Determining M2 macrophages content for the anti-tumor effects of metal-organic framework-encapsulated pazopanib nanoparticles in breast cancer.

Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

Maternal diseases and congenital anomalies of the kidney and urinary tract in offspring: a cohort study.

BACKGROUND: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of prenatally diagnosed developmental malformation. This study aimed to assess the relationship between maternal diseases and CAKUT in offspring. METHODS: This retrospective study enrolled all pregnant women registered from January 2020 to December 2022 at one medical center. Medical information on maternal noncommunicable diseases, including obesity, hypertension, diabetes mellitus, kidney disease, hyperthyroidism, hypothyroidism, psychiatric disease, epilepsy, cancer, and autoimmune disease was collected. Based on the records of ultrasound scanning during the third trimester, the diagnosis was classified as isolated urinary tract dilation (UTD) or kidney anomalies. Multivariate logistic regression was performed to establish models to predict antenatal CAKUT. RESULTS: Among the 19,656 pregnant women, perinatal ultrasound detected suspicious CAKUT in 114 (5.8/1000) fetuses, comprising 89 cases with isolated UTD and 25 cases with kidney anomalies. The risk of antenatal CAKUT was increased in the fetuses of mothers who experienced gestational diabetes, thyroid dysfunction, neuropsychiatric disease, anemia, ovarian and uterine disorders. A prediction model for isolated UTD was developed utilizing four confounding factors, namely gestational diabetes, gestational hypertension, maternal thyroid dysfunction, and hepatic disease. Similarly, a separate prediction model for kidney anomalies was established based on four distinct confounding factors, namely maternal thyroid dysfunction, gestational diabetes, disorders of ovarian/uterine, and kidney disease. CONCLUSIONS: Isolated UTD and kidney anomalies were associated with different maternal diseases. The results may inform the clinical management of pregnancy and highlight potential differences in the genesis of various subtypes of CAKUT.

Design of 3D printing osteotomy block for foot based on triply periodic minimal surface.

The ankle joint, which connects the lower limbs and the sole of the foot, is prone to sprain during walking and sports, which leads to ankle arthritis. Supratroleolar osteotomy is an ankle preserving operation for the treatment of ankle arthritis, in which the osteotomy is an important fixing and supporting part. In order to avoid stress shielding effect as much as possible, the osteotomy block is designed as a porous structure. In this study, the osteotomy block was designed based on three-period minimal surface, and the designed structure was manufactured by 3D printing. The mechanical properties of different structures were studied by mechanical test and finite element simulation. In mechanical tests, the Gyroid structure showed a progressive failure mechanism from bottom to bottom, while the Diamond structure showed a shear failure zone at 45° Angle, which was not conducive to energy absorption and was more prone to brittle fracture than the Gyroid structure. Therefore, the Gyroid structure is valuable for further research in the development of porous osteotomy.

Stability and chemical bonding in a series of inverse sandwich actinide boride clusters (An2B8) with δ bonding.

An inverse sandwich structure has been computationally predicted for uranium boride and extended to the series of actinide elements (An) from Th to Cm. The electronic structure and chemical bonding of these novel compounds have been analyzed using density functional theory and multireference wave-function based methods. We report the trends in electronic structure and bonding for An2B8, and found that (d-π)π and (d-p)δ are the most important factors in the stability of An2B8. The (f-p)δ bond provides extra stabilization for Pa2B8 and U2B8, owing to the extensive interactions of An-B8-An, resulting in a short distance for the Pa-Pa and U-U bonds.

Sponge-derived alkaloid AP-7 as a sensitizer to cisplatin in the treatment of multidrug-resistant NSCLC via Chk1-dependent mechanisms.

Multidrug resistance is a substantial obstacle in treating non-small cell lung cancer (NSCLC) with therapies like cisplatin (DDP)-based adjuvant chemotherapy and EGFR-tyrosine kinase inhibitors (TKIs). Aaptamine-7 (AP-7), a benzonaphthyridine alkaloid extracted from Aaptos aaptos sponge, has been shown to exhibit a broad spectrum of anti-tumor activity. However, the anti-cancer activity of AP-7 in combination with DDP and its molecular mechanisms in multidrug-resistant NSCLC are not yet clear. Our research indicates that AP-7 bolsters the growth inhibition activity of DDP on multidrug-resistant NSCLC cells. AP-7 notably disrupts DDP-induced cell cycle arrest and amplifies DDP-induced DNA damage effects in these cells. Furthermore, the combination of AP-7 and DDP downregulates Chk1 activation, interrupts the DNA damage repair-dependent Chk1/CDK1 pathway, and helps to overcome drug resistance and boost apoptosis in multidrug-resistant NSCLC cells and a gefitinib-resistant xenograft mice model. In summary, AP-7 appears to enhance DDP-induced DNA damage by impeding the Chk1 signaling pathway in multidrug-resistant NSCLC, thereby augmenting growth inhibition, both in vitro and in vivo. These results indicate the potential use of AP-7 as a DDP sensitizer in the treatment of multidrug-resistant NSCLC.

Early warning of atrial fibrillation using deep learning.

Atrial fibrillation (AF), the most prevalent cardiac rhythm disorder, significantly increases hospitalization and health risks. Reverting from AF to sinus rhythm (SR) often requires intensive interventions. This study presents a deep-learning model capable of predicting the transition from SR to AF on average 30.8 min before the onset appears, with an accuracy of 83% and an F1 score of 85% on the test data. This performance was obtained from R-to-R interval signals, which can be accessible from wearable technology. Our model, entitled Warning of Atrial Fibrillation (WARN), consists of a deep convolutional neural network trained and validated on 24-h Holter electrocardiogram data from 280 patients, with 70 additional patients used for testing and further evaluation on 33 patients from two external centers. The low computational cost of WARN makes it ideal for integration into wearable technology, allowing for continuous heart monitoring and early AF detection, which can potentially reduce emergency interventions and improve patient outcomes.

Molecular insights into the catalytic mechanism of a phthalate ester hydrolase.

Phthalate esters (PAEs) are emerging hazardous and toxic chemicals that are extensively used as plasticizers or additives. Diethyl phthalate (DEP) and dimethyl phthalate (DMP), two kinds of PAEs, have been listed as the priority pollutants by many countries. PAE hydrolases are the most effective enzymes in PAE degradation, among which family IV esterases are predominate. However, only a few PAE hydrolases have been characterized, and as far as we know, no crystal structure of any PAE hydrolases of the family IV esterases is available to date. HylD1 is a PAE hydrolase of the family IV esterases, which can degrade DMP and DEP. Here, the recombinant HylD1 was characterized. HylD1 maintained a dimer in solution, and functioned under a relatively wide pH range. The crystal structures of HylD1 and its complex with monoethyl phthalate were solved. Residues involved in substrate binding were identified. The catalytic mechanism of HylD1 mediated by the catalytic triad Ser140-Asp231-His261 was further proposed. The hylD1 gene is widely distributed in different environments, suggesting its important role in PAEs degradation. This study provides a better understanding of PAEs hydrolysis, and lays out favorable bases for the rational design of highly-efficient PAEs degradation enzymes for industrial applications in future.

A good response to anti-PD-1 monoclonal antibody plus SBRT in a patient with PD-L1-negative recurrent advanced esophageal cancer: a long-term follow-up case report of a possible abscopal effect.

There are limited treatment options for recurrent advanced esophageal squamous cell carcinoma. A good response with a possible abscopal effect was observed in a patient with programmed death-ligand 1 (PD-L1)-negative recurrent advanced esophageal squamous cell carcinoma treated with an anti-PD-1 monoclonal antibody plus stereotactic body radiotherapy (SBRT). A 66-year-old male patient was diagnosed with recurrent advanced esophageal squamous cell carcinoma with multiple lung metastases (13 metastatic nodules in total) four months after completing radical radiotherapy plus concurrent and consolidated chemotherapy, and PD-L1 expression in the primary esophageal tumor was negative. This patient received 25 cycles of camrelizumab (an anti-PD-1 monoclonal antibody) in total plus upfront SBRT for two metastatic nodules, which was administered after the first cycle of camrelizumab. After this combined treatment, for most nontarget nodules, an obvious volume decrease and fuzzy change were observed, including two nodules that completely vanished. At the end of follow-up, the progression-free survival and duration of response of this patient were 34 months and 32 months, respectively. This case report indicated that an anti-PD-1 monoclonal antibody combined with SBRT was a promising therapeutic strategy for recurrent esophageal squamous cell carcinoma even in patients with negative PD-L1 expression.

Electrochemical synthesis of ß-difluoromethylamide compounds by N-benzenesulfonylacrylamide with difluorine reagents.

A mild and efficient electrochemical method for radical addition, cyclization, and migration reaction was described in this work. A difluoromethyl radical was produced by anodizing CF2HSO2Na. The resulting product was then added to olefin, underwent Smiles cyclization, and migrated to form ß-difluoromethamide compounds after the release of SO2. The process was free from metals and catalysts, gram-grade, and resistant to a variety of electron-rich substrates.

Evaluation of enhanced external counterpulsation for diabetic foot based on a patient-specific 0D-1D cardiovascular system model.

BACKGROUND AND OBJECTIVE: Diabetic foot (DF) complications often lead to severe vascular issues. This study investigated the effectiveness of enhanced external counterpulsation (EECP) and its derived innovative compression strategies in addressing poor perfusion in DF. Although developing non-invasive and efficient treatment methods for DF is critical, the hemodynamic alterations during EECP remain underexplored despite promising outcomes in microcirculation. This research sought to address this gap by developing a patient-specific 0D-1D model based on clinical ultrasound data to identify potentially superior compression strategies that could substantially enhance blood flow in patients with DF complications. METHODS: Data were gathered from 10 patients with DF utilizing ultrasound for blood flow rate and computed tomography angiography (CTA) to identify lower limb conditions. Clinical measurements during standard EECP, with varying cuff pressures, facilitated the creation of a patient-specific 0D-1D model through a two-step parameter estimation process. The accuracy of this model was verified via comparison with the clinical measurements. Four compression strategies were proposed and rigorously evaluated using this model: EECP-Simp-I (removing hip cuffs), EECP-Simp-II (further removing the cuffs around the lower leg), EECP-Impr-I (removing all cuffs around the affected side), and EECP-Impr-II (building a loop circulation from the healthy side to the affected side). RESULTS: The predicted results under the rest and standard EECP states were generally closely aligned with clinical measurements. The patient-specific 0D-1D model demonstrated that EECP-Simp-I and EECP-Impr-I contributed similar enhancement to perfusion in the dorsal artery (DA) and were comparable to standard EECP, while EECP-Simp-II had the least effect and EECP-Impr-II displayed the most significant enhancement. Pressure at the aortic root (AO) remained consistent across strategies. CONCLUSIONS: EECP-Simp-I is recommended for patients with DF, emphasizing device simplification. However, EECP-Simp-II is discouraged as it significantly diminished blood perfusion in this study, except in cases of limb fragility. EECP-Impr-II showed superior enhancement of blood perfusion in DA to all other strategies but required a more complex EECP device. Despite increased AO pressure in all the proposed compression strategies, safety could be guaranteed as the pressue remained within a safe range.

Jianpi-Tiaoqi decoction inhibits tumour proliferation and lung metastasis in tumour-bearing mice with triple-negative breast cancer.

Traditional Chinese medicine, specifically the Jianpi Tiaoqi (JPTQ) decoction, has been explored for its role in treating breast cancer, particularly in inhibiting lung metastasis in affected mice. Our study evaluated the effects of JPTQ on several factors, including tumour growth, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT) and immune microenvironment regulation. We used bioluminescence imaging to observe in situ tumour growth and potential lung metastasis. Transcriptomic analysis provided insights into gene expression, whereas flow cytometry was used to examine changes in specific immune cells, such as CD4+ T cells and myeloid-derived suppressor cells. Several essential proteins and genes, including vascular endothelial growth factor (VEGF), matrix metalloprotein-9 (MMP-9) and B-cell lymphoma 2 (Bcl-2), were assessed through quantitative real-time polymerase chain reaction, western blotting and immunohistochemistry. Our findings showed that JPTQ treatment inhibited tumour proliferation in cancer-bearing mice. Bioluminescence imaging and pathological analysis indicated a reduction in lung metastasis. Transcriptome analysis of lung and tumour tissues indicated that the genes associated with EMT, angiogenesis, proliferation and apoptosis were regulated in the JPTQ-treated group. Kyoto Encyclopedia of Genes and Genomes analysis suggested enrichment of immune-related pathways. Flow cytometry indicated that JPTQ treatment reduced the proportion of monocyte-myeloid-derived suppressor cells in the lung and increased the number of CD4+ T cells in the peripheral blood and the number of T helper 1 (Th1) cells in the spleen (P < 0.05). E-cadherin and cleaved caspase 3 were upregulated, whereas Snail, Bcl-2, Ki67 and VEGF were downregulated in the lung and tumour tissues; moreover, the expression of MMP-9 was downregulated in the lung tissue (P < 0.05). In essence, JPTQ not only inhibits tumour growth in affected mice, but also promotes positive immune responses, reduces angiogenesis, boosts tumour cell apoptosis, reverses EMT and decreases breast cancer lung metastasis.

Magnetic resonance imaging scanning susceptibility weighted imaging sequences in the diagnosis and prognostic evaluation of neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Magnetic resonance imaging (MRI) scanning with susceptibility weighted imaging (SWI) sequences plays a significant role in the diagnosis and prognostic evaluation of neonatal hypoxic-ischemic encephalopathy (HIE). AIM: To observe the role of MRI multi-parameter quantitative indexes in the diagnosis of neonatal HIE. METHODS: The imaging data from 23 cases of neonatal HIE admitted to the Imaging Department of Ganyu District People's Hospital of Lianyungang City and 23 neonates without HIE admitted during the same period were analyzed retrospectively from August, 2021 to December, 2023. The results of clinical judgment were compared with the results of computed tomography (CT) and MRI examinations. RESULTS: The degree of cerebral edema (more than moderate), the number of damaged brain regions (> 2), the number of cerebral hemorrhages (> 2), and the percentage of small venous dilatation detected were higher in MRI than in CT examination, and the differences were statistically significant (P < 0.05). The total area of the largest region of cerebral damage and of cerebral hemorrhage observed by MRI examination were significantly larger than those of CT examination (P < 0.01). Multiparametric quantitative MRI combined with diffusion weighted imaging and SWI had higher sensitivity and accuracy than CT diagnosis, and the difference was statistically significant (P < 0.05). The difference in the specificity of the two modes of diagnosis was not significant (P > 0.05). CONCLUSION: The use of MRI multi-parameter quantitative indexes can accurately diagnose and evaluate neonatal HIE.

Identifying Community-Bridge Network Structures via Bayesian Learning With Mixed Sparsity Mode.

Identifying structures of complex networks based on time series of nodal data is of considerable interest and significance in many fields of science and engineering. This article presents a sparse Bayesian learning (SBL) method for identifying structures of community-bridge networks, where nodes are grouped to form communities connected via bridges. Using the structural information of such networks with unknown nodal dynamics and community formations, network structure identification is tackled similar to sparse signal reconstruction with mixed sparsity mode. The proposed method is theoretically proved to be convergent. Its superiority to mainstream baselines is demonstrated via extensive experiments without the need for manual adjustment of regularization parameters.

Rheological characterization of chia seed gum as a thickening agent used for dysphagia management.

Dysphagia has emerged as a serious health issue facing contemporary society. Consuming thickened liquids is an effective approach for improving the swallowing safety for dysphagia patients. The thickening effect of chia seed gum (CSG), a novel thickener, in different dispersing media (water, orange juice, and skim milk) was investigated. Moreover, the potential application of CSG for dysphagia management was evaluated by comparison with xanthan gum (XG) and guar gum (GG). The thickened liquids prepared with 0.4 %-1.2 % (w/v) CSG, XG, and GG could be classified into levels 1-4, 2-4, and 1-3, respectively, according to the International Dysphagia Diet Standardization Initiative (IDDSI) framework. All the thickened liquids displayed shear-thinning characteristics that facilitated safe swallowing. The viscosities (η50) of CSG dissolved in water (0.202-1.027 Pa·s) were significantly greater than those of CSG dissolved in orange juice (0.070-0.690 Pa·s) and skim milk (0.081-0.739 Pa·s), indicating that CSG had a greater thickening effect in water than in orange juice and skim milk. Compared with those prepared with GG, the thickened liquids prepared with CSG and XG exhibited greater viscoelasticity, better water-holding capacity, and more compact networks. The findings suggested that CSG can be used as a potential thickener for thickening liquid foods to manage dysphagia.

Activation of lncRNA DANCR by H3K27 acetylation regulates proliferation of colorectal cancer cells.

The long noncoding DANCR functions as a tumor oncogene in many cancers, including colorectal cancer (CRC). However, the molecular mechanism of DANCR in CRC has not been explored. This study probed the function and potential mechanism by which DANCR contributes to the progression of CRC. The obtained data indicated that DANCR is overexpressed in CRC tissues and cell lines. Knockdown of DANCR hindered CRC cell proliferation, which was mediated by cyclin D1 and CDK4. Bioinformatic analysis, luciferase reporter assays and subcellular fractionation verified that DANCR directly binds to miR-508-5p. Moreover, DANCR acts as a miR-508-5p ceRNA to regulate expression of ATF1. In addition, upregulation of DANCR is attributed to H3K27 acetylation at the promoter region. In conclusion, our study confirmed that activation of lncRNA DANCR by H3K27 acetylation has an oncogenic role in CRC progression and provides a potential therapeutic target for CRC.

Construction and characterization of alginate/calcium ß-hydroxy-ß-methylbutyrate hydrogels: Effect of M/G ratios and calcium ion concentration.

Calcium ß-hydroxy-ß-methylbutyrate (CaHMB), a functional calcium salt, is used to maintain and improve muscle health. Here, a new hydrogel material prepared from alginate (ALG) with three M/G ratios (1:1, 2:1, and 1:2) and CaHMB (0-2 mg/mL) was investigated. CaHMB regulates the formation and properties of ALG hydrogels through chelation and hydrogen bonding. When the M/G ratio was 2:1, the anionic groups of CaHMB containing carboxyl and hydroxyl groups formed hydrogen bonds with the polysaccharide chains, hindering the capture of Ca2+ by the G-residue fragments of ALG, which in turn retarded the gelation process. The noncalcium cross-linked polysaccharide chain structure of ALG and the anionic group of CaHMB also affected the water distribution in the hydrogel, especially when M residue content ≥G residue content. Lower M/G ratios and higher CaHMB concentrations could increase the number of "egg box" crosslinking junctions of calcium alginate, and the microstructure was denser in the gel pores, resulting in a stronger gel strength and more free water bound in the gel matrix. This study provides a theoretical and methodological basis for the design of novel hydrogels by studying the crosslinking features of ALG/CaHMB.

[Effect of Exogenous Chitosan on Physiological Properties, Antioxidant Activity, and Cadmium Uptake of Wheat (Triticum aestivum L.) Seedlings Under Cadmium Stress].

This research aimed to clarify the effects of exogenously applied chitosan on the physiological characteristics, antioxidant activities, and Cd accumulation of wheat (Triticum aestivum L.) seedlings under cadmium (Cd) stress and to identify the key indicators based on the partial least squares model. The wheat variety studied was Bainong207 (BN207), and Cd-stress was achieved by growing seedlings in a hydroponic culture experiment with 10 and 25 µmol·L-1 Cd2+ added to the culture solution. It was found that both Cd-stress at 10 and 25 µmol·L-1 significantly inhibited the chlorophyll content, photosynthesis, and biomass accumulation of wheat seedlings. Seedling roots became shorter and thicker, and the lateral roots decreased under Cd-stress. The Cd-stress also increased H2O2 and MDA accumulation and the degree of cell membrane lipid peroxidation and affected the activities of antioxidant enzymes such as superoxide dismutase (SOD) and peroxidase (POD). Under Cd stress, exogenous chitosan decreased the Cd content in the aboveground and underground parts of wheat by 13.22 %-21.63 % and 7.92 %-28.32 % and reduced Cd accumulation in the aboveground and underground parts by 5.37 %-6.71 % and 1.91 %-4.09 %, respectively. Whereas exogenous chitosan application significantly reduced the content of H2O2 in roots and aboveground parts of wheat by 38.21 %-47.46 % and 45.81 %-55.73 % and MDA content by 37.65 %-48.12 % and 29.87 %-32.51 %, it increased the activities of SOD and POD in roots by 2.78 %-5.61 % and 13.81 %-18.33 %, respectively. In summary, exogenous chitosan can improve the photosynthetic characteristics and antioxidant enzyme activities of wheat seedlings under Cd stress, reduce the content and accumulation of Cd in the root and aboveground parts of wheat, and alleviate the damage of lipid peroxidation to the cell membrane. All of these results provide the basal data for the application of exogenous chitosan to alleviate Cd toxicity to wheat seedlings.

A nomogram predicting pneumonia after cardiac surgery: a retrospective modeling study.

BACKGROUND: Postoperative pneumonia (POP) is the most prevalent of all nosocomial infections in patients who underwent cardiac surgery. The aim of this study was to identify independent risk factors for pneumonia after cardiac surgery, from which we constructed a nomogram for prediction. METHODS: The clinical data of patients admitted to the Department of Cardiothoracic Surgery of Nanjing Drum Tower Hospital from October 2020 to September 2021 who underwent cardiac surgery were retrospectively analyzed, and the patients were divided into two groups according to whether they had POP: POP group (n=105) and non-POP group (n=1083). Preoperative, intraoperative, and postoperative indicators were collected and analyzed. Logistic regression was used to identify independent risk factors for POP in patients who underwent cardiac surgery. We constructed a nomogram based on these independent risk factors. Model discrimination was assessed via area under the receiver operating characteristic curve (AUC), and calibration was assessed via calibration plot. RESULTS: A total of 105 events occurred in the 1188 cases. Age (>55 years) (OR: 1.83, P=0.0225), preoperative malnutrition (OR: 3.71, P<0.0001), diabetes mellitus(OR: 2.33, P=0.0036), CPB time (Cardiopulmonary Bypass Time) > 135 min (OR: 2.80, P<0.0001), moderate to severe ARDS (Acute Respiratory Distress Syndrome )(OR: 1.79, P=0.0148), use of ECMO or IABP or CRRT (ECMO: Extra Corporeal Membrane Oxygenation; IABP: Intra-Aortic Balloon Pump; CRRT: Continuous Renal Replacement Therapy )(OR: 2.60, P=0.0057) and MV( Mechanical Ventilation )> 20 hours (OR: 3.11, P<0.0001) were independent risk factors for POP. Based on those independent risk factors, we constructed a simple nomogram with an AUC of 0.82. Calibration plots showed good agreement between predicted probabilities and actual probabilities. CONCLUSION: We constructed a facile nomogram for predicting pneumonia after cardiac surgery with good discrimination and calibration. The model has excellent clinical applicability and can be used to identify and adjust modifiable risk factors to reduce the incidence of POP as well as patient mortality.