Anlotinib potentiates anti-PD1 immunotherapy via transferrin receptor-dependent CD8+ T-cell infiltration in hepatocellular carcinoma.

BACKGROUND: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. OBJECTIVE: This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC. METHODS: Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. RESULTS: The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC. CONCLUSIONS: Our findings highlight anlotinib's potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. HIGHLIGHTS: Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.

Identification of key genes involved in collagen hydrogel-induced chondrogenic differentiation of mesenchymal stem cells through transcriptome analysis: the role of m6A modification.

Collagen hydrogel has been shown promise as an inducer for chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), contributing to the repair of cartilage defects. However, the precise molecular mechanism underlying this phenomenon remains poorly elucidated. Here, we induced chondrogenic differentiation of BMSCs using collagen hydrogel and identified 4451 differentially expressed genes (DEGs) through transcriptomic sequencing. Our analysis revealed that DEGs were enriched in the focal adhesion pathway, with a notable decrease in expression levels in the collagen hydrogel group compared to the control group. Protein-protein interaction network analysis suggested that actinin alpha 1 (ACTN1) and actinin alpha 4 (ACTN4), two proteins also involved in cytoskeletal recombination, may be crucial in collagen hydrogel-induced chondrogenic differentiation of BMSCs. Additionally, we found that N6-methyladenosine RNA methylation (m6A) modification was involved in collagen hydrogel-mediated chondrogenic differentiation, with fat mass and obesity-associated protein (FTO) implicated in regulating the expression of ACTN1 and ACTN4. These findings suggest that collagen hydrogel might regulate focal adhesion and actin cytoskeletal signaling pathways through down-regulation of ACTN1 and ACTN4 mRNA via FTO-mediated m6A modification, ultimately driving chondrogenic differentiation of BMSCs. In conclusion, our study provides valuable insights into the molecular mechanisms of collagen hydrogel-induced chondrogenic differentiation of BMSCs, which may aid in developing more effective strategies for cartilage regeneration.

Hsa_circ_0064636 regulates voltage dependent anion channel 1/ubiquitination factor E4A through miR­326/miR­503­5 in osteosarcoma.

Circular RNAs (circRNAs) are a subclass of non-coding RNAs that are important for the regulation of gene expression in eukaryotic organisms. CircRNAs exert various regulatory roles in cancer progression. However, the role of hsa_circ_0064636 in osteosarcoma (OS) remains poorly understood. In the present study, the expression of hsa_circ_0064636 in OS cell lines was measured by reverse transcription-quantitative PCR (RT-qPCR). Differentially expressed mRNAs and microRNAs (miRNA or miRs) were screened using mRNA(GSE16088) and miRNA(GSE65071) expression datasets for OS. miRNAs that can potentially interact with hsa_circ_0064636 were predicted using RNAhybrid, TargetScan and miRanda. Subsequently, RNAhybrid, TargetScan, miRanda, miRWalk, miRMap and miRNAMap were used for target gene prediction based on the overlapping miRNAs to construct a circ/miRNA/mRNA interaction network. Target genes were subjected to survival analysis using PROGgeneV2, resulting in a circRNA/miRNA/mRNA interaction sub-network with prognostic significance. miRNA and circRNA in the subnetwork may also have survival significance, but relevant data are lacking and needs to be further proved. RT-qPCR demonstrated that hsa_circ_0064636 expression was significantly increased in OS cell lines. miR-326 and miR-503-5p were identified to be target miRNAs of hsa_circ_0064636. Among the target genes obtained from the miR-326 and miR-503-5p screens, ubiquitination factor E4A (UBE4A) and voltage dependent anion channel 1 (VDAC1) were respectively identified to significantly affect prognosis; only miR-326 targets UBE4A and only miR-503 targets VDAC1. To conclude, these aforementioned findings suggest that hsa_circ_0064636 may be involved in the development of OS by sponging miR-503-5p and miR-326to inhibit their effects, thereby regulating the expression of VDAC1 and UBE4A.

Galloborates as ultraviolet nonlinear optical crystals: advances and perspectives.

Metal borates are excellent source materials for exploring short-wavelength nonlinear optical (NLO) crystals. Galloborates show rich structural chemistry with various coordination configurations of Ga cation and B-O anionic units and are suitable candidates as ultraviolet NLO crystals. Up to now, the shortest cut-off edge of galloborates was reported to be down to 190 nm in KCs2Ga(B5O10)(OH), while the largest second harmonic generation (SHG) effect of galloborates was reported to be up to 4.6 times that of KH2PO4 (KDP) in Na5Ga[B7O12(OH)]2·2B(OH)3. Herein, we give a detailed summary of the recent progress in NLO inorganic galloborates, where these galloborates are grouped into two types in terms of their compositions: (1) alkali/alkaline earth metal galloborates and (2) alkali/alkaline earth metal galloborate halides. We discuss their structural features, band gaps, and SHG intensities. Finally, we give future perspectives in this field.

Early detection and prognosis evaluation for hepatocellular carcinoma by circulating tumour DNA methylation: A multicentre cohort study.

BACKGROUND: Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve patient survival. We aimed to develop a blood-based assay to aid in the diagnosis, detection and prognostic evaluation of HCC. METHODS: A three-phase multicentre study was conducted to screen, optimise and validate HCC-specific differentially methylated regions (DMRs) using next-generation sequencing and quantitative methylation-specific PCR (qMSP). RESULTS: Genome-wide methylation profiling was conducted to identify DMRs distinguishing HCC tumours from peritumoural tissues and healthy plasmas. The twenty most effective DMRs were verified and incorporated into a multilocus qMSP assay (HepaAiQ). The HepaAiQ model was trained to separate 293 HCC patients (Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 224) from 266 controls including chronic hepatitis B (CHB) or liver cirrhosis (LC) (CHB/LC, 96), benign hepatic lesions (BHL, 23), and healthy controls (HC, 147). The model achieved an area under the curve (AUC) of 0.944 with a sensitivity of 86.0% in HCC and a specificity of 92.1% in controls. Blind validation of the HepaAiQ model in a cohort of 523 participants resulted in an AUC of 0.940 with a sensitivity of 84.4% in 205 HCC cases (BCLC stage 0/A, 167) and a specificity of 90.3% in 318 controls (CHB/LC, 100; BHL, 102; HC, 116). When evaluated in an independent test set, the HepaAiQ model exhibited a sensitivity of 70.8% in 65 HCC patients at BCLC stage 0/A and a specificity of 89.5% in 124 patients with CHB/LC. Moreover, HepaAiQ model was assessed in paired pre- and postoperative plasma samples from 103 HCC patients and correlated with 2-year patient outcomes. Patients with high postoperative HepaAiQ score showed a higher recurrence risk (Hazard ratio, 3.33, p < .001). CONCLUSIONS: HepaAiQ, a noninvasive qMSP assay, was developed to accurately measure HCC-specific DMRs and shows great potential for the diagnosis, detection and prognosis of HCC, benefiting at-risk populations.

M6[Cd2(CO3)2(B12O18)(OH)6] (M = K, Rb): Borate-Carbonates with Two CdCO3 Embedded in a Cyclic Oxoboron Anion.

Two metal borate-carbonates, M6[Cd2(CO3)2(B12O18)(OH)6] [M = K (1), Rb (2)], were obtained under surfactant-thermal conditions. In 1 and 2, each cyclic [(B12O18)(OH)6]6- anion captures two CdCO3 in two sides of the rings and finally forms the unusual (CdCO3)2@[(B12O18)(OH)6] cluster. Both 1 and 2 show moderate birefringence. Density functional theory calculations indicate that carbonate groups have a major contribution to electron-related optical transition.

NIR-enhanced Pt single atom/g-C3N4 nanozymes as SOD/CAT mimics to rescue ATP energy crisis by regulating oxidative phosphorylation pathway for delaying osteoarthritis progression.

Osteoarthritis (OA) progresses due to the excessive generation of reactive oxygen and nitrogen species (ROS/RNS) and abnormal ATP energy metabolism related to the oxidative phosphorylation pathway in the mitochondria. Highly active single-atom nanozymes (SAzymes) can help regulate the redox balance and have shown their potential in the treatment of inflammatory diseases. In this study, we innovatively utilised ligand-mediated strategies to chelate Pt4+ with modified g-C3N4 by π-π interaction to prepare g-C3N4-loaded Pt single-atom (Pt SA/C3N4) nanozymes that serve as superoxide dismutase (SOD)/catalase (CAT) mimics to scavenge ROS/RNS and regulate mitochondrial ATP production, ultimately delaying the progression of OA. Pt SA/C3N4 exhibited a high loading of Pt single atoms (2.45 wt%), with an excellent photothermal conversion efficiency (54.71%), resulting in tunable catalytic activities under near-infrared light (NIR) irradiation. Interestingly, the Pt-N6 active centres in Pt SA/C3N4 formed electron capture sites for electron holes, in which g-C3N4 regulated the d-band centre of Pt, and the N-rich sites transferred electrons to Pt, leading to the enhanced adsorption of free radicals and thus higher SOD- and CAT-like activities compared with pure g-C3N4 and g-C3N4-loaded Pt nanoparticles (Pt NPs/C3N4). Based on the use of H2O2-induced chondrocytes to simulate ROS-injured cartilage invitro and an OA joint model invivo, the results showed that Pt SA/C3N4 could reduce oxidative stress-induced damage, protect mitochondrial function, inhibit inflammation progression, and rebuild the OA microenvironment, thereby delaying the progression of OA. In particular, under NIR light irradiation, Pt SA/C3N4 could help reverse the oxidative stress-induced joint cartilage damage, bringing it closer to the state of the normal cartilage. Mechanistically, Pt SA/C3N4 regulated the expression of mitochondrial respiratory chain complexes, mainly NDUFV2 of complex 1 and MT-ATP6 of ATP synthase, to reduce ROS/RNS and promote ATP production. This study provides novel insights into the design of artificial nanozymes for treating oxidative stress-induced inflammatory diseases.

Sr2[B5O8(OH)]2 ⋠[B(OH)3] ⋠H2O: A Strontium Borate That Shows Deep-Ultraviolet-Transparent Nonlinear Optical Properties.

A new noncentrosymmetric strontium borate, P1-Sr2[B5O8(OH)]2 ⋅ [B(OH)3] ⋅ H2O (1), has been synthesized under the hydrothermal condition. The P1-Sr2[B5O8(OH)]2 ⋅ [B(OH)3] ⋅ H2O shows a layered B-O network with 9-ring windows in the ab plane. Sr2+ cations, H3BO3, and H2O molecules are located in the voids of layers and interlayers, respectively. The P1-Sr2[B5O8(OH)]2 ⋅ [B(OH)3] ⋅ H2O is the first synthetic phase of veatchite, while the other three polymorphs are found in different natural minerals. This strontium borate is a potential deep-ultraviolet-transparent nonlinear-optical (NLO) crystal whose second-harmonic-generation (SHG) intensity is 1.7 times that of KH2PO4 (KDP) and is phase-matchable. The short wavelength cutoff edge of compound 1 is below 190 nm. Density functional theory (DFT) calculations show that the B-O units are responsible for the nonlinear optical property.

A Countertraction Closed Reduction Technique in Minimally Invasive Fixation of Recent Type C Pelvic Ring Injuries.

OBJECTIVE: Closed reduction of pelvic injuries is a prerequisite and critical step in minimally invasive treatment. Achieving non-invasive closed reduction of pelvic injuries is a challenging clinical problem. This study demonstrated a non-invasive traction technique for closed reduction called countertraction closed reduction technique (CCRT) and evaluated its effectiveness for type C pelvic ring injuries. METHOD: The data of patients with unstable pelvic fractures treated with CCRT and minimally invasive fixation were retrospectively reviewed from January 2017 to February 2022. Sacroiliac screws were placed to fix the posterior pelvic ring, and internal or external fixation was used to fix the anterior pelvic ring. Operation time, intraoperative blood loss, duration of hospital stay, fracture union and postoperative complications were recorded. Fracture reduction quality was evaluated using the Matta scoring criteria. Functional recovery and general quality of life were evaluated using the Majeed functional scoring criteria. RESULTS: Thirteen patients (nine males and four females), with an average age of 49.6 years were treated with CCRT and followed up for a mean of 18.5 months. The average operation time was 137.2 minutes (range 92-195 minutes), the average intraoperative blood loss was 31.2 mL (range 10-120 mL) and the average duration of hospital stay was 14.3 days (range 4-32 days). All patients achieved bony union with an average union time of 11.9 weeks (range 10-16 weeks). According to the Matta radiographic criteria, the quality of fracture reduction was excellent in eight patients, good in four, and fair in one. The average Majeed functional score was 89.7 (range 78-100). The functional evaluation revealed that the outcomes were excellent in nine patients, and good in four patients. Complications included incision fat liquefaction in one patient, and heterotopic ossification in another patient. There were no surgical complications as a result of CCRT. CONCLUSION: CCRT is a non-invasive closed reduction method for minimally invasive fixation of fresh Tile C1 and C2 pelvic fractures. The advantages of CCRT combined with minimally invasive treatment include a small surgical incision, reduced intraoperative bleeding, satisfactory fracture reduction, bone healing and functional recovery.

A practical nomogram for predicting amputation rates in acute compartment syndrome patients based on clinical factors and biochemical blood markers.

BACKGROUND: Amputation is a serious complication of acute compartment syndrome (ACS), and predicting the risk factors associated with amputation remains a challenge for surgeons. The aim of this study was to analyze the risk factors for amputation in patients with ACS and develop a nomogram to predict amputation risk more accurately. METHODS: The study population consisted of 143 patients (32 in the amputation group and 111 in the limb preservation group) diagnosed with ACS. LASSO and multivariate logistic regression were used to screen predictors and create a nomogram. The model's accuracy was assessed by receiver operating characteristic (ROC) curves, C-index, calibration curves, and decision curve analysis (DCA). RESULTS: The predictors included cause of injury, vascular damage, shock, and fibrinogen in the nomogram. The C-index of the model was 0.872 (95% confidence interval: 0.854-0.962), and the C-index calculated by internal validation was 0.838. The nomogram's area under the curve (AUC) was 0.849, and the calibration curve demonstrated a high degree of agreement between the nomogram's predictions and actual observations. Additionally, the DCA indicated good clinical utility for the nomogram. CONCLUSION: The risk of amputation in ACS patients is associated with the cause of injury, vascular damage, shock, and fibrinogen. Our nomogram integrating clinical factors and biochemical blood markers enables doctors to more conveniently predict the risk of amputation in patients with ACS.

A Double Cross-Linked Injectable Hydrogel Derived from Muscular Decellularized Matrix Promotes Myoblast Proliferation and Myogenic Differentiation.

Injectable hydrogels possess tremendous merits for use in muscle regeneration; however, they still lack intrinsic biological cues (such as the proliferation and differentiation of myogenic cells), thus considerably restricting their potential for therapeutic use. Herein, we developed a double cross-linked injectable hydrogel composed of methacrylamidated oxidized hyaluronic acid (MOHA) and muscular decellularized matrix (MDM). The chemical composition of the hydrogel was confirmed using 1H NMR and Fourier transform infrared spectroscopy. To achieve cross-linking, the aldehyde groups in MOHA were initially reacted with the amino groups in MDM through a Schiff-based reaction. This relatively weak cross-linking provided the MOHA/MDM hydrogel with satisfactory injectability. Furthermore, the methacrylation of MOHA facilitated a second cross-linking mechanism via UV irradiation, resulting in improved gelation ability, biomechanical properties, and swelling performance. When C2C12 myogenic cells were loaded into the hydrogel, our results showed that the addition of MDM significantly enhanced myoblast proliferation compared to the MOHA hydrogel, as demonstrated by live/dead staining and Cell Counting Kit-8 assay after seven days of in vitro cultivation. In addition, gene expression analysis using quantitative polymerase chain reaction indicated that the MOHA/MDM hydrogel promoted myogenic differentiation of C2C12 cells more effectively than the MOHA hydrogel, as evidenced by elevated expression levels of myogenin, troponin T, and MHC in the MOHA/MDM hydrogel group. Moreover, after four to eight weeks of implantation in a full-thickness abdominal wall-defect model, the MOHA/MDM hydrogel could promote the reconstruction and repair of functional skeletal muscle tissue with enhanced tetanic force and tensile strength. This study provides a new double cross-linked injectable hydrogel for use in muscular tissue engineering.

Recent Progress in Crystalline Borates with Edge-Sharing BO4 Tetrahedra.

Crystalline borates have received great attention due to their various structures and wide applications. For a long time, the corner-sharing B-O unit is considered a basic rule in borate structural chemistry. The Dy4B6O15 synthesized under high-pressure is the first oxoborate with edge-sharing [BO4] tetrahedra, while the KZnB3O6 is the first ambient pressure borate with the edge-sharing [BO4] tetrahedra. The edge-sharing connection modes greatly enrich the structural chemistry of borates and are expected to expand new applications in the future. In this review, we summarize the recent progress in crystalline borates with edge-sharing [BO4] tetrahedra. We discuss the synthesis, fundamental building blocks, structural features, and possible applications of these edge-sharing borates. Finally, we also discuss the future perspectives in this field.

An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression.

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as "the invasive zone". We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs' overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

Study on depolymerization kinetics of formic acid dimers in binary mixture.

In this study, polarization Raman spectra were collected for binary mixtures of formic acid/methanol and formic acid/acetonitrile with different volume fractions. The broad band of formic acid in the CO vibration region was divided into four vibration peaks, corresponding to CO symmetric and anti-symmetric stretching vibration from cyclic dimer, CO stretching from open dimer, and CO stretching from the free monomer. The experiments showed that as the volume fraction of formic acid in the binary mixture decreased, the cyclic dimer gradually converted to the open dimer, and at a volume fraction of 0.1, fully depolymerized into monomer form (free monomer, solvated monomer, and hydrogen bonding monomer clusters with solvent). The contribution percentage of the total CO stretching intensity of each structure at different concentrations was quantitatively calculated using high resolution infrared spectroscopy, and the results were consistent with the conclusions predicted by polarization Raman spectroscopy. Concentration-triggered 2D-COS synchronous and asynchronous spectra also confirmed the kinetics of formic acid diluted in acetonitrile. This work provides a spectroscopic method for studying the structure of organic compounds in solution and concentration-triggering kinetics in mixtures.

Assessing the association of leukocyte telomere length with ankylosing spondylitis and rheumatoid arthritis: A bidirectional Mendelian randomization study.

Background: Telomere length shortening can cause senescence and apoptosis in various immune cells, resulting in immune destabilization and ageing of the organism. In this study, we aimed to systematically assess the causal relationship of leukocyte telomere length (LTL) with ankylosing spondylitis (AS) and rheumatoid arthritis (RA) using a Mendelian randomization study. Methods: LTL (n=472174) was obtained from the UK Biobank genome-wide association study pooled data. AS (n=229640), RA (n=212472) were obtained from FinnGen database. MR-Egger, inverse variance weighting, and weighted median methods were used to estimate the effects of causes. Cochran's Q test, MR Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots were used to look at sensitivity, heterogeneity, and multiple effects. Forward MR analysis considered LTL as the exposure and AS, RA as the outcome. Reverse MR analysis considered AS, RA as the exposure and LTL as the outcome. Results: In the forward MR analysis, inverse variance-weighted and weighted median analysis results indicated that longer LTL might be associated with increased risk of AS (IVW: OR = 1.55, 95% CI: 1.14-2.11, p = 0.006). MR Egger regression analysis showed no pleiotropy between instrumental variables (IVs) (Egger intercept= 0.008, p = 0.294). The leave-one-out analysis showed that each single nucleotide polymorphism (SNP) of AS was robust to each outcome. No significant causal effects were found between AS, RA and LTL in the reverse MR analysis. Conclusion: Longer LTL may be related with an increased risk of developing AS, and these findings provide a foundation for future clinical research on the causal association between LTL and AS.

UPLC/Q-TOF-MS-based metabolomics evaluate the efficacy of oroxylin A against postmenopausal osteoporosis.

Post-menopausal osteoporosis (PMOP) is a common metabolic bone malady characterized by bone mass loss and bone microarchitectural deterioration; however, there is currently no effective drug for its management. According to our previous study, oroxylin A (OA) could effectively protect ovariectomized (OVX)-osteoporotic mice from bone loss; however, its therapeutic targets are still unclear. From a metabolomic perspective, we studied serum metabolic profiles to discover potential biomarkers and OVX-related metabolic networks, which could assist us to comprehend the impact of OA on OVX. Five metabolites were identified as biomarkers associated with 10 related metabolic pathways, including phenylalanine, tyrosine and tryptophan biosynthesis, and phenylalanine, tryptophan and glycerophospholipid metabolism. After OA treatment, the expression of multiple biomarkers changed, with lysophosphatidylcholine (18:2) being a major significantly regulated biomarker. Our study demonstrated that OA's effects on OVX are probably related to the regulation of phenylalanine, tyrosine and tryptophan biosynthesis. Our findings explain the role of OA against PMOP in terms of metabolism and pharmacology and provide a pharmacological foundation for OA treatment of PMOP.

Two Acentric Aluminoborates Incorporated d10 Cations: Syntheses, Structures, and Nonlinear Optical Properties.

Two acentric aluminoborates (ABOs), [Zn(en)2Al{B5O9(OH)}{BO(OH)2}] (1) and [Cd(en)2AlB5O10]·H2O (2) (en = ethylenediamine), have been solvothermally made. 1 includes a two-dimensional (2D) wavy ABO layer using B5O9(OH) clusters and AlO3{BO(OH)2} groups, in which both units can be regarded as three-connected nodes, and simplifying the ABO layer to a hcb-type network. 2 features an acentric three-dimensional (3D) porous framework with a unique unc-type network constituted by strictly alternating connected B5O10 clusters and AlO4 units. The structural transformation from a 2D layer 1 to a 3D framework 2 was achieved with the elimination of the terminal hydroxyls in layer 1 by adjusting synthetic conditions in the same solvent system. Metal-amine complexes Zn(en)2/Cd(en)2 bond to the inorganic walls and are located in the cavity of frameworks 1 and 2, respectively. Compounds 1 and 2 exhibit large second-harmonic generation (SHG) responses that are 2.2 and 2.7 times those of KH2PO4 (KDP), respectively, which are among the largest powder SHG responses for all deep-ultraviolet (deep-UV) ABOs. The UV-vis diffuse reflectance spectra of 1 and 2 show a wide transparency window below 190 nm. Density functional theory (DFT) calculations indicate that the B-O units and the introduced distorted d10 metal polyhedra played a decisive role in the optical properties of both compounds.

Efficacy and safety of lenvatinib for preventing tumor recurrence after liver transplantation in hepatocellular carcinoma beyond the Milan criteria.

Background: Lenvatinib is one of the first-line treatments for unresectable hepatocellular carcinoma (HCC). However, data are lacking on lenvatinib in the postoperative setting. Methods: This retrospective analysis enrolled 242 patients with HCC who underwent liver transplantation (LTx). Eligible patients were divided into 2 groups according to their use of adjuvant lenvatinib following LTx (lenvatinib, n=42; control, n=200). The primary outcome measures were overall survival (OS), time to recurrence (TTR), and safety. Kaplan-Meier analysis was applied to calculate the OS, while a competing risk model was used to estimate the cumulative incidence of recurrence. Results: The lenvatinib group showed more advanced tumors and a higher proportion of HCC beyond the Milan criteria (P<0.001) than the control group. There were no significant differences in both the OS and TTR between the 2 groups. After focusing on the patients with HCC beyond the Milan criteria, baseline characteristics were similar in the lenvatinib group (n=38) and the control group (n=102). Competing risk analysis showed lenvatinib significantly prolonged TTR after LTx versus the control group [sub-hazard ratio (sHR), 0.40; 95% confidence interval (CI): 0.17 to 0.93; P=0.031]. In the multivariate competing risk model, adjuvant lenvatinib was an independent protective factor for tumor recurrence after LTx in patients with HCC beyond the Milan criteria (sHR, 0.33; 95% CI: 0.13 to 0.83; P=0.018). The rate of early recurrence within t2 years after LTx was also significantly decreased in the lenvatinib group (15.8% vs. 33.3%, P=0.041). However, the lenvatinib group exhibited comparable OS with the control group in patients with HCC beyond the Milan criteria. Treatment-related adverse events (TRAEs) and Grade ≥3 TRAEs occurred in 40 (95.2%) and 13 (31%) patients who received adjuvant lenvatinib, respectively. No treatment-related death was reported. Conclusions: Postoperative lenvatinib administration may provide clinical benefits and is well tolerated in patients with HCC beyond the Milan criteria who undergo LTx.

PVA/pectin composite hydrogels inducing osteogenesis for bone regeneration.

Hydrogels composed from biomolecules have gained great interests as biomaterials for tissue engineering. However, their poor mechanical properties limit their application potential. Here, we synthesized a series of tough composite hydrogels from poly (vinyl alcohol) (PVA) and pectin for bone tissue engineering. With a balance of scaffold stiffness and pore size, PVA-Pec-10 hydrogel enhanced adhesion and proliferation of osteoblasts. The hydrogel significantly promoted osteogenesis in vitro by improving the alkaline phosphates (ALP) activity and calcium biomineralization, as well as upregulating the expressions of osteoblastic genes. The composite hydrogel also accelerated the bone healing process in vivo after transplantation into the femoral defect. Additionally, our study demonstrated that pectin and its Ca2+ crosslinking network play a crucial role of inducing osteogenesis through regulating the Ca2+/CaMKII and BMP-SMAD1/5 signaling. The optimized structure composition and multifunctional properties make PVA-Pec hydrogel highly promising to serve as a candidate for bone tissue regeneration.

Causal relationships between sex hormone traits, lifestyle factors, and osteoporosis in men: A Mendelian randomization study.

Although observational studies have explored factors that may be associated with osteoporosis, it is not clear whether they are causal. Osteoporosis in men is often underestimated. This study aimed to identify the causal risk factors associated with bone mineral density(BMD) in men. Single nucleotide polymorphisms (SNPs) associated with the exposures at the genome-wide significance (p < 5x10-8) level were obtained from corresponding genome-wide association studies (GWASs) and were utilized as instrumental variables. Summary-level statistical data for BMD were obtained from two large-scale UK Biobank GWASs. A Mendelian randomization (MR) analysis was performed to identify causal risk factors for BMD. Regarding the BMD of the heel bone, the odds of BMD increased per 1-SD increase of free testosterone (FT) (OR = 1.13, P = 9.4 × 10-17), together with estradiol (E2) (OR = 2.51, P = 2.3 × 10-4). The odds of BMD also increased with the lowering of sex-hormone binding globulin (SHBG) (OR = 0.87, P = 7.4 × 10-8) and total testosterone (TT) (OR = 0.96, P = 3.2 × 10-2) levels. Regarding the BMD of the lumbar spine, the odds of BMD increased per 1-SD increase in FT (OR = 1.18, P = 4.0 × 10-3). Regarding the BMD of the forearm bone, the odds of BMD increased with lowering SHBG (OR = 0.75, P = 3.0 × 10-3) and TT (OR = 0.85, P = 3.0 × 10-3) levels. Our MR study corroborated certain causal relationships and provided genetic evidence among sex hormone traits, lifestyle factors and BMD. Furthermore, it is a novel insight that TT was defined as a disadvantage for osteoporosis in male European populations.