion. This work highlights the potential of combining multiple PSs in MCOFs for panchromatic photocatalysis.

Time-domain slicing optical frequency domain reflectometry.

A time-domain slicing (TDS) optical frequency domain reflectometry is proposed for large strain sensing with better spatial resolution. Compared with the conventional frequency domain slicing (FDS) method, the TDS with a Burg spectrum estimation is capable of enhancing the similarity of a local spectrum under large strain and mostly suppressing the fake peaks during the strain resolving. The experimental results demonstrated that it enables measurements of strain ranging from 600 to 4200 µÎµ with a spatial resolution of 2.4 mm and a narrow optical frequency scanning range of only 10 nm. Moreover, the measurement accuracy is improved by six times by decreasing the root mean square error (RMSE) from 8.6611 to 1.3396 µÎµ without any hardware modification.

Assessment of OCT-Based Macular Curvature and Its Relationship with Macular Microvasculature in Children with Anisomyopia.

INTRODUCTION: To evaluate the intraocular differences in optical coherence tomography (OCT)-based macular curvature index (MCI) among children with anisomyopia and to investigate the relationship between MCI and the macular microvasculature. METHODS: Fifty-two schoolchildren with anisometropia > 2.00 D were enrolled and underwent comprehensive examinations including cycloplegic refraction, axial length (AL), and swept source OCT/OCT angiography. OCT-based MCIs were determined from horizontal and vertical B-scans by a customized curve fitting model in MATLAB R2022 at 1-mm-, 3-mm-, and 6-mm-diameter circles at fovea. Characteristics and topographic variation of MCI was analyzed, and the relationships with microvascularity and its associated factors were investigated. RESULTS: MCI achieved high reliability and repeatability. There were overall larger MCIs in the more myopic eyes than the less myopic eyes in 1-mm-, 3-mm-, and 6-mm-diameter circles at fovea (all p < 0.001). For the topographic variation, horizontal MCI was significantly greater than vertical MCI (all p < 0.001), and was the largest in 6-mm circle, followed by 3-mm and 1-mm circles. Stronger correlation of horizontal MCI with myopic severity than vertical MCI was found. Partial Pearson's correlation found MCI was negatively associated with deep capillary plexus (DCP) vessel density (p = 0.016). Eyes with a higher MCI in a 6-mm circle were more likely to have longer AL (p < 0.001), lower DCP vessel density (p = 0.037), and thinner choroidal thickness (ChT) (p = 0.045). CONCLUSION: Larger MCI was found in the more myopic eyes of children with anisomyopia and was significantly associated with smaller DCP density, suggesting that MCI was an important indicator of myopia-related retinal microvascularity change, and it could be a valuable metric for myopia assessment in children.

Facile Semiconductor p-n Homojunction Nanowires with Strategic p-Type Doping Engineering Combined with Surface Reconstruction for Biosensing Applications.

Photosensors with versatile functionalities have emerged as a cornerstone for breakthroughs in the future optoelectronic systems across a wide range of applications. In particular, emerging photoelectrochemical (PEC)-type devices have recently attracted extensive interest in liquid-based biosensing applications due to their natural electrolyte-assisted operating characteristics. Herein, a PEC-type photosensor was carefully designed and constructed by employing gallium nitride (GaN) p-n homojunction semiconductor nanowires on silicon, with the p-GaN segment strategically doped and then decorated with cobalt-nickel oxide (CoNiOx). Essentially, the p-n homojunction configuration with facile p-doping engineering improves carrier separation efficiency and facilitates carrier transfer to the nanowire surface, while CoNiOx decoration further boosts PEC reaction activity and carrier dynamics at the nanowire/electrolyte interface. Consequently, the constructed photosensor achieves a high responsivity of 247.8 mA W-1 while simultaneously exhibiting excellent operating stability. Strikingly, based on the remarkable stability and high responsivity of the device, a glucose sensing system was established with a demonstration of glucose level determination in real human serum. This work offers a feasible and universal approach in the pursuit of high-performance bio-related sensing applications via a rational design of PEC devices in the form of nanostructured architecture with strategic doping engineering.

TaTPS11 enhances wheat cold resistance by regulating source-sink factor.

The presence of sugar in plant tissue can lead to an increase in the osmotic pressure within cells, a decrease in the freezing point of plants, and protection against ice crystal damage to the tissue. Trehalose is closely related to sucrose, which comprises the largest proportion of sugar and has become a hot topic of research in recent years. Our previous studies have confirmed that a key trehalose synthesis gene, TaTPS11, from the cold-resistant winter wheat DM1, could enhance the cold resistance of plants by increasing sugar content. However, the underlying mechanism behind this phenomenon remains unclear. In this study, we cloned TaTPS11-6D, edited TaTPS11-6D using CRISPR/Cas9 technology and transformed 'Fielder' to obtain T2 generation plants. We screened out OE3-3 and OE8-7 lines with significantly higher cold resistance than that of 'Fielder' and Cri 4-3 edited lines with significantly lower cold resistance than that of 'Fielder'. Low temperature storage limiting factors were measured for OE3-3, OE8-7 and Cri 4-3 treated at different temperatures.The results showed that TaTPS11-6D significantly increased the content of sugar in plants and the transfer of sugar from source to storage organs under cold conditions. The TaTPS11-6D significantly increased the levels of salicylic, jasmonic, and abscisic acids while also significantly decreasing the level of gibberellic acid. Our research improves the model of low temperature storage capacity limiting factor.

Analysis of postoperative urinary incontinence and influencing factors of transurethral holmium laser enucleation of the prostate.

INTRODUCTION: To investigate the related factors of urinary incontinence after transurethral holmium laser enucleation of the prostate (HoLEP), and to provide guidance for clinical urinary control of HoLEP. METHODS: The clinical data of 548 patients who underwent HoLEP were retrospectively analyzed. The patients were followed up for the occurrence of urinary incontinence in the short term (2 weeks), medium term (3 months) and long term (6 months) after HoLEP. RESULTS: Among the 548 benign prostatic hyperplasia (BPH) patients, 79 cases (14.42%) had urinary incontinence at 2 weeks, 19 cases (3.47%) at 3 months and 2 cases (0.36%) at 6 months after surgery. Logistic regression analysis showed that age, prostate volume, diabetes mellitus, operation time, prostate tissue weight and histological prostatitis were risk factors for recent urinary incontinence (P<0.05). Age, diabetes and operation time were risk factors for mid-term urinary incontinence (P<0.05). The incidence of long-term urinary incontinence was low and no risk factor analysis was performed. CONCLUSIONS: For good urinary control after HoLEP, in addition to surgery-related factors such as surgical skills, proficiency and precise anatomy, patients' risk factors should also be paid attention to in order to improve postoperative urinary control more effectively and reduce the incidence of urinary incontinence.

Risk factors for hemorrhagic cystitis in children undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis.

BACKGROUND: The risk factors for hemorrhagic cystitis (HC) in children undergoing hematopoietic stem cell transplantation (HSCT) are unclear. Therefore, we conducted this systematic review and meta-analysis to investigate the risk factors for HC in children undergoing HSCT. METHODS: We performed this meta-analysis by retrieving studies from PubMed, EMBASE, and the Cochrane Library up to October 10, 2023, and analyzing those that met the inclusion criteria. I2 statistics were used to evaluate heterogeneity. RESULTS: Twelve studies, including 2,764 patients, were analyzed. Male sex (odds ratio [OR] = 1.52; 95% confidence interval [CI], 1.16-2.00; p = 0.003, I2 = 0%), allogeneic donor (OR = 5.28; 95% CI, 2.60-10.74; p < 0.00001, I2 = 0%), human leukocyte antigen (HLA) mismatched donor (OR = 1.86; 95% CI, 1.00-3.44; p = 0.05, I2 = 31%), unrelated donor (OR = 1.58; 95% CI, 1.10-2.28; p = 0.01, I2 = 1%), myeloablative conditioning (MAC) (OR = 3.17; 95% CI, 1.26-7.97; p = 0.01, I2 = 0%), busulfan (OR = 2.18; 95% CI, 1.33-3.58; p = 0.002, I2 = 0%) or anti-thymoglobulin (OR = 1.65; 95% CI, 1.07-2.54; p = 0.02, I2 = 16%) use, and cytomegalovirus (CMV) reactivation (OR = 2.64; 95% CI, 1.44-4.82; p = 0.002, I2 = 0%) were risk factors for HC in children undergoing HSCT. CONCLUSIONS: Male sex, allogeneic donor, HLA-mismatched, unrelated donor, MAC, use of busulfan or anti-thymoglobulin, and CMV reactivation are risk factors for HC in children undergoing HSCT.

Photoactivated Formation of an Extravascular Dynamic Hydrogel as an Intelligent Blood Flow Regulator to Reprogram the Immunogenic Landscape.

Long-term tumor starvation may be a potential strategy to elevate the antitumor immune response by depriving nutrients. However, combining long-term starvation therapy with immunotherapy often yields limited efficacy due to the blockage of immune cell migration pathways. Herein, an intelligent blood flow regulator (BFR) is first established through photoactivated in situ formation of the extravascular dynamic hydrogel to compress blood vessels, which can induce long-term tumor starvation to elicit metabolic stress in tumor cells without affecting immune cell migration pathways. By leveraging methacrylate-modified nanophotosensitizers (HMMAN) and biodegradable gelatin methacrylate (GelMA), the developed extravascular hydrogel dynamically regulates blood flow via enzymatic degradation. Additionally, aPD-L1 loaded into HMMAN continuously blocks immune checkpoints. Systematic in vivo experiments demonstrate that the combination of immune checkpoint blockade (ICB) and BFR-induced metabolic stress (BIMS) significantly delays the progression of Lewis lung and breast cancers by reshaping the tumor immunogenic landscape and enhancing antitumor immune responses.

Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism. METHODS AND RESULTS: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα). CONCLUSION: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.