Phase 2 study of pegylated liposomal doxorubicin plus cyclophosphamide, vincristine/vindesine, and prednisone in newly diagnosed PTCL: 8-year results.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the efficacy and safety of the PLD-containing CHOP regimen in newly diagnosed patients with aggressive peripheral T-cell lymphomas (PTCL). METHODS: Patients received PLD, cyclophosphamide, vincristine/vindesine, plus prednisone every 3 weeks for up to 6 cycles. The primary endpoint was the objective response rate at the end of treatment (EOT). RESULTS: From September 2015 to January 2017, 40 patients were treated. At the EOT, objective response was achieved by 82.5% of patients, with 62.5% complete response. As of the cutoff date (September 26, 2023), median progression-free survival (mPFS) and overall survival (mOS) were not reached (NR). The 2-year, 5-year, and 8-year PFS rates were 55.1%, 52.0%, and 52.0%. OS rate was 80.0% at 2 years, 62.5% at 5 years, and 54.3% at 8 years. Patients with progression of disease within 24 months (POD24) had worse prognosis than those without POD24, regarding mOS (41.2 months vs NR), 5-year OS (33.3% vs 94.4%), and 8-year OS (13.3% vs 94.4%). Common grade 3-4 adverse events were neutropenia (87.5%), leukopenia (80.0%), anemia (17.5%), and pneumonitis (17.5%). CONCLUSION: This combination had long-term benefits and manageable tolerability, particularly with less cardiotoxicity, for aggressive PTCL, which might provide a favorable benefit-risk balance. CLINICALTRIALS.GOV IDENTIFIER: Chinese Clinical Trial Registry, ChiCTR2100054588; IRB Approved: Ethics committee of Fudan University Shanghai Cancer Center (Date 2015.8.31/No. 1508151-13.

The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis.

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

Characterizing body composition modifying effects of a glucagon-like peptide 1 receptor-based agonist: A meta-analysis.

AIM: Diabetes is an independent risk factor for muscle mass loss, with possible mechanisms including impaired insulin signalling and chronic inflammation. The use of a glucagon-like peptide 1 (GLP-1) receptor-based agonist could lead to weight reduction, which might result from the loss of both fat and skeletal muscle. However, the body composition-modifying effects of GLP-1 receptor-based agonists have not been systematically characterized. METHODS: PubMed, EMBASE, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from inception to October 2023. Randomized controlled trials of GLP-1 receptor agonist or glucose-dependent insulinotropic polypeptide/GLP-1 receptor dual agonist, which reported the changes of body composition, were included. The results were computed as weighted mean differences (WMDs) and 95% confidence intervals (CIs) in a random-effects model. RESULTS: In all, 19 randomized controlled trials were included. When compared with controls, substantial reductions in fat body mass were observed in patients using GLP-1 receptor-based agonist treatment (WMD = -2.25 kg, 95% CI -3.40 to -1.10 kg), with decrease in areas of both subcutaneous fat (WMD = -38.35 cm2, 95% CI, -54.75 to -21.95 cm2) and visceral fat (WMD = -14.61 cm2, 95% CI, -23.77 to -5.44 cm2). Moreover, greater reductions in lean body mass were also observed in GLP-1 receptor-based agonist users compared with non-users (WMD = -1.02 kg, 95% CI, -1.46 to -0.57 kg), while the changes in lean mass percentage were comparable between GLP-1 receptor-based agonist users and non-users. CONCLUSION: Compared with the controls, GLP-1 receptor-based agonist users experienced greater reductions in fat body mass, with body shaping effects in terms of both subcutaneous fat mass and visceral fat mass. Although greater reductions in lean body mass were also observed in GLP-1 receptor-based agonist users, the changes in lean mass percentage were comparable between the users and non-users.

Novel Bioactive Natural Products from Marine-Derived Penicillium Fungi: A Review (2021-2023).

Marine-derived Penicillium fungi are productive sources of structurally unique and diverse bioactive secondary metabolites, representing a hot topic in natural product research. This review describes structural diversity, bioactivities and statistical research of 452 new natural products from marine-derived Penicillium fungi covering 2021 to 2023. Sediments are the main sources of marine-derived Penicillium fungi for producing nearly 56% new natural products. Polyketides, alkaloids, and terpenoids displayed diverse biological activities and are the major contributors to antibacterial activity, cytotoxicity, anti-inflammatory and enzyme inhibitory capacities. Polyketides had higher proportions of new bioactive compounds in new compounds than other chemical classes. The characteristics of studies in recent years are presented.

Unraveling neoantigen-associated genes in bladder cancer: An in-depth analysis employing 101 machine learning algorithms.

The therapeutic outcomes for bladder cancer (BLCA) remain suboptimal. Concurrently, there is a growing appreciation for the role of neoantigens in tumors. In this study, we explored the mechanisms underlying the involvement of neoantigen-associated genes in BLCA and their impact on prognosis. Our analysis incorporated both single-cell sequencing and bulk sequencing data sourced from publicly available databases. By employing a comprehensive set of 10 machine learning algorithms, we generated 101 algorithm combinations. The optimal combination, determined based on consistency indices, was utilized to construct a prognostic model comprising nine genes (CAPG, ACTA2, PDIA6, AKNA, PTMS, SNAP23, ID2, CD3G, SP140). Subsequently, we validated this model in an independent cohort, demonstrating its robust testing efficacy. Moreover, we explored the correlations between various clinical traits, model scores, and genes. Leveraging extensive public data resources, we conducted a drug sensitivity analysis to provide insights for targeted drug screening. Additionally, consensus clustering analysis and immune infiltration analysis were performed on bulk sequencing datasets and immunotherapy cohorts. These analyses yield valuable insights into the role of neoantigens in BLCA, guiding future research endeavors.

Triterpenoid saponins from Bupleurum marginatum and their anti-liver fibrotic activities.

A new triterpenoid saponin (1), along with five known compounds (2-6), was isolated from Bupleurum marginatum Wall. ex DC, of which compounds 2-4 were obtained for the first time from this plant. The structures were confirmed by the analysis of 1D, 2D NMR, and HR-ESIMS data, and comparison with previous spectral data. Anti-liver fibrotic activities of the isolates were determined as proliferation inhibition of LPS-induced activation of HSC-T6 in vitro.

Ln3+ Induced Thermally Activated Delayed Fluorescence of Chiral Heterometallic Clusters Ln2Ag28.

A series of TADF-active compounds: 0D chiral Ln-Ag(I) clusters L-/D-Ln2Ag28-0D (Ln=Eu/Gd) and 2D chiral Ln-Ag(I) cluster-based frameworks L-/D-Ln2Ag28-2D (Ln=Gd) has been synthesized. Atomic-level structural analysis showed that the chiral Ag(I) cluster units {Ag14S12} in L-/D-Ln2Ag28-0D and L-/D-Ln2Ag28-2D exhibited similar configurations, linked by varying numbers of [Ln(H2O)x]3+ (x=6 for 0D, x=3 for 2D) to form the final target compounds. Temperature-dependent emission spectra and decay lifetimes measurement demonstrated the presence of TADF in L-Ln2Ag28-0D (Ln=Eu/Gd) and L-Gd2Ag28-2D. Experimentally, the remarkable TADF properties primarily originated from {Ag14S12} moieties in these compounds. Notably, {Ag14S12} in L-Eu2Ag28-0D and L-Gd2Ag28-2D displayed higher promote fluorescence rate and shorter TADF decay times than L-Gd2Ag28-0D. Combined with theoretical calculations, it was determined that the TADF behaviors of {Ag14S12} cluster units were induced by 4 f perturbation of Ln3+ ions. Specially, while maintaining ΔE(S1-T1) small enough, it can significantly increase k(S1→S0) and reduce TADF decay time by adjusting the type or number of Ln3+ ions, thus achieving the purpose of improving TADF for cluster-based luminescent materials.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and the Risk of Fracture: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Osteoporosis and hyperlipidemia are closely correlated and statins might be associated with a decreased risk of fracture. We aimed to investigate the association between proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and the risk of fracture. The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to October 22, 2022. Randomized clinical trials (RCTs) that addressed to fracture events of participants using alirocumab, evolocumab, bococizumab or inclisiran, with a follow-up of ≥ 24 weeks were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95% confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. 30 trials assessing PCSK9i among 95, 911 adults were included. There were no significant associations between PCSK9i therapy and the risk of major osteoporotic fracture [OR 1.08 (95% Cl 0.87-1.34), p = 0.49], hip fracture [OR 1.05 (95% Cl 0.73-1.53), p = 0.79], osteoporotic non-vertebral fracture [OR 1.03 (95% Cl 0.80-1.32), p = 0.83], and total fracture [OR 1.03 (95% Cl 0.88-1.19), p = 0.74] over a period of 6-64 months. No significant associations were detected in any of the sensitivity analyses and subgroup analyses stratified by the type of PCSK9i, follow-up duration, age, sex, sample size, and patient profile. Pooled results of our meta-analysis showed that exposure to PCSK9i was not associated with reduced risks of fracture in the short term.

Plasma extracellular vesicle long RNAs predict response to neoadjuvant immunotherapy and survival in patients with non-small cell lung cancer.

Neoadjuvant immunotherapy has brought new hope for patients with non-small cell lung cancer (NSCLC). However, limited by the lack of clinically feasible markers, it is still difficult to select NSCLC patients who respond well and to predict patients' clinical outcomes before the treatment. Before the treatment, we isolated plasma extracellular vesicles (EVs) from three cohorts (discovery, training and validation) of 78 NSCLC patients treated with neoadjuvant immunotherapy. To identify differentially-expressed EV long RNAs (exLRs), we employed RNA-seq in the discovery cohort. And we subsequently used qRT-PCR to establish and validate the predictive signature in the other two cohorts. We have identified 8 candidate exLRs from 27 top-ranked exLRs differentially expressed between responders and non-responders, and tested their expression with qRT-PCR in the training cohort. We finally identified H3C2 (P = 0.029), MALAT1 (P = 0.043) and RPS3 (P = 0.0086) significantly expressed in responders for establishing the predictive signature. Integrated with PD-L1 expression, our signature performed well in predicting immunotherapeutic responses in the training (AUC=0.892) and validation cohorts (AUC=0.747). Furthermore, our signature was proven to be a predictor for favorable prognosis of patients treated with neoadjuvant immunotherapy, which demonstrates the feasibility of our signature in clinical practices (P = 0.048). Our results demonstrate that the exLR-based signature could accurately predict responses to neoadjuvant immunotherapy and prognosis in NSCLC patients.

Population attributable fractions of modifiable risk factors for microvascular complications of type 2 diabetes in China: An analysis using national cross-sectional data.

AIM: To assess the population attributable fractions (PAFs) for modifiable risk factors for microvascular complications of type 2 diabetes (T2D) in China. MATERIALS AND METHODS: Data collected from the China National HbA1c Surveillance System from 2009 to 2013 were used. The PAFs of four predefined risk factors, including an HbA1c of 7% or higher, blood pressure (BP) of 130/80 mmHg or higher, low-density lipoprotein-cholesterol (LDL-C) of 1.8 mmol/L or higher and body mass index (BMI) of 24 kg/m2 or higher, were calculated for diabetic microvascular complications, including diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN). PAFs were further adjusted for age, sex and duration of diabetes. RESULTS: In total, there were 998 379 participants with T2D from nationwide mainland China included in this analysis. As for DR, an HbA1c of 7% or higher, BP of 130/80 mmHg or higher, LDL-C of 1.8 mmol/L or higher and BMI of 24 kg/m2 or higher conferred PAFs of 16.2%, 15.2%, 5.8% and 2.8%, respectively. In the case of DKD, BP of 130/80 mmHg or higher provided a PAF of 25.2%, followed by an HbA1c of 7% or higher (13.9%), BMI of 24 kg/m2 or higher (8.0%) and LDL-C of 1.8 mmol/L or higher (5.6%). As for DSPN, an HbA1c of 7% or higher, BP of 130/80 mmHg or higher, LDL-C of 1.8 mmol/L or higher and BMI of 24 kg/m2 or higher contributed to PAFs of 14.2%, 11.7%, 5.9% and 5.8%, respectively. PAFs for diabetic microvascular complications were mildly to moderately reduced after adjusting for participants' age, sex and duration of diabetes. CONCLUSIONS: Suboptimal glycaemic and BP control were the main contributors to diabetic microvascular complications, while the PAFs of unmet LDL-C and BMI control targets were quite limited for diabetic microvascular complications. In addition to glycaemic control, BP control should be especially prioritized in the management of diabetic microvascular complications to further reduce the disease burden.

Activating α7nAChR helps post-myocardial infarction healing by regulating macrophage polarization via the STAT3 signaling pathway.

BACKGROUND: Monocytes/macrophages play critical roles in inflammation and cardiac remodeling following myocardial infarction (MI). The cholinergic anti-inflammatory pathway (CAP) modulates local and systemic inflammatory responses by activating α7 nicotinic acetylcholine receptors (α7nAChR) in monocytes/macrophages. We investigated the effect of α7nAChR on MI-induced monocyte/macrophage recruitment and polarization and its contribution to cardiac remodeling and dysfunction. METHODS: Adult male Sprague Dawley rats underwent coronary ligation and were intraperitoneally injected with the α7nAChR-selective agonist PNU282987 or the antagonist methyllycaconitine (MLA). RAW264.7 cells were stimulated with lipopolysaccharide (LPS) + interferon-gamma (IFN-γ) and treated with PNU282987, MLA, and S3I-201 (a STAT3 inhibitor). Cardiac function was evaluated by echocardiography. Masson's trichrome and immunofluorescence were used to detect cardiac fibrosis, myocardial capillary density, and M1/M2 macrophages. Western blotting was used to detect protein expression, and the proportion of monocytes was measured using flow cytometry. RESULTS: Activating the CAP with PNU282987 significantly improved cardiac function and reduced cardiac fibrosis and 28-day mortality after MI. On days 3 and 7 post-MI, PNU282987 reduced the percentage of peripheral CD172a + CD43low monocytes and the infiltration of M1 macrophages in the infarcted hearts, whereas it increased the recruitment of peripheral CD172a + CD43high monocytes and M2 macrophages. Conversely, MLA exerted the opposite effects. In vitro, PNU282987 inhibited M1 macrophage polarization and promoted M2 macrophage polarization in LPS + IFN-γ-stimulated RAW264.7 cells. These PNU282987-induced changes in LPS + IFN-γ-stimulated RAW264.7 cells were reversed by administering S3I-201. CONCLUSION: Activating α7nAChR inhibits the early recruitment of pro-inflammatory monocytes/macrophages during MI and improves cardiac function and remodeling. Our findings suggest a promising therapeutic target for regulating monocyte/macrophage phenotypes and promoting healing after MI.

Discovery of hepatoprotective activity components from Thymus quinquecostatus celak. by molecular networking, biological evaluation and molecular dynamics studies.

Thymus quinquecostatus Celak. is an edible herb that widely cultivated in Asia and possesses hepatoprotective activity, but the underlying non-volatile components of this protective activity are not well studied. In this study, combining molecular networking visualization and bioassay-guided fractionation strategies, a pair of novel skeleton diterpenoid enantiomers, (+)- and (-)-thymutatusone A [(+)- and (-)-1], along with one new and one known biogenetically related compounds (2-3) and 16 other known compounds (4-19), were identified from T. quinquecostatus. Their structures were exhaustively characterized by comprehensive spectroscopic data, X-ray diffraction analysis, and ECD calculations. Compounds (±)-1, (-)-1, and (+)-1, with a rare tricyclo [7.3.1.02,7] tridecane skeleton, exhibited potent hepatoprotective activity in HepG2 cells injured by acetaminophen, with EC50 values of 11.5 ± 2.8, 8.4 ± 1.9, and 12.2 ± 0.3 µM respectively. They were more potent than positive drug bifendate (EC50 15.2 ± 1.3). Further, the underlying mechanism for the hepatoprotective activity of compound (-)-1 related to activating the Nrf 2 signaling pathway. What's more, molecular docking and molecular dynamics simulation analysis showed that compound (-)-1 could dock with the active site of Nrf 2 protein and form a stable system through hydrogen bonding. These results suggest that T. quinquecostatus can be used as a valuable source of hepatoprotective activity compounds.

New Azaphilones from the Marine-Derived Fungus Penicillium sclerotiorum E23Y-1A with Their Anti-Inflammatory and Antitumor Activities.

Nine new azaphilones, including penicilazaphilones I-N (1, 2 and 6-9), epi-geumsanol D (3) and penidioxolanes C (4) and D (5) were isolated from the culture of the marine-derived fungus Penicillium sclerotiorum E23Y-1A. The structures of the isolates were deduced from extensive spectroscopic data (1D and 2D NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) calculations. All the azaphilones from P. sclerotiorum E23Y-1A were tested for their anti-inflammatory and antitumor activities. Penicilazaphilone N (9) showed moderate anti-inflammatory activity with an IC50 value of 22.63 ± 2.95 µM, whereas penidioxolane C (4) exhibited moderate inhibition against human myeloid leukemia cells (K562), human liver cancer cells (BEL-7402), human gastric cancer cells (SGC-7901), human non-small cell lung cancer cells (A549), and human hela cervical cancer cells, with IC50 values of 23.94 ± 0.11, 60.66 ± 0.13, 46.17 ± 0.17, 60.16 ± 0.26, and 59.30 ± 0.60 µM, respectively.

Potential α-Glucosidase Inhibitors from the Deep-Sea Sediment-Derived Fungus Aspergillus insulicola.

Three new phenolic compounds, epicocconigrones C-D (1-2) and flavimycin C (3), together with six known phenolic compounds: epicocconigrone A (4); 2-(10-formyl-11,13-dihydroxy-12-methoxy-14-methyl)-6,7-dihydroxy-5-methyl-4-benzofurancarboxaldehyde (5); epicoccolide B (6); eleganketal A (7); 1,3-dihydro-5-methoxy-7-methylisobenzofuran (8); and 2,3,4-trihydroxy-6-(hydroxymethyl)-5-methylbenzyl-alcohol (9), were isolated from fermentation cultures of a deep-sea sediment-derived fungus, Aspergillus insulicola. Their planar structures were elucidated based on the 1D and 2D NMR spectra and HRESIMS data. The absolute configurations of compounds 1-3 were determined by ECD calculations. Compound 3 represented a rare fully symmetrical isobenzofuran dimer. All compounds were evaluated for their α-glucosidase inhibitory activity, and compounds 1, 4-7, and 9 exhibited more potent α-glucosidase inhibitory effect with IC50 values ranging from 17.04 to 292.47 µM than positive control acarbose with IC50 value of 822.97 µM, indicating that these phenolic compounds could be promising lead compounds of new hypoglycemic drugs.

Design, Synthesis, and Antitumor Activities of Isomers of Artemisinin Dimer Derivatives.

In recent years, numerous studies have reported on the anti-tumor properties of artemisinin and its derivatives. However, the relationship between their artemisinin chirality and activity remains unknown. In this study, we synthesized a series of artemisinin dimer derivatives with three different chiral structures and tested their antiproliferative activity in MCF-7 and HepG2 cells using the CCK-8 assay. Interestingly, we discovered that artemisinin dimer derivatives with ß, ß and α, ß conformations at C-10 exhibited stronger anti-tumor activity than those with an α, α configuration in MCF-7 and HepG2 cells. Notably, compound 4 showed an activity of 0.06 µM in MCF-7 cells. This study demonstrates the relationship between the conformation and activity of artemisinin dimer derivatives, and these derivatives have the potential to be developed into anti-cancer drugs.

CEMIP promotes extracellular matrix-detached prostate cancer cell survival by inhibiting ferroptosis.

Cells detached from the extracellular matrix (ECM) can trigger different modes of cell death, and the survival of ECM-detached cells is one of the prerequisites for the metastatic cascade. Ferroptosis, a form of iron-dependent programmed cell death, has recently been found to be involved in matrix-detached cancer cells. However, the molecular mechanisms by which ECM-detached cells escape ferroptosis are not fully understood. Here, we observed that cell migration-inducing protein (CEMIP) upregulation facilitates ferroptosis resistance during ECM detachment by promoting cystine uptake in prostate cancer (PCa) cells. Meanwhile, silencing CEMIP causes it to lose its ability to promote cystine uptake and inhibit ferroptosis. Mechanistically, the interaction of CEMIP with inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) modulates calcium ion (Ca2+ ) leakage from the endoplasmic reticulum, activating calcium/calmodulin-dependent protein kinase II (CaMKII), which further facilitates nuclear factor erythroid 2-related factor 2 (NRF2) phosphorylation and nuclear localization, leading to elevated transcription of solute carrier family 7 member 11 (SLC7A11), a glutamate/cystine antiporter, in PCa cells. Our findings delineate a novel role of CEMIP in ferroptosis resistance during ECM detachment and provide new insights into therapeutic strategies for metastatic PCa.

An Update on Animal Models of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous disorder characterized by bone fragility, multiple fractures, bone deformity, and short stature. In recent years, the application of next generation sequencing has triggered the discovery of many new genetic causes for OI. Until now, more than 25 genetic causes of OI and closely related disorders have been identified. However, the mechanisms of many genes on skeletal fragility in OI are not entirely clear. Animal models of OI could help to understand the cellular, signaling, and metabolic mechanisms contributing to the disease, and how targeting these pathways can provide therapeutic targets. To date, a lot of animal models, mainly mice and zebrafish, have been described with defects in 19 OI-associated genes. In this review, we summarize the known genetic causes and animal models that recapitulate OI with a main focus on engineered mouse and zebrafish models. Additionally, we briefly discuss domestic animals with naturally occurring OI phenotypes. Knowledge of the specific molecular basis of OI will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches.

Association between biologic therapy and fracture incidence in patients with selected rheumatic and autoimmune diseases: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To investigate the effect of biologic therapy on risk of fracture in selected rheumatic and autoimmune diseases. METHODS: The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to June 4, 2021. Randomized clinical trials (RCTs) comparing biological disease-modifying antirheumatic drugs (bDMARDs) with non-bDMARDs or placebo in patients with five selected rheumatic and autoimmune diseases were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95 % confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. RESULTS: A total of 100 RCTs involving 51,413 participants fulfilled the inclusion criteria. In patients with psoriasis (Ps), and psoriatic arthritis (PsA), compared with placebo or non-bDMARDs therapy, the risk of major osteoporotic fracture (OR, 0.34 [95 %Cl, 0.15-0.76], p = 0.009), hip fracture (OR, 0.22 [95 %Cl, 0.05-0.89], p = 0.03), and osteoporotic non-vertebral fracture (OR, 0.26 [95 %Cl, 0.10-0.62], p = 0.003) were significantly decreased with the use of bDMARDs. In patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), the risk of fracture were not changed with biologic treatment. CONCLUSIONS: The existing evidence from RCTs indicated the use of bDMARDs was associated with a low risk of major osteoporotic fracture, hip fracture, and osteoporotic non-vertebral fracture in patients with Ps and PsA. There are still urgent needs for studies regarding the actions of biologic therapies on the risk of bone fractures in systemic inflammatory diseases.

Zr(IV)-based metal-organic framework nanocomposites with enhanced peroxidase-like activity as a colorimetric sensing platform for sensitive detection of hydrogen peroxide and phenol.

Recently, metal-organic frameworks (MOFs) have great potential as an emerging peroxide-mimicking enzyme, and the improvement of its enzyme-like activity is desired. There are few studies on improving the peroxidase-like activity of MOFs by using the strategy of size reduction. Moreover, it is challenging to enhance the activity of Zr-based MOFs with peroxidase-mimicking activity by size reduction strategy. In this work, the synthesis of Zr-based MOFs capped with polyvinylpyrrolidone (Zr-MOF-PVP) was firstly reported to reduce crystal size of peroxidase-mimicking enzyme for enhanced catalytic activity. Using the 3,3',5,5'-Tetramethylbenzidine (TMB) as substrate, the synthesized Zr-MOF-PVP nanocomposites with nanosize (about 45 nm) possessed obviously enhanced peroxidase-like activity compared with the pristine Zr-MOF. Based on the above, the Zr-MOF-PVP was also successfully applied in constructing colorimetric detection. By using hydrogen peroxide (H2O2) and phenol as the model analytes, the satisfactory detection performance was obtained, indicating that the proposed method had an attractive application prospect in the field of peroxidase-related detection. Besides, this work also provided a new perspective for improving the catalytic activity of nanozymes.

Synergetic integration of catalase and Fe3O4 magnetic nanoparticles with metal organic framework for colorimetric detection of phenol.

Toxic phenol pollutants pose a great threat to the environment, it is urgent to develop an efficient and recyclable method to monitor phenol. Herein, we reported the synthesis of catalase-Fe3O4@ZIF-8 (CAT-Fe3O4@ZIF-8) through a novel amino-acid-boosted one-pot embedding strategy that synergically integrated catalase and magnetic Fe3O4 nanoparticles with ZIF-8. As expected, CAT-Fe3O4@ZIF-8 exhibited enhanced catalytic activity compared with Fe3O4@ZIF-8, CAT@ZIF-8 and catalase. Depending on the satisfactory performance of CAT-Fe3O4@ZIF-8, a colorimetric detection platform for phenol based on CAT-Fe3O4@ZIF-8 was constructed. The corresponding detection limit was as low as 0.7 µM, and a wide linear range of 5-100 µM was obtained. Besides, CAT-Fe3O4@ZIF-8-based colorimetric detection platform has been verified to possess high stability and recyclability. The proposed method was proven to have potential practical applications in the field of water treatment, which would advance efficient, recyclable monitoring of water quality.