Application of slow-controlled release fertilizer coordinates the carbon flow in carbon-nitrogen metabolism to effect rice quality.

Slow-controlled release fertilizers are experiencing a popularity in rice cultivation due to their effectiveness in yield and quality with low environmental costs. However, the underlying mechanism by which these fertilizers regulate grain quality remains inadequately understood. This study investigated the effects of five fertilizer management practices on rice yield and quality in a two-year field experiment: CK, conventional fertilization, and four applications of slow-controlled release fertilizer (UF, urea formaldehyde; SCU, sulfur-coated urea; PCU, polymer-coated urea; BBF, controlled-release bulk blending fertilizer). In 2020 and 2021, the yields of UF and SCU groups showed significant decreases when compared to conventional fertilization, accompanied by a decline in nutritional quality. Additionally, PCU group exhibited poorer cooking and eating qualities. However, BBF group achieved increases in both yield (10.8 t hm-2 and 11.0 t hm-2) and grain quality reaching the level of CK group. The adequate nitrogen supply in PCU group during the grain-filling stage led to a greater capacity for the accumulation of proteins and amino acids in the PCU group compared to starch accumulation. Intriguingly, BBF group showed better carbon-nitrogen metabolism than that of PCU group. The optimal nitrogen supply present in BBF group suitable boosted the synthesis of amino acids involved in the glycolysis/ tricarboxylic acid cycle, thereby effectively coordinating carbon-nitrogen metabolism. The application of the new slow-controlled release fertilizer, BBF, is advantageous in regulating the carbon flow in the carbon-nitrogen metabolism to enhance rice quality.

Robotic-assisted low anterior resection for rectal cancer shows similar clinical efficacy to laparoscopic surgery: A propensity score matched study.

BACKGROUND: Rectal cancer ranks as the second leading cause of cancer-related mortality worldwide, necessitating surgical resection as the sole treatment option. Over the years, there has been a growing adoption of minimally invasive surgical techniques such as robotic and laparoscopic approaches. Robotic surgery represents an innovative modality that effectively addresses the limitations associated with traditional laparoscopic techniques. While previous studies have reported favorable perioperative outcomes for robot-assisted radical resection in rectal cancer patients, further evidence regarding its oncological safety is still warranted. AIM: To conduct a comparative analysis of perioperative and oncological outcomes between robot-assisted and laparoscopic-assisted low anterior resection (LALAR) procedures. METHODS: The clinical data of 125 patients who underwent robot-assisted low anterior resection (RALAR) and 279 patients who underwent LALAR resection at Shandong Provincial Hospital Affiliated to Shandong First Medical University from December 2019 to November 2022 were retrospectively analyzed. After performing a 1:1 propensity score matching, the patients were divided into two groups: The RALAR group and the LALAR group (111 cases in each group). Subsequently, a comparison was made between the short-term outcomes within 30 d after surgery and the 3-year survival outcomes of these two groups. RESULTS: Compared to the LALAR group, the RALAR group exhibited a significantly earlier time to first flatus [2 (2-2) d vs 3 (3-3) d, P = 0.000], as well as a shorter time to first fluid diet [4 (3-4) d vs 5 (4-6) d, P = 0.001]. Additionally, the RALAR group demonstrated reduced postoperative indwelling catheter time [2 (1-3) d vs 4 (3-5) d, P = 0.000] and decreased length of hospital stay after surgery [5 (5-7) d vs 7(6-8) d, P = 0.009]. Moreover, there was an observed increase in total cost of hospitalization for the RALAR group compared to the LALAR group [10777 (10780-11850) dollars vs 10550 (8766-11715) dollars, P = 0.012]. No significant differences were found in terms of conversion rate to laparotomy or incidence of postoperative complications between both groups. Furthermore, no significant disparities were noted regarding the 3-year overall survival rate and 3-year disease-free survival rate between both groups. CONCLUSION: Robotic surgery offers potential advantages in terms of accelerated recovery of gastrointestinal and urologic function compared to LALAR resection, while maintaining similar perioperative and 3-year oncological outcomes.

IL-23 inhibitor enhances the effects of PTEN DNA-loaded lipid nanoparticles for metastatic CRPC therapy.

Introduction: Metastatic castration-resistant prostate cancer (mCRPC) patients face challenges due to limited treatment options. About 50% of patients with mCRPC have a functional loss of phosphatase and tensin homology deleted on chromosome 10 (PTEN), leading to tumor progression, metastasis, and immune suppression. Moreover, elevated IL-23 produced by myeloid-derived suppressor cells (MDSCs) is found in CRPC patients, driving tumor progression. Therefore, a combination strategy based on PTEN restoration and IL-23 inhibition may block CRPC progression and metastasis. Methods: The antitumor effect of restoring PTEN expression combined with the IL-23 inhibitor Apilimod was studied in a mouse model of bone metastasis CRPC and mouse prostate cancer RM-1 cells. To verify the targeting ability of PTEN DNA coated with lipid nanoparticles (LNP@PTEN) in vitro and in vivo. In addition, RT-qPCR and flow cytometry were used to investigate the related mechanisms of the antitumor effect of LNP@PTEN combined with Apilimod. Results: LNPs exhibited significant tumor-targeting and tumor accumulation capabilities both in vitro and in vivo, enhancing PTEN expression and therapeutic efficacy. Additionally, the combination of LNP@PTEN with the IL-23 inhibitor Apilimod demonstrated enhanced inhibition of tumor growth, invasion, and metastasis (particularly secondary organ metastasis) compared to other groups, and extended the survival of mice to 41 days, providing a degree of bone protection. These effects may be attributed to the PTEN function restoration combined with IL-23 inhibition, which help reverse immune suppression in the tumor microenvironment by reducing MDSCs recruitment and increasing the CD8+/CD4+ T cell ratio. Discussion: In summary, these findings highlight the potential of LNPs for delivering gene therapeutic agents. And the combination of LNP@PTEN with Apilimod could achieve anti-tumor effects and improve tumor microenvironment. This combinational strategy opens new avenues for the treatment of mCRPC.

Causal relationship between anti-inflammatory drugs and cancer: a pan-cancer study with Mendelian randomization.

Background: Numerous epidemiological studies have elucidated the intricate connection between inflammation and cancer, highlighting how sustained inflammatory responses can fuel carcinogenesis by fostering proliferation, angiogenesis, and metastasis, while dampening immune responses and sensitivity to chemotherapy. Previous clinical investigations have underscored the potential of anti-inflammatory medications in either preventing or mitigating tumor formation. Here, the causal relationship between anti-inflammatory drugs and cancer was further explored through Mendelian randomization studies. Methods: Employing Mendelian randomization, we scrutinized the causal links between three anti-inflammatory drugs-NSAIDs, Aspirin, and Anilide-and 37 types of cancer. We primarily utilized inverse variance weighting (IVW) as the primary analytical approach to delineate the causal association between these drugs and cancer types. Concurrently, sensitivity analyses were conducted to ascertain the absence of horizontal pleiotropy and heterogeneity. Results: Our investigation revealed a discernible causal relationship between certain anti-inflammatory drugs and a subset of cancers, albeit without a pervasive impact across all cancer types. Specifically, NSAIDs exhibited a risk-reducing effect on non-small cell lung cancer (OR: 0.76, 95% CI: 0.59-0.97, p-value: 0.03) and gastric cancer (OR: 0.57, 95% CI: 0.34-0.98, p-value: 0.04). Conversely, aspirin was associated with an increased risk of oral malignant tumors (OR: 2.18, 95% CI: 1.13-4.21, p-value: 0.02). Notably, no statistically significant findings were observed for anilide drugs (p < 0.05). Conclusion: We identified several cancers with potential causal links to NSAIDs, including non-small cell lung cancer and gastric cancer. Despite our extensive analysis, we did not identify a substantial causal relationship between the use of anti-inflammatory drugs and the development of various cancers.

Using three-dimensional model-based tumour volume change to predict the symptom improvement in patients with renal cell cancer.

In our recent study, we explored the efficacy of three-dimensional (3D) measurement of tumor volume in predicting the improvement of quality of life (QoL) in patients suffering from renal cell cancer (RCC), who were treated with axitinib and anti-PD-L1 antibodies. This study encompassed 18 RCC patients, including 10 men and 8 women, with an average age of 56.83 ± 9.94 years. By utilizing 3D Slicer software, we analyzed pre- and post-treatment CT scans to assess changes in tumor volume. Patients' QoL was evaluated through the FKSI-DRS questionnaire. Our findings revealed that 3D models for all patients were successfully created, and there was a moderate agreement between treatment response classifications based on RECIST 1.1 criteria and volumetric analysis (kappa = 0.556, p = 0.001). Notably, nine patients reported a clinically meaningful improvement in QoL following the treatment. Interestingly, the change in tumor volume as indicated by the 3D model showed a higher area under the curve in predicting QoL improvement compared to the change in diameter measured by CT, although this difference was not statistically significant (z = 0.593, p = 0.553). Furthermore, a multivariable analysis identified the change in tumor volume based on the 3D model as an independent predictor of QoL improvement (odds ratio = 1.073, 95% CI 1.002-1.149, p = 0.045).In conclusion, our study suggests that the change in tumor volume measured by a 3D model may be a more effective predictor of symptom improvement in RCC patients than traditional CT-based diameter measurements. This offers a novel approach for assessing treatment response and patient well-being, presenting a significant advancement in the field of RCC treatment.

Associations of Ambient Particulate Matter with Maternal Thyroid Autoimmunity and Thyroid Function in Early Pregnancy.

This prospective birth cohort study evaluated the association of exposure to PM2.5 (diameter ≤2.5 µm), PM1-2.5 (1-2.5 µm), and PM1 (≤1 µm) with maternal thyroid autoimmunity and function during early pregnancy. A total of 15,664 pregnant women were included at 6 to 13+6 gestation weeks in China from 2018 to 2020. Single-pollutant models using generalized linear models (GLMs) showed that each 10 µg/m3 increase in PM2.5 and PM1-2.5 was related with 6% (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.01, 1.12) and 15% (OR = 1.15, 95% CI: 1.08, 1.22) increases in the risk of thyroid autoimmunity, respectively. The odds of thyroid autoimmunity significantly increased with each interquartile range increase in PM2.5 and PM1-2.5 exposure (P for trend <0.001). PM1 exposure was not significantly associated with thyroid autoimmunity. GLM with natural cubic splines demonstrated that increases in PM2.5 and PM1-2.5 exposure were associated with lower maternal FT4 levels, while a negative association between PM1 and FT4 levels was found when exposure exceeded 32.13 µg/m3. Only PM2.5 exposure was positively associated with thyrotropin (TSH) levels. Our findings suggest that high PM exposure is associated with maternal thyroid disruption during the early pregnancy.

MiR26a reverses enzalutamide resistance in a bone-tumor targeted system with an enhanced effect on bone metastatic CRPC.

Resistance to androgen receptor (AR) inhibitors, including enzalutamide (Enz), as well as bone metastasis, are major challenges for castration-resistant prostate cancer (CRPC) treatment. In this study, we identified that miR26a can restore Enz sensitivity and inhibit bone metastatic CRPC. To achieve the highest combination effect of miR26a and Enz, we developed a cancer-targeted nano-system (Bm@PT/Enz-miR26a) using bone marrow mesenchymal stem cell (BMSC) membrane and T140 peptide to co-deliver Enz and miR26a. The in vitro/in vivo results demonstrated that miR26a can reverse Enz resistance and synergistically shrink tumor growth, invasion, and metastasis (especially secondary metastasis) in both subcutaneous and bone metastatic CRPC mouse models. We also found that the EZH2/SFRP1/WNT5A axis may be involved in this role. These findings open new avenues for treating bone metastatic and Enz-resistant CRPC.

Levothyroxine treatment in pregnant women with thyroid stimulating hormone levels ranging between 2.5 and 10 mIU/L: A propensity score matched analysis.

OBJECTIVE: To clarify the association between levothyroxine (LT-4) treatment and various adverse pregnancy outcomes in pregnant women with thyroid stimulating hormone (TSH) levels ranging between 2.5 to 10.0 mIU/L in the first trimester, stratified according to thyroid peroxidase antibody (TPOAb) positivity and TSH level. METHODS: This retrospective analysis of retrospectively and prospectively collected cohort data included Chinese pregnant women with TSH levels of 2.5-10 mIU/L and normal free thyroxine levels (11.8-18.4 pmol/L) in the first trimester. All participants were followed up until the completion of pregnancy, and information on LT-4 treatment, pregnancy complications, and pregnancy outcomes was recorded. A 1:1 nearest-neighbor propensity score matching (PSM) between the LT-4-treated and -untreated groups with a caliper distance of 0.02 was performed using a multivariable logistic regression model. Multivariable-adjusted modified Poisson regression was used to estimate the relative risk (RR) and 95% confidence interval (CI) of LT-4 treatment for adverse pregnancy outcomes. Subgroup analyses were also performed in four subgroups simultaneously stratified by TPOAb status (negative or positive) and TSH levels (2.5-4.0 mIU/L as high-normal group and 4.0-10.0 mIU/L as SCH group). The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100047394). RESULTS: Among the 4,370 pregnant women in the study, 1,342 received LT-4 treatment, and 3,028 did not. The 1:1 PSM yielded 668 pairs of individuals and revealed that LT-4 treatment was significantly associated with a decreased risk of pregnancy loss (RR=0.528, 95% CI: 0.344-0.812) and an increased risk of small-for-gestational-age infants (RR=1.595, 95% CI: 1.023-2.485). Subgroup analyses suggested that the above effects of LT-4 treatment were mainly from TPOAb-negative participants. LT-4 treatment was associated with an increased risk of preterm birth (RR=2.214, 95% CI: 1.016-4.825) in TPOAb-positive pregnant women with high-normal TSH levels. CONCLUSION: LT-4 treatment was significantly associated with a lower risk of pregnancy loss and a higher risk of small-for-gestational-age infants in pregnant women with TSH levels of 2.5-10 mIU/L. An increased risk of preterm birth was observed in the LT-4-treated group among TPOAb-positive participants with TSH levels of 2.5-4.0 mIU/L.

Topical Ophthalmic Liposomes Dual-Modified with Penetratin and Hyaluronic Acid for the Noninvasive Treatment of Neovascular Age-Related Macular Degeneration.

Introduction: Since intrinsic ocular barrier limits the intraocular penetration of therapeutic protein through eye drops, repeated intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents are the standard therapy for neovascular age-related macular degeneration (nAMD), which are highly invasive and may cause particular ocular complications, leading to poor patient compliance. Methods: Using Penetratin (Pen) as the ocular penetration enhancer and hyaluronic acid (HA) as the retina-targeting ligand, a dual-modified ophthalmic liposome (Penetratin hyaluronic acid-liposome/Conbercept, PenHA-Lip/Conb) eye drop was designed to non-invasively penetrate the ocular barrier and deliver anti-VEGF therapeutic agents to the targeted intraocular tissue. Results: PenHA-Lip effectively penetrates the ocular barrier and targets the retinal pigment epithelium via corneal and non-corneal pathways. After a single topical administration of conbercept-loaded PenHA-Lip (PenHA-Lip/Conb), the intraocular concentration of conbercept peaked at 18.74 ± 1.09 ng/mL at 4 h, which is 11.55-fold higher than unmodified conbercept. In a laser-induced choroidal neovascularization (CNV) mouse model, PenHA-Lip/Conb eye drops three times daily for seven days inhibited CNV formation and progression without any significant tissue toxicity and achieved an equivalent effect to a single intravitreal conbercept injection. Conclusion: PenHA-Lip efficiently and safely delivered conbercept to the posterior eye segment and may be a promising noninvasive therapeutic option for nAMD.

Chronic cadmium exposure impairs flight behavior by dampening flight muscle carbon metabolism in bumblebees.

Cadmium pollution affects the global ecosystem because cadmium can be transferred up the food chain. The bumblebee, Bombus terrestris, is an important insect pollinator. Their foraging activity on flowers exposes them to harmful heavy metals, which damages their health and leads to massive population declines. However, the effects of chronic exposure to heavy metals on the flight performance of bumblebees have not yet been characterized. Here, we studied variation in the flight capacity of bumblebees induced by chronic cadmium exposure at field-realistic concentrations using behavioral, physiological, and molecular approaches. Chronic cadmium exposure caused a significant reduction in the duration, distance, and mean velocity of bumblebee flight. Transcriptome analysis showed that the impairment of carbon metabolism and mitochondrial dysfunction in the flight muscle were the primary causes. Physiological, biochemical, and metabolomic analyses validated disruptions in energy metabolism, and impairments in mitochondrial respiratory chain complexes activities. Histological analysis revealed muscle fiber damage and mitochondrial loss. Exogenous decanoic acid or citric acid partially restored sustained flight ability of bumblebees by mitigating muscle fiber damage and increasing energy generation. These findings provide insights into how long-term cadmium stress affects the flight ability of insects and will aid human muscle or exercise-related disease research.

The association between dyslipidaemia in the first trimester and adverse pregnancy outcomes in pregnant women with subclinical hypothyroidism: a cohort study.

BACKGROUND: Subclinical hypothyroidism (SCH) is linked to dyslipidaemia and adverse pregnancy outcomes. However, the impact of dyslipidaemia on the outcome of pregnancy in SCH is unclear. METHODS: We enrolled 36,256 pregnant women and evaluated their pregnancy outcomes. The following data was gathered during the first trimester (≤ 13+ 6 weeks of gestation): total cholesterol (TC), low-density lipoprotein (LDL-C), triglyceride (TG), high-density lipoprotein (HDL-C), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) concentrations. The reference ranges for lipids were estimated to range from the 5th to the 95th percentile. Logistic regression assessed the relationships between dyslipidaemia and adverse pregnancy outcomes, including abortion, preeclampsia/eclampsia, low birth weight, foetal growth restriction, premature rupture of foetal membranes, gestational hypertension, preterm birth, macrosomia and gestational diabetes mellitus (GDM). Additionally, the best thresholds for predicting adverse pregnancy outcomes based on TSH, FT4, and lipid levels were determined using receiver operating characteristic curves. RESULTS: In the first trimester, LDL-C > 3.24 mmol/L, TG > 1.92 mmol/L, HDL-C < 1.06 mmol/L, and TC > 5.39 mmol/L were used to define dyslipidaemia. In this cohort, 952 (3.56%) patients were diagnosed with SCH, and those who had dyslipidaemia in the first trimester had higher incidences of gestational hypertension (6.59% vs. 3.25%), preeclampsia/eclampsia (7.14% vs. 3.12%), GDM (22.53% vs. 13.77%), and low birth weight (4.95% vs. 2.08%) than did those without dyslipidaemia. However, after adjusting for prepregnancy body mass index (pre-BMI), dyslipidaemia was no longer related to these risks. Furthermore, elevated TG dyslipidaemia in SCH patients was connected to an enhanced potential of gestational hypertension (odds ratio [OR]: 2.687, 95% confidence interval [CI]: 1.074 ~ 6.722), and elevated LDL-C dyslipidaemia correlated with increased preeclampsia/eclampsia risk (OR: 3.172, 95% CI: 1.204 ~ 8.355) after accounting for age, smoking status, alcohol use, pre-BMI, and levothyroxine use. Additionally, the combination of TC, TG, LDL-C, pre-BMI, and TSH exhibited enhanced predictive capabilities for gestational hypertension, preeclampsia/eclampsia, and GDM. Values of 0.767, 0.704, and 0.706 were obtained from the area under the curve. CONCLUSIONS: Among pregnant women with SCH, dyslipidaemia in early pregnancy was related to elevated risks of adverse pregnancy consequences. The combined consideration of age, pre-BMI, TSH, and lipid levels in the first trimester could be beneficial for monitoring patients and implementing interventions to reduce adverse pregnancy outcomes.

Efficacy and Mechanism of a Biomimetic Nanosystem Carrying Doxorubicin and an IDO Inhibitor for Treatment of Advanced Triple-Negative Breast Cancer.

Introduction: Chemotherapy is still the treatment of choice for advanced triple-negative breast cancer. Chemotherapy combined with immunotherapy is being tried in patients with triple-negative breast cancer. As a kind of "cold tumor", triple-negative breast cancer has a bottleneck in immunotherapy. Indoleamine 2, 3-dioxygenase-1 inhibitors can reverse the immunosuppressive state and enhance the immune response. Methods: In this study, mesoporous silica nanoparticles were coated with the chemotherapeutic drug doxorubicin and indoleamine 2, 3-dioxygenase 1 inhibitor 1-Methyl-DL-tryptophan (1-MT), and then encapsulate the surfaces of a triple-negative breast cancer cell membrane to construct the tumor dual-targeted delivery system CDIMSN for chemotherapy and immunotherapy, and to investigate the immunogenic death effect of CDIMSN. Results and discussion: The CDIMSN could target the tumor microenvironment. Doxorubicin induced tumor immunogenic death, while 1-MT reversed immunosuppression. In vivo findings showed that the tumor size in the CDIMSN group was 2.66-fold and 1.56-fold smaller than that in DOX and DIMSN groups, respectively. CDIMSN group was better than naked DIMSN in stimulating CD8+T cells, CD4+T cells and promoting Dendritic Cells(DC) maturation. In addition, blood analysis, biochemical analysis and Hematoxylin staining analysis of mice showed that the bionic nanoparticles had good biological safety.

Association Between Maternal Thyroid Function in Early Pregnancy and Gestational Diabetes: A Prospective Cohort Study.

CONTEXT: Previous studies on the relationship between thyroid gland function and the development of gestational diabetes mellitus (GDM) have reported different results, leading to the need for a cohort study design with a large sample size. OBJECTIVE: We aimed to investigate the relationship between thyroid function in early pregnancy and GDM. METHODS: This was a prospective cohort study based on the China Birth Cohort Study (CBCS), from February 2018 to December 2020. The study took place at a tertiary maternal and child health hospital. A total of 36 256 pregnant women were successfully recruited based on the CBCS. The main outcome measure was GDM. RESULTS: This study consisted of 26 742 pregnant women who met the inclusion criteria, of whom 3985 (14.90%) were diagnosed with GDM, and the women with GDM were older than their healthy counterparts (33.26 ± 4.01 vs 31.51 ± 3.76 years, P < .001). After removing potential influencing variables, we found that increased thyroid-stimulating hormone (TSH) (adjusted odds ratio [aOR] 1.030, 95% CI 1.007, 1.054, P = .012) and subclinical hypothyroidism (aOR 1.211, 95% CI 1.010, 1.451, P = .039), but not free thyroxine or thyroid peroxidase antibody, were associated with the occurrence of GDM. Further analysis indicated a nonlinear relationship between TSH and GDM (P < .05): when TSH ≤ 1.24 mIU/L, the occurrence of GDM was elevated with increasing TSH, but when TSH > 1.24 mIU/L, this trend was not obvious. CONCLUSION: High TSH might be associated with increased risk of GDM.

Intelligent Size-Switchable Iron Carbide-Based Nanocapsules with Cascade Delivery Capacity for Hyperthermia-Enhanced Deep Tumor Ferroptosis.

The ferroptosis pathway is recognized as an essential strategy for tumor treatment. However, killing tumor cells in deep tumor regions with ferroptosis agents is still challenging because of distinct size requirements for intratumoral accumulation and deep tumor penetration. Herein, intelligent nanocapsules with size-switchable capability that responds to acid/hyperthermia stimulation to achieve deep tumor ferroptosis are developed. These nanocapsules are constructed using poly(lactic-co-glycolic) acid and Pluronic F127 as carrier materials, with Au-Fe2 C Janus nanoparticles serving as photothermal and ferroptosis agents, and sorafenib (SRF) as the ferroptosis enhancer. The PFP@Au-Fe2 C-SRF nanocapsules, designed with an appropriate size, exhibit superior intratumoral accumulation compared to free Au-Fe2 C nanoparticles, as evidenced by photoacoustic and magnetic resonance imaging. These nanocapsules can degrade within the acidic tumor microenvironment when subjected to laser irradiation, releasing free Au-Fe2 C nanoparticles. This enables them to penetrate deep into tumor regions and disrupt intracellular redox balance. Under the guidance of imaging, these PFP@Au-Fe2 C-SRF nanocapsules effectively inhibit tumor growth when exposed to laser irradiation, capitalizing on the synergistic photothermal and ferroptosis effects. This study presents an intelligent formulation based on iron carbide for achieving deep tumor ferroptosis through size-switchable cascade delivery, thereby advancing the comprehension of ferroptosis in the context of tumor theranostics.

Rapamycin Exacerbates Staphylococcus aureus Pneumonia by Inhibiting mTOR-RPS6 in Macrophages.

Purpose: This study aimed to explore the effect of Rapamycin (Rapa) in Staphylococcus aureus (S. aureus) pneumonia and clarify its possible mechanism. Methods: We investigated the effects of Rapa on S. aureus pneumonia in mouse models and in macrophages cultured in vitro. Two possible mechanisms were investigated: the mTOR-RPS6 pathway phosphorylation and phagocytosis. Furthermore, for the mechanism verification in vivo, mice with specific Mtor knockout in myeloid cells were constructed for pneumonia models. Results: Rapa exacerbated S. aureus pneumonia in mouse models, promoting chemokines secretion and inflammatory cells infiltration in lung. In vitro, Rapa upregulated the secretion of chemokines and cytokines in macrophages induced by S. aureus. Mechanistically, the mTOR-ribosomal protein S6 (RPS6) pathway in macrophages was phosphorylated in response to S. aureus infection, and the inhibition of RPS6 phosphorylation upregulated the inflammation level. However, Rapa did not increase the phagocytic activity. Accordingly, mice with specific Mtor knockout in myeloid cells experienced more severe S. aureus pneumonia. Conclusion: Rapa exacerbates S. aureus pneumonia by increasing the inflammatory levels of macrophages. Inhibition of mTOR-RPS6 pathway upregulates the expression of cytokines and chemokines in macrophages, thus increases inflammatory cells infiltration and exacerbates tissue damage.

Predicting Breast Cancer Subtypes Using Magnetic Resonance Imaging Based Radiomics With Automatic Segmentation.

OBJECTIVE: The aim of the study is to demonstrate whether radiomics based on an automatic segmentation method is feasible for predicting molecular subtypes. METHODS: This retrospective study included 516 patients with confirmed breast cancer. An automatic segmentation-3-dimensional UNet-based Convolutional Neural Networks, trained on our in-house data set-was applied to segment the regions of interest. A set of 1316 radiomics features per region of interest was extracted. Eighteen cross-combination radiomics methods-with 6 feature selection methods and 3 classifiers-were used for model selection. Model classification performance was assessed using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. RESULTS: The average dice similarity coefficient value of the automatic segmentation was 0.89. The radiomics models were predictive of 4 molecular subtypes with the best average: AUC = 0.8623, accuracy = 0.6596, sensitivity = 0.6383, and specificity = 0.8775. For luminal versus nonluminal subtypes, AUC = 0.8788 (95% confidence interval [CI], 0.8505-0.9071), accuracy = 0.7756, sensitivity = 0.7973, and specificity = 0.7466. For human epidermal growth factor receptor 2 (HER2)-enriched versus non-HER2-enriched subtypes, AUC = 0.8676 (95% CI, 0.8370-0.8982), accuracy = 0.7737, sensitivity = 0.8859, and specificity = 0.7283. For triple-negative breast cancer versus non-triple-negative breast cancer subtypes, AUC = 0.9335 (95% CI, 0.9027-0.9643), accuracy = 0.9110, sensitivity = 0.4444, and specificity = 0.9865. CONCLUSIONS: Radiomics based on automatic segmentation of magnetic resonance imaging can predict breast cancer of 4 molecular subtypes noninvasively and is potentially applicable in large samples.

Vasoprotective Effects of Hyperoside against Cerebral Ischemia/Reperfusion Injury in Rats: Activation of Large-Conductance Ca2+-Activated K+ Channels.

Hyperoside (Hyp), a kind of Chinese herbal medicine, exerts multiple therapeutic effects on many diseases. However, the role and mechanisms of Hyp in vascular pathophysiology in ischemic stroke need to be further established. The study aimed to investigate the role of (large-conductance Ca2+-activated K+) BK channels on the vasoprotection of Hyp against cerebral ischemia and reperfusion (I/R) injury in rats. The concentration gradient of Hyp was pretreated in both the middle cerebral artery occlusion and reperfusion model and oxygen-glucose deprivation/reoxygenation (OGD/R) model of primary vascular smooth muscle cells (VSMCs) in rats. A series of indicators were detected, including neurological deficit score, infarct volume, malondialdehyde (MDA), superoxide dismutase (SOD), cerebral blood flow (CBF), cell viability, membrane potential, and BK channels α- and ß1-subunits expression. The results showed that Hyp significantly reduced infarct volume and ameliorated neurological dysfunction in I/R-injured rats. Besides, the effects of I/R-induced reduction of BK channels α- and ß1-subunits expression were significantly reversed by Hyp in endothelial-denudated cerebral basilar arteries. Furthermore, the protective effect against I/R-induced increases of MDA and reduction of SOD as well as CBF induced by Hyp was significantly reversed by iberiotoxin (IbTX). In OGD/R-injured VSMCs, downregulated cellular viability and BK channels ß1-subunits expression were remarkably reversed by Hyp. However, neither OGD/R nor Hyp affected BK channels α-subunits expression, and Hyp failed to induced hyperpolarization of VSMCs. Moreover, the protective effect against OGD/R-induced reduction of cell viability and SOD level and increases of MDA production induced by Hyp was significantly reversed by IbTX in VSMCs. The study indicates that Hyp has the therapeutic potential to improve vascular outcomes, and the mechanism is associated with suppressing oxidative stress and improving CBF through upregulating BK channels.

Serum uric acid and the risk of gestational diabetes mellitus: a systematic review and meta-analysis.

AIMS: Serum uric acid (SUA) is considered as a risk factor for gestational diabetes mellitus (GDM). However, current studies showed inconsistent results. This study aimed to explore the relationship between SUA levels and GDM risk. METHODS: Eligible studies were retrieved from PubMed, Web of Science, Embase, China National Knowledge Infrastructure, and Wanfang databases up to November 1, 2022. The pooled standardized mean difference (SMD) and 95% confidence interval (CI) were used to represent the difference in SUA levels between GDM women and controls. The combined odds ratios (OR) and 95% CI were applied to assess association between SUA levels and GDM risk. Subgroup analyses were conducted on study continents, design, and quality, detection time of SUA, and GDM diagnostic criteria. RESULTS: Totally 11 studies including five case-control and six cohort studies, in which 80,387 pregnant women with 9815 GDM were included. The overall meta-analysis showed that the mean SUA level in GDM group was significantly higher than in controls (SMD = 0.423, 95%CI = 0.019-0.826, p = .040, I2 = 93%). Notably, pregnant women with elevated levels of SUA had a significantly increased risk of GDM (OR = 1.670, 95%CI = 1.184-2.356, p = .0035, I2 = 95%). Furthermore, subgroup analysis performed on the detection time of SUA showed a significant difference in the association between SUA and GDM risk within different trimesters (1st trimester: OR = 3.978, 95%CI = 2.177-7.268; 1st to 2nd trimester: OR = 1.340, 95%CI = 1.078-1.667; p between subgroups <.01). CONCLUSIONS: Elevated SUA was positively associated with GDM risk, particularly in the 1st trimester of pregnancy. Further studies with high quality are required to validate the findings of this study.

The effect of circulating adiponectin levels on incident gestational diabetes mellitus: systematic review and meta­analysis.

BACKGROUND: To quantitatively synthesize evidence from prospective observational studies regarding the mean levels of circulating adiponectin in patients with gestational diabetes mellitus (GDM) and the association between adiponectin levels and GDM risk. METHODS: PubMed, EMBASE and Web of Science were searched from their inception until November 8th, 2022, for nested case-control studies and cohort studies. Random-effect models were applied to the synthesized effect sizes. The difference in circulating adiponectin levels between the GDM and control groups was measured using the pooled standardized mean difference (SMD) and 95% confidence interval (CI). The relationship between circulating adiponectin levels and GDM risk was examined using the combined odds ratio (OR) and 95% CI. Subgroup analyses were performed according to the study continent, GDM risk in the study population, study design, gestational weeks of circulating adiponectin detection, GDM diagnostic criteria, and study quality. Sensitivity and cumulative analyses were performed to evaluate the stability of the meta-analysis. Publication bias was assessed by funnel plots and Egger's test. RESULTS: The 28 studies included 13 cohort studies and 15 nested case-control studies, containing 12,256 pregnant women in total. The mean adiponectin level in GDM patients was significantly lower than in controls (SMD = -1.514, 95% CI = -2.400 to -0.628, p = .001, I2 = 99%). The risk of GDM was significantly decreased among pregnant women with increasing levels of circulating adiponectin (OR = 0.368, 95% CI = 0.271-0.500, p < .001, I2=83%). There were no significant differences between the subgroups. CONCLUSIONS: Our findings indicate that increasing circulating adiponectin levels were inversely associated with the risk of GDM. Given the inherent heterogeneity and publication bias of the included studies, further well-designed large-scale prospective cohort or intervention studies are needed to confirm our finding.

Increasing circulating adiponectin levels in the first to the second trimester could decrease the risk of incident GDM.

Self-Propelled Janus Nanocatalytic Robots Guided by Magnetic Resonance Imaging for Enhanced Tumor Penetration and Therapy.

Biomedical micro/nanorobots as active delivery systems with the features of self-propulsion and controllable navigation have made tremendous progress in disease therapy and diagnosis, detection, and biodetoxification. However, existing micro/nanorobots are still suffering from complex drug loading, physiological drug stability, and uncontrollable drug release. To solve these problems, micro/nanorobots and nanocatalytic medicine as two independent research fields were integrated in this study to achieve self-propulsion-induced deeper tumor penetration and catalytic reaction-initiated tumor therapy in vivo. We presented self-propelled Janus nanocatalytic robots (JNCRs) guided by magnetic resonance imaging (MRI) for in vivo enhanced tumor therapy. These JNCRs exhibited active movement in H2O2 solution, and their migration in the tumor tissue could be tracked by non-invasive MRI in real time. Both increased temperature and reactive oxygen species production were induced by near-infrared light irradiation and iron-mediated Fenton reaction, showing great potential for tumor photothermal and chemodynamic therapy. In comparison with passive nanoparticles, these self-propelled JNCRs enabled deeper tumor penetration and enhanced tumor therapy after intratumoral injection. Importantly, these robots with biocompatible components and byproducts exhibited biosecurity in the mouse model. It is expected that our work could promote the combination of micro/nanorobots and nanocatalytic medicine, resulting in improved tumor therapy and potential clinical transformations.