Safety of low-intensity extracorporeal shock wave therapy in prostate disorders: in vitro and in vivo evidence.

ABSTRACT: Recent evidence suggests that low-intensity extracorporeal shock wave therapy (Li-ESWT) is a promising treatment for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); however, its safety in pelvic organs, particularly prostate tissues and cells, remains unclear. The current study evaluates the risks of prostate cell damage or oncogenesis following the administration of Li-ESWT for prostatitis. To this end, a robust in vitro model (Cell Counting Kit-8 [CCK-8] assay, clone formation assay, cell scratch assay, lactate dehydrogenase [LDH] release assay, flow cytometry, and immunoblotting assay) was designed to examine the effects of Li-ESWT on cell proliferation, clonogenicity, migration, membrane integrity, and DNA damage. Exome sequencing of Li-ESWT-treated cells was performed to determine the risk of carcinogenesis. Furthermore, an in vivo rat model (n = 20) was employed to assess the effects of Li-ESWT on cancer biomarkers (carcinoembryonic antigen [CEA], Ki67, proliferating cell nuclear antigen [PCNA], and gamma-H2A histone family member X, phosphorylation of the H2AX Ser-139 [γ-H2AX]) in prostate tissue. Based on our findings, Li-ESWT promotes cellular growth and motility without inducing significant cell membrane or DNA damage or alterations. Genetic analyses did not demonstrate an increase in mutations, and no damage to prostate tissue or upregulation of cancer biomarkers was detected in vivo. This comprehensive in vitro and in vivo assessment confirms the safety of Li-ESWT in managing prostate disorders.

Engineering Versatile Bacteria-Derived Outer Membrane Vesicles: An Adaptable Platform for Advancing Cancer Immunotherapy.

In recent years, cancer immunotherapy has undergone a transformative shift toward personalized and targeted therapeutic strategies. Bacteria-derived outer membrane vesicles (OMVs) have emerged as a promising and adaptable platform for cancer immunotherapy due to their unique properties, including natural immunogenicity and the ability to be engineered for specific therapeutic purposes. In this review, a comprehensive overview is provided of state-of-the-art techniques and methodologies employed in the engineering of versatile OMVs for cancer immunotherapy. Beginning by exploring the biogenesis and composition of OMVs, unveiling their intrinsic immunogenic properties for therapeutic appeal. Subsequently, innovative approaches employed to engineer OMVs are delved into, ranging from the genetic engineering of parent bacteria to the incorporation of functional molecules. The importance of rational design strategies is highlighted to enhance the immunogenicity and specificity of OMVs, allowing tailoring for diverse cancer types. Furthermore, insights into clinical studies and potential challenges utilizing OMVs as cancer vaccines or adjuvants are also provided, offering a comprehensive assessment of the current landscape and future prospects. Overall, this review provides valuable insights for researchers involved in the rapidly evolving field of cancer immunotherapy, offering a roadmap for harnessing the full potential of OMVs as a versatile and adaptable platform for cancer treatment.

Prognostic significance of LRPPRC and its association with immune infiltration in liver hepatocellular carcinoma.

BACKGROUND: Leucine rich pentatricopeptide repeat containing (LRPPRC) protein is a multifunctional protein involved in cell cycle progression and tumor development. However, its prognostic significance and association with immune infiltration in Liver hepatocellular carcinoma (LIHC) remain unclear. METHODS: We utilized transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases of LIHC patients to investigate the potential pro-cancer role of LRPPRC, including differential expression of LRPPRC in LIHC, prognostic value, clinicopathological features, immune cell infiltration relevance and function enrichment analysis. RESULTS: Our findings suggest that LRPPRC is upregulated in LIHC and exhibits correlations with survival, clinical stage, and tumor grade in LIHC patients. Additionally, immune infiltration analysis revealed significant negative correlations between LRPPRC expression and multiple tumor-infiltrating immune cells, including CTLs, DCs, pDCs, B cells, Th17 cells, neutrophils, T cells, Mast cells, Th1 cells, Tregs, and NK cells, whereas a significant positive correlation was observed with infiltration of Th2 cells, T helper cells and Tcms. Furthermore, functional enrichment analysis indicated that LRPPRC may be involved in G2m checkpoint, mitotic spindle, E2f targets, Wnt Beta catenin signaling, spermatogenesis and other processes.

Synergistic effects of PARP inhibition and cholesterol biosynthesis pathway modulation.

An in-depth multi-omic molecular characterisation of poly(adenosine 5'-diphosphate [ADP]-ribose) polymerase (PARP) inhibitors revealed a distinct poly-pharmacology of niraparib (Zejula®) mediated by its interaction with lanosterol synthase (LSS), which is not observed with other PARP inhibitors. Niraparib, in a similar way to the LSS inhibitor Ro-48-8071, induced activation of the 24,25-epoxysterol shunt pathway, which is a regulatory signalling branch of the cholesterol biosynthesis pathway. Interestingly, the combination of a LSS inhibitor with a PARP inhibitor that does not bind to LSS, such as olaparib, had an additive effect on killing of cancer cells to levels comparable to Niraparib as single agent. In addition, the combination of PARP inhibitors and statins, inhibitors of HMGCR, an enzyme catalysing the rate-limiting step in the mevalonate pathway, had a synergistic effect on tumor cell killing in cell lines and patient-derived ovarian tumor organoids. These observations suggest that concomitant inhibition of cholesterol biosynthesis pathway and PARP activity might result in stronger efficacy of these inhibitors against tumor types highly dependent on cholesterol metabolism.

Maternal Vitamin D3 Supplementation in an Oxidized-Oil Diet Protects Fetus from Developmental Impairment and Ameliorates Oxidative Stress in Mouse Placenta and Fetus.

BACKGROUND: Fried food has increased in popularity worldwide. However, deep frying can increase the production of peroxidative toxins in food, which might be harmful to fetal development. The antioxidative effect of vitamin D3 (VD3) has been reported previously. OBJECTIVES: This study aimed to explore how maternal VD3 supplementation in an oxidized-oil diet during gestation affects fetal antioxidative ability and development. METHODS: Pregnant mice were randomly assigned into 3 groups: Control group (diet with fresh soybean oil), OSO group [diet with oxidized soybean oil (OSO)], and OSOV group (diet with OSO and 10,000 IU/Kg VD3). Mice were fed with the corresponding diet during gestation. On day 16.5 of gestation, the placenta and fetus were harvested to analyze antioxidative status. RESULTS: Maternal oxidized-oil diet during gestation significantly reduced placental vessel abundance, labyrinth zone area, and fetal body weight. However, dietary VD3 supplementation prevented these negative effects of oxidized-oil diet. Maternal intake of oxidized-oil diet increased serum concentrations of malondialdehyde, total-nitric oxide synthase, and inducible nitric oxide synthase, whereas VD3 supplementation showed a protection effect on it. Additionally, maternal VD3 supplementation increased the levels of antioxidative enzymes and the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), thereby protecting placenta and fetus from apoptosis and oxidative stress caused by an oxidized-oil diet. The gene expression and protein levels of a fatty acid transporter solute carrier family 27 member 1 in the fetal liver were increased by maternal VD3 supplementation under oxidized-oil diet. Notably, NRF2 could be co-immunoprecipitated with the VD receptor in the placenta. CONCLUSIONS: Maternal VD3 supplementation could protect fetus from oxidized-oil diet induced developmental impairment by alleviating oxidative stress in the placenta and fetus through the VD receptor/NRF2 pathway, at least partially. Thus, ensuring adequate levels of VD3 through supplementation is often critical during pregnancy.

Incidence and treatment-related risk factors of inhibitor development after intensive FVIII replacement for major orthopaedic surgery in previous treated haemophilia A.

INTRODUCTION: Haemophilia A (HA) is an X-linked recessive bleeding disorder caused by lack or deficiency of coagulation factor VIII. AIM: The aim of this study is to determine the incidence and treatment-related risk factors of inhibitor development after intensive FVIII replacement for major orthopaedic surgery in previous treated persons with HA. METHODS: A total of 151 HA who underwent 221 major orthopaedic surgical procedures after intensive FVIII treatment were reviewed. The results of inhibitor tests were collected. Potential clinical risk factors for inhibitor development were analyzed. RESULTS: 111 people were diagnosed with severe HA. Thirty-seven persons (24.5%) had history of previous intensive FVIII treatment for surgical procedure. They received a mean perioperative cumulative FVIII of 498 iu/kg within first week after surgery. Seven cases (4.6%) developed an inhibitor post-operatively in our study. Surgical procedure for pseudotumor and the group of persons who experienced postoperative complications had the higher incidence of inhibitor development (9.5%, 13.3% respectively). Only previous history for intensive FVIII exposure was considered as a significant predictor for postoperative inhibitor development after multivariate logistic regression analysis (OR: 29.5, P = 0.002). CONCLUSION: The incidence of inhibitor development in previously treated persons with HA undergoing major orthopaedic surgery was 4.6% and the history of previous intensive FVIII treatment for surgery was associated with higher risk of inhibitor development.

High-fidelity imaging of a tumour-associated lysosomal enzyme with an acceptor engineering-boosted near-infrared fluorescent probe.

To facilitate the understanding of the dynamic distribution and activity of lysosomal enzymes, it is highly desirable to develop high-fidelity near-infrared (NIR) activatable fluorescent probes. Here, we propose a general acceptor engineering strategy to construct NIR probes with lysosome-targeting capability. Upon isosteric replacement and additional functionalization, the ß-gal-activatable probe OELyso-Gal exhibited excellent lysosome-targeting capability and favorable responsive performance to the enzyme of interest. Notably, the steric hindrance effect from acceptor engineering is modest, which renders the probe unprecedented affinity to enzymes. Upon the introduction of acceptor engineering, the lysosome-targeting probe became more sensitive to ß-gal in cells and tissues, boosting the discrimination of high ß-gal-expressing ovarian cancer tumours from low ß-gal-expressing tissues. Furthermore, the superiority of OELyso-Gal was validated in real-time visualization of ovarian cancer in tumour-bearing mice. This elegant acceptor engineering strategy provides inspirational insights into the development of customized fluorescent probes for monitoring disease-associated biomarkers within subcellular organelles.

4-Octyl itaconate inhibits inflammation via the NLRP3 pathway in neuromyelitis optica spectrum disorders.

OBJECTIVE: Neuromyelitis optica spectrum disorders (NMOSD) are rare inflammatory astrocytic diseases of the central nervous system (CNS). The roles of immune response gene-1 (IRG1) and the IRG1-itaconic acid-NLRP3 inflammatory pathway in the pathogenesis of NMOSD and the effects of 4-octyl itaconate (4-OI) on the NLRP3 inflammatory pathway in NMOSD are unclear. This study aimed to determine the role of IRG1 and the activation status of the NLRP3 inflammatory pathway in acute-onset NMOSD and to investigate the inhibitory effects of 4-OI on NLRP3 inflammasome activation via the IRG1-itaconic acid-NLRP3 pathway in monocytes and macrophages by using in vitro models. METHODS: Peripheral blood mononuclear cells (PBMCs) and serum were collected from patients with acute NMOSDs and healthy controls (HC), followed by monocyte typing and detection of the expression of NLRP3-related inflammatory factors. Subsequently, the effects of 4-OI on the IRG1-itaconic acid-NLRP3 pathway were investigated in peripheral monocytes from patients with NMOSD and in macrophages induced by human myeloid leukemia mononuclear cells (THP-1 cells) via in vitro experiments. RESULTS: Patients with acute NMOSD exhibited upregulated IRG1 expression. In particular, the upregulation of the expression of the NLRP3 inflammasome and proinflammatory factors was notable in monocytes in acute NMOSD patients. 4-OI inhibited the activation of the IRG1-itaconic acid-NLRP3 inflammatory pathway in the PBMCs of patients with NMOSD. INTERPRETATION: 4-OI could effectively inhibit NLRP3 signaling, leading to the inhibition of proinflammatory cytokine production in patients with NMOSD-derived PBMCs and in a human macrophage model. Thus, 4-OI and itaconate could have important therapeutic value for the treatment of NMOSD in the future.

Survival and safety analysis of COVID-19 vaccine in Chinese patients with non-small cell lung cancer.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 disease (COVID-19) has caused a worldwide challenging and threatening pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccines in Non-Small Cell Lung Cancer (NSCLC) patients. METHODS: Patient self-reported adverse events related to vaccines were recorded by follow-up through a uniform questionnaire. Survival analysis was performed by Kaplan-Meier method. A multivariate analysis was performed by the Cox proportional hazard regression model to determine the effect of each variable on the survival of lung cancer patients. RESULTS: A total of 860 patients with NSCLC on treatment were enrolled. Mean age was 57 years in patients with early stage group and 62 years in advanced stage group. The vaccination rate was 71.11% for early-stage patients and 19.48% for advanced-stage patients; most of them (86.5%) received the COVID-19 inactivated virus (Vero cell) vaccine (Coronavac; Sinovac). The most common systemic adverse reaction was weakness. The main reason for vaccine refusal in those unvaccinated patients was concern about the safety of vaccination in the presence of a tumor and undergoing treatment (56.9% and 53.4%). The 1-year disease-free survival (DFS) rate was 100% for vaccinated and 97.4% for unvaccinated early-stage patients. Then we compared the progression-free survival (PFS) of vaccinated (median PFS 9.0 months) and unvaccinated (median PFS 7.0 months) advanced stage patients (p = 0.815). Advanced NSCLC patients continued to be divided into groups receiving radio-chemotherapy, immunotherapy, and targeted therapy, with no statistical difference in PFS between the groups (p > 0.05). The median overall survival (OS) of vaccinated patients was 20.5 months, and that of unvaccinated patients was 19.0 months (p = 0.478) in advanced NSCLC patients. CONCLUSIONS: COVID-19 vaccination is safe for Chinese NSCLC patients actively receiving different antitumor treatments without increasing the incidence of adverse reactions, and vaccination does not affect cancer patient survival.

Standardized ileal digestibility of amino acids in Chinese fermented soybean meal from different sources fed to mid and late-gestating sows.

We determined apparent ileal digestibility (AID) and standardized ileal digestibility (SID) values of crude protein (CP) and amino acids (AA) in fermented soybean meal from five different sources (FSBM 1 to 5) in China when fed to mid and late-gestating sows. Twenty-four parity four sows (12 at 30 d in gestation and 12 at 80 d in gestation) were fitted with a T-cannula in the distal ileum and used in this experiment. Sows were randomly assigned to a replicated 6 × 3 Youden square design including six diets and three periods. Six diets were provided for sows in mid and late gestation, including a nitrogen-free diet and five test diets containing 26% FSBM from different sources. Results showed that there were differences in AID and SID of CP among the different FSBM samples, but no differences between sow physiological stages were observed. Specifically, when mid-gestating sows were fed FSBM 2, the AID of CP was the lowest, whereas FSBM 3 exhibited a greater AID of CP when compared to the other FSBM samples (P < 0.01). Furthermore, during late gestation, FSBM 3 consistently had greater SID of CP when compared to other FSBM samples (P < 0.01). The ileal digestibility of most AA varied with different FSBM samples. In both mid and late gestation, differences (P < 0.05) were observed for AID of lysine, tryptophan, histidine, and arginine across different FSBM samples. Similarly, the AID of dispensable AA (cysteine, glutamine, and serine) also exhibited differences (P < 0.05) across different FSBM samples in both mid and late-gestating sows. For mid-gestating sows, SID differences relating to lysine, phenylalanine, tryptophan, threonine, and arginine were observed among different diets (P < 0.05). In late-gestating sows, SID values for lysine, tryptophan, leucine, and arginine differed across diets (P < 0.05). Furthermore, the ileal digestibility of some dispensable AA was influenced by physiological stage, as evidenced by greater AID and SID values for glycine, glutamine, cysteine, and serine in late-gestating sows when compared to mid-gestating sows (P < 0.01). In summary, our study determined AA ileal digestibility of different FSBM fed to mid and late-gestating sows. We observed that the AA ileal digestibility differed among five FSBM samples, but the physiological stage of sows did not affect the ileal digestibility of CP and most AA. Additionally, when formulating diets for sows, it is crucial to consider the nutritional value differences of FSBM.

Fermented soybean meal (FSBM) is obtained from the microbial fermentation of soybean meal, which reduces anti-nutritional factor levels and enhances other nutrient content. Substituting soybean meal with FSBM in piglet and growing pig diets improves nutrient digestibility. However, its nutritional value for sows remains unclear. Therefore, five sources of FSBM were fed to sows in mid and late gestation to evaluate apparent ileal digestibility (AID) and standardized ileal digestibility (SID) values of amino acids (AA). We found that different FSBM samples impacted the SID value of AA when fed to gestating sows. Additionally, sow physiological stage influenced the SID of some dispensable AA. These findings provide valuable insights into the incorporation of FSBM into sow diets.

Prediction of tumor origin in cancers of unknown primary origin with cytology-based deep learning.

Cancer of unknown primary (CUP) site poses diagnostic challenges due to its elusive nature. Many cases of CUP manifest as pleural and peritoneal serous effusions. Leveraging cytological images from 57,220 cases at four tertiary hospitals, we developed a deep-learning method for tumor origin differentiation using cytological histology (TORCH) that can identify malignancy and predict tumor origin in both hydrothorax and ascites. We examined its performance on three internal (n = 12,799) and two external (n = 14,538) testing sets. In both internal and external testing sets, TORCH achieved area under the receiver operating curve values ranging from 0.953 to 0.991 for cancer diagnosis and 0.953 to 0.979 for tumor origin localization. TORCH accurately predicted primary tumor origins, with a top-1 accuracy of 82.6% and top-3 accuracy of 98.9%. Compared with results derived from pathologists, TORCH showed better prediction efficacy (1.677 versus 1.265, P < 0.001), enhancing junior pathologists' diagnostic scores significantly (1.326 versus 1.101, P < 0.001). Patients with CUP whose initial treatment protocol was concordant with TORCH-predicted origins had better overall survival than those who were administrated discordant treatment (27 versus 17 months, P = 0.006). Our study underscores the potential of TORCH as a valuable ancillary tool in clinical practice, although further validation in randomized trials is warranted.

Surgical treatment for pelvic haemophilic pseudotumour: a retrospective analysis of 21 cases.

Background: Due to the rarity of pelvic haemophilic pseudotumour (PHPT) and demanding surgical technique for PHPT excision, no study reports the mid-term follow-up outcomes of surgical treatment of PHPT in a relatively large cohort. PHPT with varying degrees of bony pelvic involvement and infection status necessitates different operative procedures, yet there is currently no classification system for PHPT based on surgical practice. Methods: The study was conducted between June 25, 2004 and July 18, 2023, in Peking Union Medical College Hospital and Nanfang Hospital in China. We performed a retrospective analysis involving 21 patients with 24 PHPTs with a mean follow-up period of 7.1 years. The demographic information, PHPT characteristics, surgical data, and perioperative complications were analysed. Findings: 21 consecutive male patients with 24 PHPTs (21 primary PHPTs and three recurrent PHPTs) that underwent surgical treatment were involved in the study. A classification system including four subtypes was introduced as (I) PHPT confined to soft tissue; (II) PHPT involving bony pelvic without pelvic discontinuity; (III) PHPT causing pelvic discontinuity; (IV) Infectious PHPT. Of the 24 PHPTs, 11 (45.8%) were identified as Type I, five (20.8%) as Type II, three (12.5%) as Type III, and five (20.8%) as Type IV. At the time of surgery, the patients had a mean age of 37.0 ± 9.5 years (Range, 24-52 years). The mean maximum diameter of PHPTs upon surgery was 17.0 ± 7.7 cm (Range, 4.3-40.0 cm). The mean surgical duration was 192 ± 77 min (Range, 60-330 min) and the median intraoperative blood loss was 400 mL (IQR, 225-950 mL, Range, 100-3000 mL). One patient (4.8%) underwent intraoperative cardiopulmonary arrest and expired the following week. Four PHPTs (16.7%) presented postoperative wound infections and poor wound healing. During the follow-up period, five PHPTs (20.8%) experienced pseudotumour recurrence. Interpretation: Our findings suggest that surgical treatment for PHPTs is feasible and relatively safe. Symptomatic and progressive PHPTs should undergo surgical intervention as early as possible to minimise the surgical risks. Intraoperative use of abundant gelatin sponges in PHPT excision draws attention to severe embolism complications. Funding: There are no sources of funding for this manuscript.

Identification of glycosyltransferase-related genes signature and integrative analyses in patients with ovarian cancer.

BACKGROUND: Glycosyltransferases (GT) play a crucial role in glycosylation reactions, and aberrant expression of glycosyltransferase-related genes (GTs) leads to abnormal glycosylation, which is associated with tumor progression. However, the prognostic value of aberrant expression of GTs in ovarian cancer (OC) and the correlation between GTs and tumor microenvironment (TME) remain unknown. METHODS: TCGA and GSE53963 databases were used to obtain data on OC patient samples. The association of GTs with OC was analyzed. Molecular subtypes were identified by consensus unsupervised clustering, followed by immune infiltration and functional enrichment analyses. Survival analysis was performed using Kaplan-Meier curves and log-rank tests. Least Absolute Shrinkage and Selection Operator (LASSO) and multifactorial cox regression were used to screen for signature genes associated with OC and used to establish prognostic models. RESULT: OC patients were categorized into 5 GTs clusters using consensus unsupervised cluster analysis. Clusters D and E showed significant differences between survival, signaling pathways and immune infiltration. Then, a risk model was developed based on the 12 signature genes, which provides a more accurate evaluation of the prognosis of OC patients. We categorized patients into high-risk and low-risk groups based on the risk score and found that the survival of patients in the high-risk group was significantly lower than that in the low-risk group. Moreover, the risk score was significantly correlated with tumor microenvironment, immune infiltration, and chemotherapy sensitivity. CONCLUSION: Overall, we performed a comprehensive analysis of GTs in OC patients and developed a risk model for OC. Our findings will provide a new insight to OC prognosis and treatment.

Exploring the role of NAA40 in immune infiltrates and prognostic prediction in hepatocellular carcinoma.

NAA40 belongs to the N-terminal acetyltransferase (NATs) family, responsible for protein N-terminal modification, and it exerts crucial roles across various cancers. However, its impact on patient prognosis and immune infiltration in hepatocellular carcinoma (HCC) remains elusive. To address this, our study delved into the comprehensive analysis of NAA40 in the context of cancer. Our pan-cancer analysis unveiled elevated NAA40 expression in multiple tumor types, including BLCA, BRCA, CHOL, COAD, ESCA, HNSC, LIHC, LUAD, LUSC, STAD, and THCA. Additionally, through a comprehensive examination across various cancer types within TCGA, we discovered that high NAA40 gene expression correlated with poor prognosis in HCC, pointing toward its role in promoting oncogenesis. Further investigation illuminated the association of increased NAA40 expression with T stage, pathologic stage, tumor status, and histologic grade. Interestingly, we noted a significant inverse correlation between NAA40 expression and the infiltration levels of immune cells, such as DC cells, neutrophils, NK cells, and T cells, in liver cancer. This observation underpins the hypothesis that NAA40 influences HCC development by modulating immune cell infiltration. Functional enrichment analysis provided valuable insights into the pathways influenced by NAA40. Enriched pathways encompassed oxidative phosphorylation, xenobiotic metabolism, bile acid metabolism, fatty acid metabolism, G2M checkpoint, and E2F targets. These findings collectively position NAA40 as a potential biomarker for prognostic prediction and monitoring the effects of immunotherapy in HCC.

Clinical outcome and survival rate of condylar constrained knee prosthesis in revision total knee arthroplasty: an average nine point six year follow-up.

PURPOSE: Condylar constrained knee prostheses (CCK) are increasingly used in revision total knee arthroplasty (rTKA), but the clinical effectiveness and long-term survival remain a debate. The purpose of this study is to report the long-term clinical and radiographic outcome, implant survival rate, and surgical safety of revision total knee arthroplasty with condylar constrained knee prosthesis. METHODS: A retrospective cohort study was performed on patients undergoing rTKA with CCK. The cases who received rTKA with CCK from January 2005 to January 2022 were selected. The duration of operation, the estimated perioperative blood loss, and the intraoperative blood transfusion rate were recorded to evaluate surgical safety. The pain visual analog scale (VAS), range of motion (ROM), the Hospital for Special Surgery (HSS) score, the Knee Society Score (KSS), the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and the Oxford knee score (OKS) was recorded to assess clinical outcome. Standard anteroposterior, lateral, skyline and long-standing AP radiographs of the lower limbs were conducted to assess radiographic outcome. Implant survival was analyzed by Kaplan-Meier survival estimates. RESULTS: Fifty-five cases were followed up for an average of 9.6 years (1-18 years), including 16 males and 38 females, with an average age of 66 and an average BMI of 26.9 kg/m2. The  main reasons for revision were periprosthetic infection (32 knees, 58.2%) and aseptic loosening (13 knees, 23.6%). The duration of operation was 149 ± 56.2 min. The perioperative blood loss was 973.6 ± 421.6 ml. At the last follow-up, VAS (8.0 ± 1.1 to 1.3 ± 1.4), ROM (82.7° ± 26.1° to 108.4° ± 11.8°), HSS (45.0 ± 10.4 to 85.3 ± 8.6), KSKS (38.4 ± 12.1 to 88.5 ± 12.0), KSFS (19.6 ± 12.9 to 68.8 ± 15.1), WOMAC (67.9 ± 12.5 to 14.4 ± 9.5), and OKS (9.9 ± 4.2 to 41.6 ± 7.7) were significantly improved (P < 0.001). A total of five complications were observed, all of which were periprosthetic infection. Non-progressive radiolucent lines were observed in 26 knees (47.3%). The 10-year survival rate for no operation was 96.0%. The ten year survival rate for no revision was 98.0%. CONCLUSION: The use of CCK prosthesis for rTKA can achieve good long-term efficacy and prosthesis survival.

Revealing the mechanism of fiber promoting sow embryo implantation by altering the abundance of uterine fluid proteins: A proteomic perspective.

Many studies have shown that fiber in the diet plays an important role in improving the reproductive performance of sows, but there is rarely research on the impact of fiber on early embryo implantation. This study used 4D-Label free technology to identify and analyze the effect of the fiber composition in the diet on the protein in the early pregnancy uterine fluid (UF) of sows. The results indicate that ratio of insoluble fibers to soluble fibers (ISF/SF) 4.89 can increase the concentration of progesterone (PROG) and reduce tumor necrosis factorα (TNF-α) concentration in sow UF. In addition, through 4D-Label free, we identified a total of 4248 proteins, 38 proteins abundance upregulated and 283 proteins abundance downregulated in UF. Through enrichment analysis of these differential abundance proteins (DAPs), it was found that these differential proteins are mainly related to the docking of extracellular vesicles, vesicular transport, inflammatory response, and insulin resistance. Therefore, the results of this study reveal the possible mechanism by which fiber improves the reproductive performance of sows, laying a theoretical foundation for future research on the effects of diet on reproduction. SIGNIFICANCE: This study demonstrates the importance of dietary fiber for early embryo implantation in sows. The effect of dietary ISF/SF on early embryo implantation in sows was elucidated from a proteomic perspective through 4D-Label free technology. This study not only has significant implications for improving sow reproductive efficiency, but also provides important theoretical references for studying early miscarriage and reproductive nutrition in human pregnancy.

Effects of maternal methyl donor intake during pregnancy on ileum methylation and function in an intrauterine growth restriction pig model.

BACKGROUND: Intrauterine growth retardation (IUGR) affects intestinal growth, morphology, and function, which leads to poor growth performance and high mortality. The present study explored whether maternal dietary methyl donor (MET) supplementation alleviates IUGR and enhances offspring's growth performance by improving intestinal growth, function, and DNA methylation of the ileum in a porcine IUGR model. METHODS: Forty multiparous sows were allocated to the control or MET diet groups from mating until delivery. After farrowing, 8 pairs of IUGR and normal birth weight piglets from 8 litters were selected for sampling before suckling colostrum. RESULTS: The results showed that maternal MET supplementation tended to decrease the IUGR incidence and increased the average weaning weight of piglets. Moreover, maternal MET supplementation significantly reduced the plasma concentrations of isoleucine, cysteine, urea, and total amino acids in sows and newborn piglets. It also increased lactase and sucrase activity in the jejunum of newborn piglets. MET addition resulted in lower ileal methionine synthase activity and increased betaine homocysteine S-methyltransferase activity in the ileum of newborn piglets. DNA methylation analysis of the ileum showed that MET supplementation increased the methylation level of DNA CpG sites in the ileum of newborn piglets. Down-regulated differentially methylated genes were enriched in folic acid binding, insulin receptor signaling pathway, and endothelial cell proliferation. In contrast, up-regulated methylated genes were enriched in growth hormone receptor signaling pathway and nitric oxide biosynthetic process. CONCLUSIONS: Maternal MET supplementation can reduce the incidence of IUGR and increase the weaning litter weight of piglets, which may be associated with better intestinal function and methylation status.

Integrated transcriptome and metabolome analysis revealed that HaMYB1 modulates anthocyanin accumulation to deepen sunflower flower color.

KEY MESSAGE: HanMYB1 was found to play positive roles in the modulation of anthocyanins metabolism based on the integrative analysis of different color cultivars and the related molecular genetic analyses. As a high value ornamental and edible crop with various colors, sunflowers (Helianthus annuus L.) provide an ideal system to understand the formation of flower color. Anthocyanins are major pigments in higher plants, which is associated with development of flower colors and ability of oxidation resistance. Here, we performed an integrative analysis of the transcriptome and flavonoid metabolome in five sunflower cultivars with different flower colors. According to differentially expressed genes and differentially accumulated flavonoids, these cultivars could be grouped into yellow and red. The results showed that more anthocyanins were accumulated in the red group flowers, especially the chrysanthemin. Some anthocyanins biosynthesis-related genes like UFGT (UDP-glycose flavonoid glycosyltransferase) also expressed more in the red group flowers. A MYB transcriptional factor, HanMYB1, was found to play vital positive roles in the modulation of anthocyanins metabolism by the integrative analysis. Overexpressed HanMYB1 in tobacco could deepen the flower color, increase the accumulation of anthocyanins and directly active the express of UFGT genes. Our findings indicated that the MYB transcriptional factors provide new insight into the dynamic regulation of the anthocyanin biosynthesis in facilitating sunflower color formation and anthocyanin accumulation.

Cascade Co8FeS8@Co1-xS nano-enzymes trigger efficiently apoptosis-ferroptosis combination tumor therapy.

This study involved the preparation of Metal Organic Frameworks (MOF)-derived Co8FeS8@Co1-xS nanoenzymes with strong interfacial interactions. The nanoenzymes presented the peroxidase (POD)-like activity and the oxidation activity of reduced glutathione (GSH). Accordingly, the dual activities of Co8FeS8@Co1-xS provided a self-cascading platform for producing significant amounts of hydroxyl radical (•OH) and depleting reduced glutathione, thereby inducing tumor cell apoptosis and ferroptosis. More importantly, the Co8FeS8@Co1-xS inhibited the anti-apoptosis protein B-cell lymphoma-2 (Bcl-2) and activated caspase family proteins, which caused tumor cell apoptosis. Simultaneously, Co8FeS8@Co1-xS affected the iron metabolism-related genes such as Heme oxygenase-1 (Hmox-1), amplifying the Fenton response and promoting apoptosis and ferroptosis. Therefore, the nanoenzyme synergistically killed anti-apoptotic tumor cells carrying Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Furthermore, Co8FeS8@Co1-xS demonstrated good biocompatibility, which paved the way for constructing a synergistic catalytic nanoplatform for an efficient tumor treatment.

Metagenomic next-generation sequencing, instead of procalcitonin, could guide antibiotic usage in patients with febrile acute necrotizing pancreatitis: a multicenter, prospective cohort study.

BACKGROUNDS: The effectiveness of procalcitonin-based algorithms in guiding antibiotic usage for febrile acute necrotizing pancreatitis (ANP) remains controversial. Metagenomic next-generation sequencing (mNGS) has been applied to diagnose infectious diseases. The authors aimed to evaluate the effectiveness of blood mNGS in guiding antibiotic stewardship for febrile ANP. MATERIALS AND METHODS: The prospective multicenter clinical trial was conducted at seven hospitals in China. Blood samples were collected during fever (T ≥38.5°C) from ANP patients. The effectiveness of blood mNGS, procalcitonin, and blood culture in diagnosing pancreatic infection was evaluated and compared. Additionally, the real-world utilization of antibiotics and the potential mNGS-guided antimicrobial strategy in febrile ANP were also analyzed. RESULTS: From May 2023 to October 2023, a total of 78 patients with febrile ANP were enrolled and 30 patients (38.5%) were confirmed infected pancreatic necrosis (IPN). Compared with procalcitonin and blood culture, mNGS showed a significantly higher sensitivity rate (86.7% vs. 56.7% vs. 26.7%, P <0.001). Moreover, mNGS outperformed procalcitonin (89.5 vs. 61.4%, P <0.01) and blood culture (89.5 vs. 69.0%, P <0.01) in terms of negative predictive value. Blood mNGS exhibited the highest accuracy (85.7%) in diagnosing IPN and sterile pancreatic necrosis, significantly superior to both procalcitonin (65.7%) and blood culture (61.4%). In the multivariate analysis, positive blood mNGS (OR=60.2, P <0.001) and lower fibrinogen level (OR=2.0, P <0.05) were identified as independent predictors associated with IPN, whereas procalcitonin was not associated with IPN, but with increased mortality (Odds ratio=11.7, P =0.006). Overall, the rate of correct use of antibiotics in the cohort was only 18.6% (13/70) and would be improved to 81.4% (57/70) if adjusted according to the mNGS results. CONCLUSION: Blood mNGS represents important progress in the early diagnosis of IPN, with particular importance in guiding antibiotic usage for patients with febrile ANP.