Meta-analysis of peripheral blood eosinophils in clinical testing of chronic obstructive pulmonary disease patients.

Introduction: Meta-analysis was used to investigate the relationship between peripheral blood eosinophil (EOS) levels, clinical characteristics, and prognosis in chronic obstructive pulmonary disease (COPD)patients in previous literature. Aim: To analyse the correlation between peripheral blood EOS levels and clinical characteristics and prognosis of patients with COPD using meta-analysis. Material and methods: In databases such as PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wan Fang Data, literature related to the clinical characteristics or prognosis of COPD patients with high-level EOS published before July 2023 was searched for meta-analysis. Results: Through computer search and screening, 29 articles were ultimately included. The meta-analysis results showed that compared to conventional EOS levels, COPD patients with high EOS levels had a lower proportion of GOLD III-IV grade patients (OR = 00.78, 95% CI (0.68, 0.88), p < 0.001), lower CAT scores (OR = -1.01, 95% CI (-1.75, -0.28), p = 0.007), shorter hospital stay (OR = -1.33, 95% CI (-1.52, -1.14), p < 0.001), and lower mortality rate (OR = 0.53, 95% CI (0.42, 0.66), p < 0.001). The readmission rate was low (OR = 0.40, 95% CI (0.33, 0.48), p < 0.001), and there was no statistically significant difference in FEV1%pred (OR = -0.55, 95% CI (-1.33, 0.23), p = 0.17), higher FEV1/FVC values (OR = -0.45, 95% CI (-1.08, 0.18), p = 0.160), and mechanical ventilation usage rate (OR = 0.89, 95% CI (0.65, 1.21), p = 0.450) among COPD patients with different EOS levels. Conclusions: The levels of peripheral blood EOS in COPD patients are related to lung function, respiratory symptoms, etc.; Moreover, COPD patients with high-level EOS have shorter hospital stays, lower mortality and readmission rates. Therefore, ESO can be used as an auxiliary indicator for clinical symptom diagnosis of COPD patients and as an auxiliary indicator for predicting prognosis.

Olgotrelvir as a Single-Agent Treatment of Nonhospitalized Patients with Covid-19.

BACKGROUND: Olgotrelvir is an oral antiviral with dual mechanisms of action targeting severe acute respiratory syndrome coronavirus 2 main protease (i.e., Mpro) and human cathepsin L. It has potential to serve as a single-agent treatment of coronavirus disease 2019 (Covid-19). METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of olgotrelvir in 1212 nonhospitalized adult participants with mild to moderate Covid-19, irrespective of risk factors, who were randomly assigned to receive orally either 600 mg of olgotrelvir or placebo twice daily for 5 days. The primary and key secondary end points were time to sustained recovery of a panel of 11 Covid-19-related symptoms and the viral ribonucleic acid (RNA) load. The safety end point was incidence of treatment-emergent adverse events. RESULTS: The baseline characteristics of 1212 participants were similar in the two groups. In the modified intention-to-treat population (567 patients in the placebo group and 558 in the olgotrelvir group), the median time to symptom recovery was 205 hours in the olgotrelvir group versus 264 hours in the placebo group (hazard ratio, 1.29; 95% confidence interval [CI], 1.13 to 1.46; P<0.001). The least squares mean (95% CI) changes of viral RNA load from baseline were -2.20 (-2.59 to -1.81) log10 copies/ml in olgotrelvir-treated participants and -1.40 (-1.79 to -1.01) in participants receiving placebo at day 4. Skin rash (3.3%) and nausea (1.5%) were more frequent in the olgotrelvir group than in the placebo group; there were no treatment-related serious adverse events, and no deaths were reported. CONCLUSIONS: Olgotrelvir as a single-agent treatment significantly improved symptom recovery. Adverse effects were not dose limiting. (Funded by Sorrento Therapeutics, a parent company of ACEA Therapeutics; ClinicalTrials.gov number, NCT05716425.).

Indigenous data governance approaches applied in research using routinely collected health data: a scoping review.

Globally, there is a growing acknowledgment of Indigenous Peoples' rights to control data related to their communities. This is seen in the development of Indigenous Data Governance standards. As health data collection increases, it's crucial to apply these standards in research involving Indigenous communities. Our study, therefore, aims to systematically review research using routinely collected health data of Indigenous Peoples, understanding the Indigenous Data Governance approaches and the associated advantages and challenges. We searched electronic databases for studies from 2013 to 2022, resulting in 85 selected articles. Of these, 65 (77%) involved Indigenous Peoples in the research, and 60 (71%) were authored by Indigenous individuals or organisations. While most studies (93%) provided ethical approval details, only 18 (21%) described Indigenous guiding principles, 35 (41%) reported on data sovereignty, and 28 (33%) addressed consent. This highlights the increasing focus on Indigenous Data Governance in utilising health data. Leveraging existing data sources in line with Indigenous data governance principles is vital for better understanding Indigenous health outcomes.

Pathogenic and genomic characterization of rabbit-sourced Pasteurella multocida serogroup F isolates recovered from dead rabbits with respiratory disease.

Pasteurella multocida serogroup F can infect a number of animals. However, the pathogenicity and genomic features of this serogroup are still largely unknown. In the present study, the pathogenicity and genomic sequences of 19 rabbit-sourced P. multocida serogroup F isolates were determined. The 19 isolates were highly pathogenic for rabbits causing severe pathologic lesions and high mortality in inoculated rabbits. Nevertheless, the pathologic lesions in rabbits caused by the 19 isolates were distinct from those caused by the previously reported high-virulent serogroup F strains J-4103 (rabbit), P-4218 (turkey), and C21724H3km7 (chicken). Moreover, the 19 isolates were avirulent to white feather broilers. The genomes of the 19 isolates were determined to understand the pathogenicity of these isolates. The finding of a number of functional genes in the 19 isolates by comparison with the low-virulent rabbit-sourced serogroup F strain s4 might contribute to the high virulence of these isolates. Notably, polymorphisms were determined in the lipopolysaccharide outer core biosynthetic genes natC and gatF among the serogroup F strains of different hosts. However, the sequences of natC and gatF from rabbit-sourced strains (except for SD11) were identical, which might be responsible for the host specific of the 19 isolates. The observations and findings in this study would be helpful for the understanding of the pathogenicity variation and host predilection of P. multocida. IMPORTANCE: The 19 rabbit-sourced Pasteurella multocida serogroup F isolates showing high virulence to rabbits were avirulent to the broilers. Notably, polymorphisms were determined in the lipopolysaccharide outer core biosynthetic genes natC and gatF among all serogroup F strains of different hosts. However, the sequences of natC and gatF from rabbit-sourced strains (except for SD11) were identical, which might be responsible for the host specific of the 19 isolates.

Dual effects of gonadotropin-inhibitory hormone on testicular development in prepubertal Minxinan Black rabbits (Oryctolagus cuniculus).

Gonadotropin-inhibitory hormone (GnIH) is a neurohormone that not only suppresses reproduction at the brain level but also regulates steroidogenesis and gametogenesis at the gonad level. However, its function in gonadal physiology has received little attention in rabbits. The main objective of this study was to evaluate the effects of GnIH on testicular development and function in prepubertal Minxinan Black rabbits (Oryctolagus cuniculus). In the present study, we investigated the serum reproductive hormone concentration, testicular parameters, morphology of seminiferous tubules, apoptosis of testicular cells, and expression of reproductive-related genes in male prepubertal Minxinan Black rabbits intraperitoneally administered with 0, 0.5, 5, or 50 µg quail GnIH-related peptides (qGnIH) for 10 days. Compared with the vehicle, administration with 5 µg of qGnIH downregulated the serum testosterone concentration and mRNA levels of spermatogenic genes (PCNA, FSHR, INHßA, HSF1, and AR) and upregulated the apoptosis rate of testicular cells; administration with 50 µg of qGnIH decreased the serum testosterone concentration and hypothalamic GnIH gene mRNA level and increased the serum LH concentration, pituitary LHß gene mRNA level, testicular weight, gonadosomatic index (GSI), and spermatogenic cell layer thickness. It is concluded that GnIH could exert dual actions on testicular development depending on the male prepubertal rabbits receiving different intraperitoneal doses.

Effects of the Species and Growth Stage on the Antioxidant and Antifungal Capacities, Polyphenol Contents, and Volatile Profiles of Bamboo Leaves.

Bamboo leaves contain high concentrations of various biologically active compounds, such as polyphenols and volatiles, making them attractive as raw resources for antioxidant additives in the food industry. Here, we investigated the total phenolic content (TPC) and total flavonoid content (TFC) of four bamboo leaf extracts from two species (Phyllostachys edulis and Chimonocalamus delicatus) at two growth stages (first and second years). Antioxidant capacity was determined based on the radical-scavenging capacity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+). We also assessed the antifungal capacity based on mycelial growth inhibition of Colletotrichum musae (C. musae), Botrytis cinerea (B. cinereain), and Alternaria alternata (A. alternata). Pearson's correlation coefficients showed that the TPC was significantly (p < 0.01) negatively correlated with the half-maximal inhibitory concentrations against DPPH and ABTS+, whereas the TFC was positively correlated with C. musae and B. cinereain growth inhibition, which suggest that TPC and TFC might be the major contributors to the antioxidant and antifungal capacities of bamboo leaves, respectively. The volatile organic compounds (VOCs) of bamboo leaves were also analyzed using gas chromatography-ion mobility spectrometry. The VOCs included twenty-four aldehydes, eleven alcohols, four furans, seven esters, fifteen terpenes, three ketones, one pyrazine, and thirty unidentified compounds. Principal component analysis, partial least squares discriminant analysis, and hierarchical cluster analysis were performed to assess the differences in the volatile profiles of the four bamboo leaf samples, from which 23 discriminatory VOCs with variable importance in the projection values > 1 were screened, and part of them were impacted by species or growth stage. These findings provide a theoretical foundation for the use of bamboo leaves.

The soybean sugar transporter GmSWEET6 participates in sucrose transport towards fungi during arbuscular mycorrhizal symbiosis.

In arbuscular mycorrhizal (AM) symbiosis, sugars in root cortical cells could be exported as glucose or sucrose into peri-arbuscular space for use by AM fungi. However, no sugar transporter has been identified to be involved in sucrose export. An AM-inducible SWEET transporter, GmSWEET6, was functionally characterised in soybean, and its role in AM symbiosis was investigated via transgenic plants. The expression of GmSWEET6 was enhanced by inoculation with the cooperative fungal strain in both leaves and roots. Heterologous expression in a yeast mutant showed that GmSWEET6 mainly transported sucrose. Transgenic plants overexpressing GmSWEET6 increased sucrose concentration in root exudates. Overexpression or knockdown of GmSWEET6 decreased plant dry weight, P content, and sugar concentrations in non-mycorrhizal plants, which were partly recovered in mycorrhizal plants. Intriguingly, overexpression of GmSWEET6 increased root P content and decreased the percentage of degraded arbuscules, while knockdown of GmSWEET6 increased root sugar concentrations in RNAi2 plants and the percentage of degraded arbuscules in RNAi1 plants compared with wild-type plants when inoculated with AM fungi. These results in combination with subcellular localisation of GmSWEET6 to peri-arbuscular membranes strongly suggest that GmSWEET6 is required for AM symbiosis by mediating sucrose efflux towards fungi.

Cathepsin V drives lung cancer progression by shaping the immunosuppressive environment and adhesion molecules cleavage.

Cathepsin V (CTSV) is a cysteine cathepsin protease that plays a crucial role in extracellular matrix degradation. CTSV is correlated with poor prognosis in various cancers, but the underlying mechanism remains elusive. Here, we observed that CSTV is upregulated in lung cancer and is a poor prognosis factor for lung cancer. CTSV acts as a driver in the metastasis of lung cancer both in vitro and in vivo. CTSV promotes lung cancer metastasis by downregulating adhesion molecules, including fibronectin, E-cadherin, and N-cadherin. Our data revealed that CTSV functions by mediating the fragmentation of fibronectin, E-cadherin, and N-cadherin in cleavage, remodeling the extracellular matrix (ECM). The rationally designed antibody targeting CTSV blocks its cleaving ability towards fibronectin, E-cadherin, and N-cadherin, suppressing migration and invasion. Furthermore, we found that CTSV expression is negatively correlated with immune cell infiltration and immune scores and inhibits T cell activity. Targeting CTSV with specific antibodies effectively suppressed lung cancer metastasis in a mouse model. Our study demonstrates the critical role of CTSV in the immunity and metastasis of lung cancer, suggesting that the CTSV-targeting approach is a promising strategy for lung cancer.

Characteristics of pulmonary infarction in patients with acute pulmonary embolism in China: a single-center retrospective observational study.

Background: Pulmonary infarction (PI) is an uncommon complication of pulmonary embolism (PE). The risk factors of PI are still relatively unclear. Methods: This was a single-center retrospective review conducted on 500 patients with PE. After applying the inclusion and exclusion criteria, 386 patients diagnosed with PE were enrolled in our study. These patients were then categorized into the PI group (n=64) and the non-PI group (n=322). A comparison was conducted between the two groups regarding the clinical characteristics. Results: The occurrence of PI secondary to PE was 16.58%. In univariate analysis, recent trauma (21.9% vs. 9.9%, P=0.007), pleuritic chest pain (46.9% vs. 17.4%, P<0.001), hemoptysis (29.7% vs. 2.5%, P<0.001), fever (26.6% vs. 8.1%, P<0.001), lower limb edema/pain (37.5% vs. 14.0%, P<0.001), white blood cell (WBC) counts (37.5% vs. 24.5%, P=0.032), C-reactive protein (CRP) (65.6% vs. 41.3%, P<0.001), and pleural effusion (45.3% vs. 18.6%, P<0.001) were associated with an increased risk of PI. Multivariate analysis demonstrated that age [odds ratio (OR) 0.975, 95% confidence interval (CI): 0.951-0.999, P=0.045], pleuritic chest pain (OR 2.878, 95% CI: 1.424-5.814, P=0.003), hemoptysis (OR 10.592, 95% CI: 3.503-32.030, P<0.001), lower limb edema/pain (OR 2.778, 95% CI: 1.342-5.749, P=0.006) and pleural effusion (OR 3.127, 95% CI: 1.531-6.388, P=0.002) were independent factors of PI due to PE. No significant difference was recorded between the two groups in treatment and mortality. Conclusions: Young patients were found to be a higher risk of PI. Pleural effusion was found to be a factor for PI. PI should be considered when pleuritic chest pain, hemoptysis, or lower limb edema/pain are present with peripheral opacity.

Development of a nomogram to estimate the risk of community-acquired pneumonia in adults with acute asthma exacerbations.

OBJECTIVE: The aim of this study is to investigate the clinical characteristics of acute asthma exacerbations (AEs) with community-acquired pneumonia (CAP) in adults and establish a CAP prediction model for hospitalized patients with AEs. METHODS: We retrospectively collected clinical data from 308 patients admitted to Beijing Luhe Hospital, Capital Medical University, for AEs from December 2017 to August 2021. The patients were divided into CAP and non-CAP groups based on whether they had CAP. We used the Lasso regression technique and multivariate logistic regression analysis to select optimal predictors. We then developed a predictive nomogram based on the optimal predictors. The bootstrap method was used for internal validation. We used the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) to assess the nomogram's discrimination, accuracy, and clinical practicability. RESULTS: The prevalence of CAP was 21% (65/308) among 308 patients hospitalized for AEs. Independent predictors of CAP in patients hospitalized with an AE (P < 0.05) were C-reactive protein > 10 mg/L, fibrinogen > 4 g/L, leukocytes > 10 × 109 /L, fever, use of systemic corticosteroids before admission, and early-onset asthma. The AUC of the nomogram was 0.813 (95% CI: 0.753-0.872). The concordance index of internal validation was 0.794. The calibration curve was satisfactorily consistent with the diagonal line. The DCA indicated that the nomogram provided a higher clinical net benefit when the threshold probability of patients was 3% to 89%. CONCLUSIONS: The nomogram performed well in predicting the risk of CAP in hospitalized patients with AEs, thereby providing rapid guidance for clinical decision-making.

The effectiveness of shockwave therapy on patellar tendinopathy, Achilles tendinopathy, and plantar fasciitis: a systematic review and meta-analysis.

Background: Tendinopathy is a growing global concern affecting many people, like athletes, workers, and the elderly. Despite its commonality among the sporting population, there is no practical clinical guideline for patellar tendinopathy (PT). Furthermore, there is conflicting evidence between clinical guidelines on shockwave therapy's application and clinical utility for Achilles tendinopathy (AT) and plantar fasciitis (PF). Thus, our aim of this study is to evaluate the evidence for shockwave therapy; to provide a Grading of Recommendation, Assessment, Development and Evaluation (GRADE) level of the evidence and effectiveness of shockwave therapy for patellar tendinopathy, Achilles tendinopathy, and Plantar fasciitis. Method: Medical Literature Analysis and Retrieval System Online (Medline), Embase, The Cumulative Index to Nursing and Allied Health Literature (CINAHL), Physiotherapy Evidence Database (PEDro) and China National Knowledge Infrastructure database (CNKI) were searched to find relevant studies published before December 14th, 2022. Results: Our study showed that for PT in the short term, extracorporeal shockwave therapy (ESWT) or ESWT + eccentric exercise (EE) has a negligible effect on pain and function compared to a placebo or placebo + EE. On the contrary, ESWT significantly affects pain compared to conservative treatment (CT). For AT, ESWT has a small inconclusive effect on pain and function in the short term compared to EE. On the other hand, a placebo outperformed ESWT in improving function for AT but not pain outcomes. PF showed that ESWT significantly affects short- and long-term pain and function. When ESWT was compared to other interventions such as low laser therapy (LLLT), corticosteroid injection (CSI), or CT, there was a small inconclusive effect on pain and function in the short term. Conclusion: There is low-moderate evidence that ESWT has a negligible effect on pain and function for PT and AT. However, high-quality evidence suggests ESWT has a large effect on pain and function for PF. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023396835, identifier CRD42023396835.

Arabidopsis transcription factor WRKY45 confers cadmium tolerance via activating PCS1 and PCS2 expression.

Cadmium (Cd) has long been recognized as toxic pollutant to crops worldwide. The biosynthesis of glutathione-dependent phytochelatin (PC) plays crucial roles in the detoxification of Cd in plants. However, its regulatory mechanism remains elusive. Here, we revealed that Arabidopsis transcription factor WRKY45 confers Cd tolerance via promoting the expression of PC synthesis-related genes PCS1 and PCS2, respectively. Firstly, we found that Cd stress induces the transcript levels of WRKY45 and its protein abundance. Accordingly, in contrast to wild type Col-0, the increased sensitivity to Cd is observed in wrky45 mutant, while overexpressing WRKY45 plants are more tolerant to Cd. Secondly, quantitative real-time PCR revealed that the expression of AtPCS1 and AtPCS2 is stimulated in overexpressing WRKY45 plants, but decreased in wrky45 mutant. Thirdly, WRKY45 promotes the expression of PCS1 and PCS2, electrophoresis mobility shift assay analysis uncovered that WRKY45 directly binds to the W-box cis-element of PCS2 promoter. Lastly, the overexpression of WRKY45 in Col-0 leads to more accumulation of PCs in Arabidopsis, and the overexpression of PCS1 or PCS2 in wrky45 mutant plants rescues the phenotypes induced by Cd stress. In conclusion, our results show that AtWRKY45 positively regulates Cd tolerance in Arabidopsis via activating PCS1 and PCS2 expression.

Targeting proteasomal deubiquitinases USP14 and UCHL5 with b-AP15 reduces 5-fluorouracil resistance in colorectal cancer cells.

5-Fluorouracil (5-FU) is the first-line treatment for colorectal cancer (CRC) patients, but the development of acquired resistance to 5-FU remains a big challenge. Deubiquitinases play a key role in the protein degradation pathway, which is involved in cancer development and chemotherapy resistance. In this study, we investigated the effects of targeted inhibition of the proteasomal deubiquitinases USP14 and UCHL5 on the development of CRC and resistance to 5-FU. By analyzing GEO datasets, we found that the mRNA expression levels of USP14 and UCHL5 in CRC tissues were significantly increased, and negatively correlated with the survival of CRC patients. Knockdown of both USP14 and UCHL5 led to increased 5-FU sensitivity in 5-FU-resistant CRC cell lines (RKO-R and HCT-15R), whereas overexpression of USP14 and UCHL5 in 5-FU-sensitive CRC cells decreased 5-FU sensitivity. B-AP15, a specific inhibitor of USP14 and UCHL5, (1-5 µM) dose-dependently inhibited the viability of RKO, RKO-R, HCT-15, and HCT-15R cells. Furthermore, treatment with b-AP15 reduced the malignant phenotype of CRC cells including cell proliferation and migration, and induced cell death in both 5-FU-sensitive and 5-FU-resistant CRC cells by impairing proteasome function and increasing reactive oxygen species (ROS) production. In addition, b-AP15 inhibited the activation of NF-κB pathway, suppressing cell proliferation. In 5-FU-sensitive and 5-FU-resistant CRC xenografts nude mice, administration of b-AP15 (8 mg·kg-1·d-1, intraperitoneal injection) effectively suppressed the growth of both types of tumors. These results demonstrate that USP14 and UCHL5 play an important role in the development of CRC and resistance to 5-FU. Targeting USP14 and UCHL5 with b-AP15 may represent a promising therapeutic strategy for the treatment of CRC.

Analysis of the characteristics of major pollutants discharged from wastewater in China's provinces.

In recent years, the discharge of major pollutants in China's wastewater has been decreasing but remains at a high level. Controlling the discharge of pollutants in sewage is of great importance for protecting water quality and maintaining ecological balance. Based on data collected from 31 provinces in China from 2011 to 2020 (except 2018), this study analyzes the spatiotemporal variation emissions of the wastewater pollutants: chemical oxygen demand (COD), ammonia nitrogen (NH3-N), total nitrogen (TN), and total phosphorus (TP). The entropy method was used to evaluate the effectiveness of water pollution control in different provinces. Our results revealed that the total emission per gross domestic product (GDP) for COD, NH3-N, TN and TP in China decreased by 50.7%, 81.9%, 65.4% and 70.8%, respectively. In terms of regional annual emission differences, the Northwest region was the lowest compared with other regions, accounting for 4.87%-6.59% of the national pollutant emissions, and the Central China region was the highest, accounting for 22.4%-26.05% of the national pollutant emissions. The average value of pollutant emissions per unit of GDP decreased year-to-year overall, but Guangxi and Tibet showed a trend of first decreasing and then increasing. The correlation results indicated a significant correlation (0.977) between TN and TP emissions in wastewater in China during 2011-2020. Through clustering and Multidimensional Scaling model (MDS) analysis, Beijing and Shanghai have been performing well in controlling water pollution discharge, while the provinces of Tibet and Guangxi must still increase their efforts in water pollution control. Furthermore, these results demonstrate the experience and achievements of the Chinese government in the treatment of wastewater pollution and provide a useful reference for treatment of wastewater pollution in the world.

Development of a Diagnostic Nomogram to Predict CAP in Hospitalized Patients with AECOPD.

The purpose of this study was to establish a nomogram for predicting community-acquired pneumonia (CAP) in hospitalized patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The retrospective cohort study included 1249 hospitalized patients with AECOPD between January 2012 and December 2019. The patients were divided into pneumonia-complicating AECOPD (pAECOPD) and non-pneumonic AECOPD (npAECOPD) groups. The least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression were utilized to identify prognostic factors. A prognostic nomogram model was established, and the bootstrap method was used for internal validation. Discrimination and calibration of the nomogram model were evaluated by receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Logistic and LASSO regression analysis showed that C-reactive protein (CRP) >10 mg/L, albumin (Alb) <40 g/L, alanine transferase (ALT) >50 U/L, fever, bronchiectasis, asthma, previous hospitalization for pAECOPD in the past year (Pre-H for pAECOPD), and age-adjusted Charlson score (aCCI) ≥6 were independent predictors of pAECOPD. The area under the ROC curve (AUC) of the nomogram model was 0.712 (95% CI: 0.682-0.741). The corrected AUC of internal validation was 0.700. The model had well-fitted calibration curves and good clinical usability DCA curve. A nomogram model was developed to assist clinicians in predicting the risk of pAECOPD.China Clinical Trials Registry: ChiCTR2000039959.

Effects of strength training on functional ambulation following knee replacement: a systematic review, meta-analysis, and meta-regression.

Strength training is recommended by the American Physical Therapy Association to improve muscle strength, mobility, and balance following knee replacement. Few studies have focused on the direct effects of strength training on functional ambulation, and potential dose-response relationships between strength training parameters and the effect remain unclear. The aim of this systematic review, meta-analysis, and meta-regression was to evaluate the effects of strength training on functional ambulation following knee replacement (KR). We also aimed to explore potential dose-response relationships between strength training parameters and performance in functional ambulation. A systematic literature search of eight online databases was performed on March 12, 2023, for randomized controlled trials evaluating the effects of strength training on functional ambulation by six-minute walk test (6MWT) or timed-up and go test (TUG) after KR. Data were pooled by random-effect meta-analyses and presented as weighted mean difference (WMD). A random-effect meta-regression was performed for four predetermined training parameters, namely, duration (weeks), frequency (sessions per week), volume (time per session), and initial time (after surgery) separately to explore dose-response relationships with WMD. Fourteen trials encompassing 956 participants were included in our study. Meta-analyses showed an improvement in 6MWT performance after strength training (WMD: 32.15, 95% CI 19.44-44.85) and a decrease in time to complete TUG (WMD: - 1.92, 95% CI - 3.43 to - 0.41). Meta-regression revealed a dose-response relationship only between volume and 6MWT, with a decreasing trend (P = 0.019, 95% CI - 1.63 to - 0.20). Increasing trends of improvement in 6MWT and TUG were observed with increasing training duration and frequency. A slight decreasing trend of improvement was observed in 6MWT with postponed initial time, while an opposite trend was observed in TUG. Based on existing studies, moderate-certainty evidence suggests that strength training could increase 6MWT distance, and low-certainty evidence shows that strength training could decrease the time to complete TUG after KR. Meta-regression results only suggested a dose-response relationship between volume and 6MWT with a decreasing trend.Registration: PROSPERO: CRD42022329006.

Inhibition of phosphoglycerate dehydrogenase induces ferroptosis and overcomes enzalutamide resistance in castration-resistant prostate cancer cells.

Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the first step of the serine synthesis pathway (SSP), is overexpressed in multiple types of cancers. The androgen receptor inhibitor enzalutamide (Enza) is the primary therapeutic drug for patients with castration-resistant prostate cancer (CRPC). However, most patients eventually develop resistance to Enza. The association of SSP with Enza resistance remains unclear. In this study, we found that high expression of PHGDH was associated with Enza resistance in CRPC cells. Moreover, increased expression of PHGDH led to ferroptosis resistance by maintaining redox homeostasis in Enza-resistant CRPC cells. Knockdown of PHGDH caused significant GSH reduction, induced lipid peroxides (LipROS) increase and significant cell death, resulting in inhibiting growth of Enza-resistant CRPC cells and sensitizing Enza-resistant CRPC cells to enzalutamide treatment both in vitro and in vivo. We also found that overexpression of PHGDH promoted cell growth and Enza resistance in CRPC cells. Furthermore, pharmacological inhibition of PHGDH by NCT-503 effectively inhibited cell growth, induced ferroptosis, and overcame enzalutamide resistance in Enza-resistant CRPC cells both in vitro and in vivo. Mechanically, NCT-503 triggered ferroptosis by decreasing GSH/GSSG levels and increasing LipROS production as well as suppressing SLC7A11 expression through activation of the p53 signaling pathway. Moreover, stimulating ferroptosis by ferroptosis inducers (FINs) or NCT-503 synergistically sensitized Enza-resistant CRPC cells to enzalutamide. The synergistic effects of NCT-503 and enzalutamide were verified in a xenograft nude mouse model. NCT-503 in combination with enzalutamide effectively restricted the growth of Enza-resistant CRPC xenografts in vivo. Overall, our study highlights the essential roles of increased PHGDH in mediating enzalutamide resistance in CRPC. Therefore, the combination of ferroptosis inducer and targeted inhibition of PHGDH could be a potential therapeutic strategy for overcoming enzalutamide resistance in CRPC.

The continuing discovery on the evidence for RNA editing in SARS-CoV-2.

Recent studies have presented strong evidence that C-to-U RNA editing is the driving force that fuels severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution. The findings finally ended the long-term debate on the evolutionary driving force behind SARS-CoV-2 evolution. Here, we would first acknowledge the breakthroughs made by the recent works, such as using the global SARS-CoV-2 data to demonstrate the major mutation source of this virus. Meanwhile, we would raise a few concerns on the accuracy of their interpretation on C-to-U RNA editing. By re-analysing the SARS-CoV-2 population data, we found that the editing frequency on C-to-U sites did not perfectly correlate with the binding motif of the editing enzyme APOBEC, suggesting that there might be false-positive sites among the C-to-U mutations or the original data did not fully represent the novel mutation rate. We hope our work could help people understand the molecular basis underlying SARS-CoV-2 mutation and also be useful to guide future studies on SARS-CoV-2 evolution.

RTKN2 Inhibits the Growth, Migration, Invasion and Glycolysis of Lung Adenocarcinoma Cells by Inactivating the NF-κB Signalling Pathway.

BACKGROUND: Lung adenocarcinoma (LUAD) is a malignant tumour that seriously threatens the life and health of people worldwide. This research was carried out to investigate the role of Rhotekin 2 (RTKN2) in LUAD progression. METHODS AND RESULTS: The GEPIA online database was used to analyse abnormally expressed genes in lung adenocarcinoma and RTKN2 expression in various cancers. Cell proliferation was detected with CCK-8 and colony formation assays. Transwell assays were carried out to assess cell migration and invasion. The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were evaluated by a Seahorse XFe96 analyser. The interaction between RTKN2 and p65 was confirmed using a coimmunoprecipitation assay. RTKN2 expression was detected with qPCR, immunohistochemistry, and western blot assays. The p65 levels in the cytoplasm and nucleus were determined by western blot assays. RTKN2 levels were prominently decreased in LUAD tissues and cell lines. RTKN2 overexpression suppressed LUAD cell growth, invasion, migration, and glycolysis, while RTKN2 knockdown showed the opposite effects. Additionally, p65 could be negatively regulated by RTKN2. RTKN2 overexpression increased p65 levels in the cytoplasm but decreased p65 levels in the nucleus. Furthermore, blocking the NF-κB signalling pathway neutralized the effect of RTKN2 silencing in LUAD cells. CONCLUSION: RTKN2 inhibited the malignant behaviour and glycolysis of LUAD cells by blocking the NF-κB signalling pathway, implying that RTKN2 could be a cancer suppressor in LUAD progression.