Time-dependent efficacy analysis of first-line immunotherapies for advanced non-small cell lung cancer.

BACKGROUND: Many randomized controlled trials (RCTs) and network meta-analyses have demonstrated that the progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients can be improved through combination immunotherapy or monotherapies. However, time-dependent analysis of the treatment effect is currently lacking. Thus, we aimed to evaluate the efficacy of first-line immunotherapy, and establish a hazard ratio function to reflect the time-varying progression or mortality risk of patients with NSCLC. METHODS: Seventeen clinical trials were selected based on search strategy. Baseline characteristics, including the age, sex, smoking status, geographical region, and Eastern Cooperative Oncology Group (ECOG) performance status of patients, were balanced, resulting in ten immunotherapies from nine appropriate clinical trials to conduct treatment effect comparison. RESULTS: We found that nivolumab plus ipilimumab (nivo + ipi) improved the PFS and OS over time. The hazard ratio of nivo + ipi, relative to that of pembrolizumab, decreased from 1.11 to 0.36 for PFS, and from 0.93 to 0.49 for OS over a 10-year period. In terms of the response to immunotherapy in patients with different PD-L1 expression levels, patients with PD-L1 > = 50% experienced lower rates of progression and a reduced mortality risk over time. The hazard ratio of patients with PD-L1 > = 50% relative to all of the patients decreased from 0.73 to 0.69 for PFS, and from 0.78 to 0.67 for OS. CONCLUSIONS: Based on the fact that time-dependent progression and mortality risk existed during the treatment duration, physicians should select a suitable treatment regimen for patients based on the hazard ratio.

Exploring driving anger-caused impairment of takeover performance among professional taxi drivers during partially automated driving.

Partially automated systems are expected to reduce road crashes related to human error, even amongst professional drivers. Consequently, the applications of these systems into the taxi industry would potentially improve transportation safety. However, taxi drivers are prone to experiencing driving anger, which may subsequently affect their takeover performance. In this research, we explored how driving anger emotion affects taxi drivers' driving performance in various takeover scenarios, namely Mandatory Automation-Initiated transition (MAIT), Mandatory Driver-Initiated transition (MDIT), and Optional Driver-Initiated transition (ODIT). Forty-seven taxi drivers participated in this 2·3 mixed design simulator experiment (between-subjects: anger vs. calmness; within-subjects: MAIT vs. MDIT vs. ODIT). Compared to calmness, driving anger emotion led to a narrower field of attention (e.g., smaller standard deviations of horizontal fixation points position) and worse hazard perception (e.g., longer saccade latency, smaller amplitude of skin conductance responses), which resulted in longer takeover time and inferior vehicle control stability (e.g., higher standard deviations of lateral position) in MAIT and MDIT scenarios. Angry taxi drivers were more likely to deactivate vehicle automation and take over the vehicle in a more aggressive manner (e.g., higher maximal resulting acceleration, refusing to yield to other road users) in ODIT scenarios. The findings will contribute to addressing the safety concerns related to driving anger among professional taxi drivers and promote the widespread acceptance and integration of partially automated systems within the taxi industry.

AlGaN/GaN-based Photoimaging Transistors and Arrays with Reconfigurable Triple-Mode Functionalities Enabled by Voltage-Programmed Two-Dimensional Electron Gas.

High-quality imaging units are indispensable in modern optoelectronic systems for accurate recognition and processing of optical information. To fulfill massive and complex imaging tasks in digital age, devices with remarkable photoresponsive characteristics and versatile reconfigurable functions on a single device platform are in demand but remain challenging to fabricate. We report an AlGaN/GaN-based double-heterostructure, incorporated with a unique compositionally graded AlGaN structure to generate a channel of polarization-induced two-dimensional electrons that can be modulated to control electron separation, collection, and storage process in the channel of the fabricated phototransistor. As a result, when exposed to different light sources, the device shows reconfigurable multifunctional photoresponsive behaviors with superior characteristics owing to the successful programming of the 2DEGs by the combined gate and drain voltage inputs. A self-powered mode with a responsivity over 100 A/W and a photoconductive mode with a responsivity of ∼108 A/W were achieved, with the ultimate demonstration of a 10×10 device array for imaging. More intriguingly, the device can be switched to photoelectric synapse mode, emulating synaptic functions to denoise the imaging process while prolonging the image storage capability. Demonstrating three-in-one operational characteristics in a single device offers a new path toward future integrated and multifunctional imaging units. This article is protected by copyright. All rights reserved.

Biological Functions and Potential Therapeutic Significance of O-GlcNAcylation in Hepatic Cellular Stress and Liver Diseases.

O-linked-ß-D-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation), which is dynamically regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), is a post-translational modification involved in multiple cellular processes. O-GlcNAcylation of proteins can regulate their biological functions via crosstalk with other post-translational modifications, such as phosphorylation, ubiquitination, acetylation, and methylation. Liver diseases are a major cause of death worldwide; yet, key pathological features of the disease, such as inflammation, fibrosis, steatosis, and tumorigenesis, are not fully understood. The dysregulation of O-GlcNAcylation has been shown to be involved in some severe hepatic cellular stress, viral hepatitis, liver fibrosis, nonalcoholic fatty acid liver disease (NAFLD), malignant progression, and drug resistance of hepatocellular carcinoma (HCC) through multiple molecular signaling pathways. Here, we summarize the emerging link between O-GlcNAcylation and hepatic pathological processes and provide information about the development of therapeutic strategies for liver diseases.

Tislelizumab combined with sunitinib in the treatment of metastatic clear cell renal cell carcinoma with renal venous tumor thrombus: A case report and literature review.

In recent years, with the in-depth study of PD-1/PD-L1 related pathways, great progress has been made in cancer immunotherapy. However, the immunotherapy regimen for mccRCC is still controversial in clinical practice. A 50-year-old man with mccRCC complicated with renal venous tumor thrombus from 2019 to present, including surgical treatment, targeted therapy and the combined treatment regimen of "Tislelizumab combined with Sunitinib". Although he experienced a roller coaster of adverse reactions during treatment, the patient's prognosis was good. Tislelizumab combined with Sunitinib is safe and effective in the Treatment of mccRCC.

Bidirectional two-sample mendelian randomization analysis identifies causal associations of MRI-based cortical thickness and surface area relation to NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) patients have exhibited extra-hepatic neurological changes, but the causes and mechanisms remain unclear. This study investigates the causal effect of NAFLD on cortical structure through bidirectional two-sample Mendelian randomization analysis. METHODS: Genetic data from 778,614 European individuals across four NAFLD studies were used to determine genetically predicted NAFLD. Abdominal MRI scans from 32,860 UK Biobank participants were utilized to evaluate genetically predicted liver fat and volume. Data from the ENIGMA Consortium, comprising 51,665 patients, were used to evaluate the associations between genetic susceptibility, NAFLD risk, liver fat, liver volume, and alterations in cortical thickness (TH) and surface area (SA). Inverse-variance weighted (IVW) estimation, Cochran Q, and MR-Egger were employed to assess heterogeneity and pleiotropy. RESULTS: Overall, NAFLD did not significantly affect cortical SA or TH. However, potential associations were noted under global weighting, relating heightened NAFLD risk to reduced parahippocampal SA and decreased cortical TH in the caudal middle frontal, cuneus, lingual, and parstriangularis regions. Liver fat and volume also influenced the cortical structure of certain regions, although no Bonferroni-adjusted p-values reached significance. Two-step MR analysis revealed that liver fat, AST, and LDL levels mediated the impact of NAFLD on cortical structure. Multivariable MR analysis suggested that the impact of NAFLD on the cortical TH of lingual and parstriangularis was independent of BMI, obesity, hyperlipidemia, and diabetes. CONCLUSION: This study provides evidence that NAFLD causally influences the cortical structure of the brain, suggesting the existence of a liver-brain axis in the development of NAFLD.

Facilitating nitrification and biofilm formation of Vibrio sp. by N-acyl-homoserine lactones in high salinity environment.

The N-acyl-homoserine lactones (AHLs)-mediated quorum-sensing (QS) system played a crucial role in regulating biological nitrogen removal and biofilm formation. However, the regulatory role of AHLs on nitrogen removal bacteria in high salinity environment has remained unclear. This study evaluated the roles and release patterns of AHLs in Vibrio sp. LV-Q1 under high salinity condition. Results showed that Vibrio sp. primarily secretes five AHLs, and the AHLs activity is strongly correlated with the bacterial density. Exogenous C10-HSL and 3OC10-HSL were found to significantly enhance ammonium removal, while making a minor contribution to the growth rate. Both the C10-HSL and 3OC10-HSL promoted the biofilm formation of Vibrio sp. with an enhancement of 1.64 and 1.78 times, respectively. The scanning electron microscope (SEM) and confocal laser scanning microscope (CLSM) observations confirmed the biofilm-enhancing effect of AHLs. Further analysis revealed that AHLs significantly improved bacterial self-aggregation and motility, as well as the level of extracellular polymeric substances (EPS). These findings provide significant guidance on construction of nitrification system at high salinity.

Sulforaphane attenuates irradiation induced testis injury in mice.

OBJECTIVE: The testis is vulnerable to ionizing radiation, sexual dysfunction and male infertility are common problems after local radiation or whole-body exposure. Currently, there are no approved drugs for the prevention or treatment of radiation testicular injury. Sulforaphane (SFN) is an indirect antioxidant that induces phase II detoxification enzymes and antioxidant genes. Herein, we investigated the radiation protective effect of SFN on testicular injury in mice and its potential mechanism. MATERIALS AND METHODS: Mice were randomly divided into blank control group (Ctrl), radiation + no pretreatment group (IR), and radiation + SFN groups (IRS). In the radiation + SFN groups, starting from 72 h before radiation, SFN solution was intraperitoneally injected once a day until they were sacrificed. Mice in the blank control group and the radiation + no pretreatment group were simultaneously injected intraperitoneally with an equal volume of the solvent used to dissolve SFN (PBS with a final concentration of 0.1%DMSO) until they were sacrificed. They were subjected to 6Mev-ray radiation to the lower abdominal testis area (total dose 2Gy). Twenty-four hours after radiation, six mice in each group were randomly sacrificed. Seventy-two hours after radiation, the remaining mice were sacrificed. RESULTS: The results showed that the harmful effects of ionizing radiation on testes were manifested as damage to histoarchitecture, increased oxidative stress, and apoptosis, and thus impaired male fertility. SFN injections can reverse these symptoms. CONCLUSIONS: The results showed that SFN can improve the damage of mouse testis caused by irradiation. Furthermore, SFN prevents spermatogenesis dysfunction caused by ionizing radiation by activating Nrf2 and its downstream antioxidant gene.

The Clinical and Cellular Impact of RBMS2 on the Progression and Prognosis of Kidney Renal Clear Cell Carcinoma.

This research delves into the implications of the RNA binding motif, single stranded interacting protein 2 (RBMS2)-a gene associated with tumor-suppressing functions-in the context of kidney renal clear cell carcinoma (ccRCC). Through meticulous exploration of online databases, we have identified a negative association between RBMS2 expression and adverse clinico-pathological features, such as advanced TNM stage. Furthermore, our findings indicate that RBMS2 acts as a prognostic predictor for clinical outcomes in ccRCC, evidenced by both univariate and multivariate analyses. Cellular assays have corroborated these findings, revealing that an overexpression of RBMS2 curtails ccRCC cell proliferation and migration. Additionally, our research has unearthed links between RBMS2 and immune infiltration within the ccRCC tumor microenvironment. Collectively, our results underscore the tumor-inhibiting role of RBMS2 in ccRCC and spotlight its potential as a prognostic marker and therapeutic intervention target.

Identification and validation of diagnostic signature genes in non-obstructive azoospermia by machine learning.

Non-obstructive azoospermia (NOA) is a common cause of male infertility, and no specific diagnostic indicators exist. In this study, we used human testis datasets GSE45885, GSE45887, and GSE108886 from GEO database as training datasets, and screened 6 signature genes (all lowly expressed in the NOA group) using Boruta algorithm and Lasso regression: C12orf54, TSSK6, OR2H1, FER1L5, C9orf153, XKR3. The diagnostic efficacy of the above genes was examined by constructing models with LightGBM algorithm: the AUC (Area Under Curve) of both ROC and Precision-Recall curves for internal validation was 1.0 (p < 0.05). For the external validation dataset GSE145467 (human testis), the AUC of its ROC curve was 0.9 and that of its Precision-Recall curve was 0.833 (p < 0.05). Next, we confirmed the cellular localization of the above genes using human testis single-cell RNA sequencing dataset GSE149512, which were all located in spermatid. Besides, the downstream regulatory mechanisms of the above genes in spermatid were inferred by GSEA algorithm: C12orf54 may be involved in the repression of E2F-related and MYC-related pathways, TSSK6 and C9orf153 may be involved in the repression of MYC-related pathways, while FER1L5 may be involved in the repression of spermatogenesis pathway. Finally, we constructed a NOA model in mice using X-ray irradiation, and quantitative Real-time PCR results showed that C12orf54, TSSK6, OR2H1, FER1L5, and C9orf153 were all lowly expressed in NOA group. In summary, we have identified novel signature genes of NOA using machine learning methods and complete experimental validation, which will be helpful for its early diagnosis.

Cost-effectiveness of first-line immunotherapy combinations with or without chemotherapy for advanced non-small cell lung cancer: a modelling approach.

BACKGROUND: Many studies have explored the cost-effectiveness of immunotherapy versus chemotherapy alone. However, there is paucity of evidence on direct pharmacoeconomic studies related to immunotherapy combinations. Thus, we aimed at assessing the economic outcomes of first-line immunotherapy combinations in the treatment of advanced non-small cell lung cancer (NSCLC) from the Chinese health care perspective. METHODS: The mutual hazard ratios (HRs) of ten immunotherapy combinations and one chemotherapy regimen for the overall survival (OS) and progression-free survival (PFS) were obtained from a network meta-analysis. Based on proportional hazard (PH) assumption, adjusted OS and PFS curves were established to make the effects comparable. With the parameters of cost and utility, and of scale and shape from the fit of adjusted OS and PFS curves obtained from previous studies, a partitioned survival model was designed to estimate the cost-effectiveness of immunotherapy combinations versus chemotherapy alone. Parameter uncertainty in model inputs was assessed using one-way deterministic and probabilistic sensitivity analyses. RESULTS: The incremental cost of camrelizumab plus chemotherapy versus chemotherapy alone was $13,180.65, the lowest among all the other immunotherapy combinations. Furthermore, sintilimab plus chemotherapy (sint-chemo) provided the highest quality-adjusted life-year (QALY) benefit versus chemotherapy alone (incremental QALYs = 0.45). Sint-chemo yielded the best incremental cost-effectiveness ratio (ICER) versus chemotherapy alone (ICER = $34,912.09/QALY), at the current price. The cost-effectiveness probabilities were 32.01% and 93.91% for pembrolizumab plus chemotherapy, and atezolizumab plus bevacizumab plus chemotherapy, respectively (if the original price of the pembrolizumab, atezolizumab, and bevacizumab were decreased by 90%). CONCLUSIONS: Based on the fact that there is fierce competition in the PD-1/PD-L1 market, pharmaceutical enterprises should strive for greater efficacy, and optimal pricing strategy for therapies.

Medullary cavity application of tranexamic acid to reduce blood loss in tibial intramedullary nailing procedures-a randomized controlled trial.

PURPOSE: Studies have shown an average postoperative hidden blood loss (HBL) of 473.29 ml and an average Hb loss of 16.71 g/l after intramedullary nailing. Reducing HBL has become a primary consideration for orthopaedic surgeons. METHODS: Patients with only tibial stem fractures who visited the study clinic between December 2019 and February 2022 were randomized into two groups using a computer-generated form. Two grams of tranexamic acid (TXA) (20 ml) or 20 ml of saline was injected into the medullary cavity before implantation of the intramedullary nail. On the morning of the surgery, as well as on days one, three and five after surgery, routine blood tests and analyses of CRP and interleukin-6 were completed. The primary outcomes were total blood loss (TBL), HBL, and blood transfusion, in which the TBL and HBL were calculated according to the Gross equation and the Nadler equation. Three months after surgery, the incidence of wound complications and thrombotic events, including deep vein thrombosis and pulmonary embolism, was recorded. RESULTS: Ninety-seven patients (47 in the TXA group and 50 in the NS group) were analyzed; the TBL (252.10 ± 10.05 ml) and HBL (202.67 ± 11.86 ml) in the TXA group were significantly lower than the TBL (417.03 ± 14.60 ml) and HBL (373.85 ± 23.70 ml) in the NS group (p < 0.05). At the three month postoperative follow-up, two patients (4.25%) in the TXA group and three patients (6.00%) in the NS group developed deep vein thrombosis, with no significant difference in the incidence of thrombotic complications (p = 0.944). No postoperative deaths or wound complications occurred in either group. CONCLUSIONS: The combination of intravenous and topical TXA reduces blood loss after intramedullary nailing of tibial fractures without increasing the incidence of thrombotic events.

Novel treatment and insight for irradiation-induced injuries: Dibucaine ameliorates irradiation-induced testicular injury by inhibiting fatty acid oxidation in primary Leydig cells.

BACKGROUND: Male infertility is a worldwide problem but few treatments, especially irradiation-induced testicular injury. The aim of this research was to investigate novel drugs for the treatment of irradiation-induced testicular injury. METHODS: We administered dibucaine (0.8 mg/kg) intraperitoneally to male mice (6 mice per group) after five consecutive daily 0.5 Gy whole-body irradiation, and evaluated its ameliorating efficacy by testicular HE staining and morphological measurements. Drug affinity responsive target stability assay (Darts) were used to find target protein and pathway; mouse primary Leydig cells were isolated and to explore the mechanism (Flow cytometry, Western blot, and Seahorse palmitate oxidative stress assays); finally rescue experiments were completed by combining dibucaine with fatty acid oxidative pathway inhibitors and activators. RESULTS: The testicular HE staining and morphological measurements in dibucaine treatment group was significantly better than that in irradiation group (P < 0.05); sperm motility and mRNA levels of spermatogenic cell markers were also higher than those in the latter (P < 0.05). Darts and Western blot results showed that dibucaine targets CPT1A and downregulate fatty acid oxidation. Flow cytometry, Western blot, and Palmitate oxidative stress assays of primary Leydig cells demonstrated that dibucaine inhibits fatty acid oxidation in Leydig cells. Dibucaine combined with etomoxir/baicalin confirmed that its inhibition of fatty acid oxidation was beneficial in ameliorating irradiation-induced testicular injury. CONCLUSIONS: In conclusion, our data suggest that dibucaine ameliorates irradiation-induced testicular injury in mice by inhibiting fatty acid oxidation in Leydig cells. This will provide novel ideas for the treatment of irradiation-induced testicular injury.

Research progress on complications of Brucellosis.

Brucellosis is a common zoonotic disease that is widely spread worldwide and poses a major threat to human health. Clinically, it often presents with non-specific symptoms such as fever, excessive sweating, malaise, myalgia, arthralgia, loss of appetite, weight loss, and enlarged liver, spleen and lymph nodes. The disease has a long and recurrent course, often accumulating in multiple systems and organs. Of these, osteoarticular involvement is the most common complication, with a prevalence of approximately 2-77%, usually manifesting as spondylitis, sacroiliac arthritis and peripheral arthritis. Hepatosplenomegaly is seen in about 50% of patients with brucellosis, and gastrointestinal disturbances such as abdominal pain, nausea, and vomiting are common. Although respiratory involvement is less common, pneumonia, pleurisy, pleural effusion, and pulmonary nodules have been reported. Besides, approximately 2-20% of cases involve infections of the male genitourinary system, mainly manifesting as unilateral epididymal-orchitis and orchitis. The most serious complication facing brucellosis is cardiovascular involvement, and although the overall mortality rate of brucellosis is about 1% and the incidence of brucellosis endocarditis is less than 2%, more than 80% of deaths are associated with endocarditis. Furthermore, brucellosis is complicated by hematologic disease, with anemia occurring in approximately 20-53% of children during the acute phase. In addition, the neurological incidence of brucellosis is about 0.5-25%, mainly manifested as meningitis. In this study, we review the multisystem complications of brucellosis with the aim of improving early diagnosis, timely treatment and prevention of long-term complications.

Improving effects of telmisartan on spermatogenic disorder induced by fractionated low-dose irradiation in mice.

BACKGROUND: Male infertility is a hot problem worldwide, but there are few treatments, especially male infertility caused by irradiation is difficult to treat. The aim of this study was to investigate and evaluate novel drugs for the treatment of male infertility caused by irradiation. METHODS: we randomly divided 18 male BALB/c mice into 3 groups: control, irradiated, and telmisartan. Both irradiated and telmisartan group completed whole-body 0.5 Gy five times irradiation, and the telmisartan group received intraperitoneal injection of telmisartan (1.2 mg/kg) daily on the next day after irradiation, and all groups were sampled on day 25 after irradiation. RESULTS: Sperm motility results show that total sperm motility of irradiated group was significantly lower compared with control group, and testicular HE results showed that testis in irradiated group were severely damaged. Compared with irradiated group, the total sperm motility, sperm concentration, testicular index, Johnsen score, and the seminiferous tubule layer numbers were higher in telmisartan group (P < 0.05). The immunohistochemical staining showed γ-H2AX expression is higher in telmisartan group compared with irradiated group. And the relative mRNA expression of PLZF, GFRA1, STRA8, DMRT1, SPO11, SYCP2, OVOL2, CCNA1, TJP3, RUNX2, TXNDC2 TNP1, and PRM3 in telmisartan group was all significantly higher than irradiated group (P < 0.05). CONCLUSION: In conclusion, in vivo experiments confirmed that telmisartan ameliorated the spermatogenic disorder in mice caused by fractionated low-dose irradiation via promoting spermatogenesis.

Berberine regulates pulmonary inflammatory microenvironment and decreases collagen deposition in response to bleomycin-induced pulmonary fibrosis in mice.

The purpose of this study was to explore the protective effect and potential mechanism of berberine on bleomycin (BLM)-induced fibrosis after lung injury in conjunction with network pharmacology. Berberine and pulmonary fibrosis prediction targets were collected for Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and so forth. A single intranasal dose of BLM (2.5 mg/kg) was administered to establish a model of fibrosis after lung injury, and berberine (50 mg/kg) was administered intraperitoneally daily for treatment. Network pharmacology results suggested that the mitogen-activated protein kinase (MAPK) signalling pathway may be a potential mechanism of berberine in delaying pulmonary fibrosis. The results of animal experiments showed that compared with the BLM group, after 14 days of berberine treatment, lung inflammatory cell aggregation was reduced and the expression levels of tumour necrosis factor-α (TNF-α), interleukin (IL)-8 and IL-6 were down-regulated in mice (p < 0.05); after 42 days of berberine treatment, the expression levels of transforming growth factor (TGF)-ß1, platelet-derived growth factor-AB (PDGF-AB), hydroxyproline (HYP) and α-smooth muscle actin (α-SMA) were significantly down-regulated (p < 0.05), and the expression levels of total p38 MAPKα and p38 MAPKα (pT180/Y182) were down-regulated also (p < 0.05), inhibited collagen production and deposition, and increased the survival rate of mice to 70%. In conclusion, berberine attenuated inflammation mice, inhibited collagen production and showed some anti-pulmonary fibrosis potential in the MAPK signalling pathway.

Custom-made 3D-printed porous metal acetabular composite component in revision hip arthroplasty with Paprosky type III acetabular defects: A case report.

BACKGROUND: Increases in the numbers of surgical procedures for primary total hip arthroplasty (THA) inevitably lead to increases in the requirements for revision THA. The achievement of long-term stability is difficult or impossible by conventional implants in patients with severe destruction of the acetabulum. OBJECTIVE: This case report presents a successful treatment using a specific three-dimensional (3D)-printed porous titanium acetabular composite component without a flange in the management of Paprosky type IIIB acetabular defects. METHOD: A 65-year-old female diagnosed with right hip prosthetic loosening with a huge acetabular defect presented to our hospital. We designed the 3D model of the pelvis and created an individualized 3D-printed porous titanium acetabular composite component for revision THA. The procedure was performed through a posterolateral approach, and the component was implanted in the defect and fixed with cup screws using the drill guides. RESULTS: At the last follow-up at 2 years, the patient had a satisfactory hip joint function and no signs of loosening or other complications were found. CONCLUSIONS: The 3D-printed porous titanium acetabular composite component without a flange is showing promising clinical and radiological outcomes in the management of Paprosky type III acetabular defects.

[Differential expressions of seminal plasma piRNAs in men and its significance].

OBJECTIVE: To study the differential expressions of piRNAs in the seminal plasma of men and the role of piRNAs in spermatogenesis. METHODS: We sequenced the seminal plasma samples collected from 187 male infertility patients and 58 normal healthy men, obtained differentially expressed piRNAs, and detected the relative expressions of piRNAs in different types of sperm by RT-qPCR to explore their significance in the diagnosis of male infertility. Using histopathology, RNA-protein pull-down and Western blot, we investigated the action mechanism of piRNAs in spermatogenesis in the mouse model. RESULTS: RT-qPCR of the seminal plasma samples revealed a high expression of hsa_piR_000478 in teratozoospermia and ROC curve analysis showed an auxiliary significance of hsa_piR_000478 in the diagnosis of the disease (AUC = 0.7549). Transfection of hsa_piR_000478 and its homologous sequence piR_mmu_54800729 into the seminiferous tubules of the mouse model significantly decreased sperm motility, increased the percentage of morphologically abnormal sperm and destroyed the testicular structure. Molecular biological experiments exhibited a close correlation between piRNAs and the energy metabolism-related pathway, which elevated the level of cell glycolysis and interfered with normal spermatogenesis. CONCLUSION: hsa_piR_000478 has an auxiliary significance in the diagnosis of male infertility, and piRNAs may interfere with spermatogenesis by affecting the glycolysis-related pathway in the spermatogenic microenvironment of the testis.

The study of metabolism and metabolomics in a mouse model of silica pulmonary fibrosis based on UHPLC-QE-MS.

The small diameter crystalline silica is inhaled into the lung and cannot be cleared. As a result, the patient suffers from silicosis, a lung disease for which there is no effective treatment except lung transplantation. The aim of this study is to reveal the histological, cytological and metabolic characteristics of mice with pulmonary fibrosis induced by different doses of silica, and to provide an ideal animal model for drug development and disease research of pulmonary fibrosis. The experimental mice were divided into five groups. The mice were sacrificed 42 d later by nasal inhalation of normal saline and suspension containing silica 1 mg, 2 mg, 4 mg and 8 mg. Lung specimens and bronchoalveolar lavage fluid (BALF) were collected for histological and cytological examination. Carotid blood was collected and centrifuged to obtain serum for UHPLC-QE-MS non-target metabolomics detection. Compared with the normal control group, except 1 mg silica group, the other dosage groups showed different degree of disease characteristics. Metabolomics analysis showed that arginine and proline metabolism, pentose phosphate pathway, histidine metabolism, cysteine and methionine metabolism, ascorbic acid and aldoglucose metabolism were important metabolic pathways. This study reveals the histological, cytological and metabolic features of four-dose-gradient silica-induced pulmonary fibrosis mouse models.