Nomograms Predict PFS and OS for SCLC Patients After Standardized Treatment: A Real-World Study.

Purpose: This study aims to investigate the process of small cell lung cancer (SCLC) patients from achieving optimal efficacy to experiencing disease progression until death. It examines the predictive value of the treatment response on progression free survival (PFS) and overall survival (OS) of SCLC patients. Patients and Methods: We conducted a retrospective analysis on 136 SCLC patients diagnosed from 1992 to 2018. Important prognostic factors were identified to construct nomogram models. The predictive performance of the models was evaluated using the receiver operating characteristic curves and calibration curves. Survival differences between groups were compared using Kaplan-Meier survival curves. Subsequently, an independent cohort consisting of 106 SCLC patients diagnosed from 2014 to 2021 was used for validation. Results: We constructed two nomograms to predict first-line PFS (PFS1) and OS of SCLC. The area under the receiver operating characteristic curves for the PFS1 nomogram predicting PFS at 3-, 6-, and 12-months were 0.919 (95% CI: 0.867-0.970), 0.908 (95% CI: 0.860-0.956) and 0.878 (95% CI: 0.798-0.958), and for the OS nomogram predicting OS at 6-, 12-, and 24-months were 0.814 (95% CI: 0.736-0.892), 0.819 (95% CI: 0.749-0.889) and 0.809 (95% CI: 0.678-0.941), indicating those two models with a high discriminative ability. The calibration curves demonstrated the models had a high degree of consistency between predicted and observed values. According to the risk scores, patients were divided into high-risk and low-risk groups, showing a significant difference in survival rate. And these findings were validated in another independent validation cohort. Conclusion: Based on the patients' treatment response after standardized treatment, we developed and validated two nomogram models to predict PFS1 and OS of SCLC. The models demonstrated good accuracy, reliability and clinical applicability by validating in an independent cohort.

Prognostic impact of spread through air spaces in patients with ≤2 cm stage IA lung adenocarcinoma.

Background: In 2015, the World Health Organization (WHO) included spread through air space (STAS) as a new invasive mode of lung cancer. As a new mode of lung cancer dissemination, STAS has a significant and negative impact on patient prognosis. The surgical approach as well as lymph node dissection (LND) for STAS-positive patients is currently unclear. The aim of this study was to investigate the impact of different surgical approaches to STAS and LND on the prognosis of patients with ≤2 cm stage IA lung adenocarcinoma (LUAD). This study also investigated the possible relationship between STAS and the micropapillary histological subtype and its impact on patient prognosis. Methods: A total of 212 patients with LUAD were included in this study from January 2016 to December 2017, and the overall survival (OS) of the patients was compared. The chi-square test and t-test were applied to compare the clinicopathological data of the patients, and the Cox model was used for the multivariate survival analysis. Results: Of the 212 patients, 93 (43.9%) were STAS positive. The univariate analysis showed that the surgical approach, LND type, micropapillary pattern (MP), solid pattern, and STAS were risk factors for OS. The multivariate analysis showed that the surgical approach, MP, and STAS were risk factors for OS. The STAS-positive patients who underwent lobectomy had a better prognosis than those who underwent sublobar resection; however, there was no significant difference between the two surgical procedures in the STAS-negative group. Additionally, the STAS-positive patients who underwent systematic lymph node dissection (SLND) had a better prognosis than those who underwent limited lymph node dissection (LLND); however, there was no significant difference between the two LNDs in the STAS-negative group. Conclusions: STAS plays an important role in patient prognosis and is an independent risk factor for OS of patients with ≤2 cm stage IA LUAD. When STAS is positive, the choice of lobectomy with SLND may result in a better long-term prognosis for patients.

First Report of Strawberry Root Rot Caused by Fusarium falciforme in China.

Root rot caused by Fusarium spp. is a destructive disease affecting agricultural regions worldwide. Strawberries (Fragaria × ananassa Duch.) are an economically important crop in China. In March 2023, root rot was observed in strawberries grown in Jinan, Shandong Province, China. Symptoms included leaf wilt, necrotic roots, and plant death (Figure 1). Four strawberry samples (two symptomatic and two asymptomatic) were collected from ~2-acre fields where the disease incidence rate ranged from 2 to 3%. Tissue pieces (5 mm × 5 mm × 5 mm) from two healthy and two diseased strawberry root tissues were surface-disinfected with 75% ethanol for 3 min, treated with 10% sodium hypochlorite for 5 min, and washed three times with sterile water. These pieces were cultured for 5 days at 28°C on potato dextrose agar (PDA) containing 200 mg/L timentin. Typical Fusarium spp. like growth was observed on plates with the two symptomatic samples. Two representative fungal isolates (CM1 and CM2) with similar morphological characteristics were purified using the single-spore method (Figure 1). CM1 showed an average growth rate of 5 mm/d in PDA and comprised of several white-to-cream aerial mycelia after 5 d. After cultivation in carnation leaf agar medium for 7 d, falciform macroconidia, with blunt apical cells and slightly hooked basal cells comprising 3 to 4 septa of varying sizes (20 to 39)×(3.6 to 6.7 µm) were observed (n=50) (Figure 1). The chlamydospores were spherical, terminal or intercalary, solitary or chain-forming, and 3.1-10.5 µm in diameter (Figure 1). The microconidia on PDA were (5.8 to 13.6)× (2.5 to 3.3) µm in size (n=50). These morphological characteristics are consistent with previous descriptions of the Fusarium solani species complex (FSSC). DNA was extracted using the CTAB method (Stenglein and Balatti 2006). The internal transcribed spacer (ITS), translation elongation factor 1-α gene (tef1), RNA polymerase II largest subunit (rpb1), and RNA polymerase II second largest subunit (rpb2) were amplified and sequenced using specific primers (O'Donnell et al. 2010). The ITS (OR526528, OR526529), tef1 (OR536947, OR536948), rpb1 (OR536949, OR536950), and rpb2 (OR536951, OR536952) sequences of the CM1 and CM2 isolates were uploaded to the NCBI database. BLASTn analysis revealed that the ITS, tef1, rpb1, and rpb2 sequences were 99.1-100% identical to those of the Fusarium falciforme reference strains NRRL 54989 and NRRL 54978. A phylogenetic tree based on the ITS, tef1, rpb1, and rpb2 sequences was generated using MEGA v.11 via the maximum-likelihood method (Tamura et al. 2021). CM1 clustered with the Fusarium falciforme reference strains NRRL 54989 and NRRL 54978 and belonged to the FSSC based on its morphological and molecular characteristics (Figure 2). To test for pathogenicity, the roots of nine 3-month-old healthy strawberry (cv. Akihime) plants were exposed to conidial suspensions (1×108 spores/mL) of the CM1 isolate. Another nine root samples were treated with sterile water and used as controls. All strawberry plants were maintained in a growth chamber under a 12/12 h light/dark cycle at 28°C and 90% relative humidity and the experiment was repeated three times. After one month, the inoculated plants had withered and died, and the pith became dark red (similar to field plants) (Figure 1). The fungi isolated from the experimental plants were confirmed as F. falciforme using morphological and sequence analyses. F. falciforme causes root rot in several species including Nicotiana tabacum (Qiu et al. 2023) and Weigela florida (Shen et al. 2020); however, this study is the first to report root rot caused by F. falciforme in strawberries in China. Overall, F. falciforme infection poses a threat to strawberry production and breeding.

Lifestyle and genetic predisposition are associated with incident irritable bowel syndrome: A population-based prospective cohort study.

Few prospective studies have investigated the joint effect of lifestyle factors and genetic susceptibility on the risk of irritable bowel syndrome (IBS). This study aims to evaluate the associations of lifestyle and genetic factors with incident IBS in the UK Biobank. We analyzed data from 481,057 participants (54% female) without prevalent IBS at enrollment in the UK Biobank. An overall healthy lifestyle was defined using six modifiable lifestyle factors, including smoking, body mass index (BMI), sleep duration, diet, physical activity, and alcohol consumption, and hence categorized into 'favorable', 'intermediate', and 'unfavorable' lifestyles. A Cox proportional hazard model was used to investigate the association between a healthy lifestyle and incident IBS. Furthermore, we constructed a polygenic risk score (PRS) for IBS and assessed whether lifestyle modified the effect of genetics on the development of IBS. During a median follow-up of 12.1 years, 8645 incident IBS were ascertained. Specifically, among the six modifiable lifestyle factors, adequate sleep demonstrates the greatest protective effect (hazard ratio [HR]: 0.72, 95% CI: 0.69,0.75) against IBS. Compared with a favorable lifestyle, an unfavorable lifestyle was associated with a 56% (95% CI: 46%-67%) increased risk of IBS (P = 8.99 × 10-40). The risk of incident IBS was 12% (95% CI: 4%-21%) higher among those at high genetic risk compared with those at low genetic risk (P = 0.005). When considering the joint effect of lifestyle and genetic susceptibility, the HR nearly doubled among individuals with high genetic risk and unfavorable lifestyle (HR: 1.80; 95% CI:1.51-2.15; P = 3.50 × 10-11) compared to those with low genetic risk and favorable lifestyle. No multiplicative or addictive interaction was observed between lifestyle and genetics. The findings from this study indicated that lifestyle and genetic factors were independently associated with the risk of incident IBS. All these results implicated a possible clinical strategy of lowering the incidence of IBS by advocating a healthy lifestyle.

Drug-target Mendelian randomization revealed a significant association of genetically proxied metformin effects with increased prostate cancer risk.

The association between metformin use and risk of prostate cancer remains controversial, while data from randomized trials is lacking. We aim to evaluate the association of genetically proxied metformin effects with prostate cancer risk using a drug-target Mendelian randomization (MR) approach. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium (79,148 cases and 61,106 controls). Cis-expression quantitative trait loci (cis-eQTL) variants in the gene targets of metformin were identified in the GTEx project and eQTLGen consortium. We also obtained male-specific genome-wide association study data for type 2 diabetes, body mass index (BMI), total testosterone, bioavailable testosterone, estradiol, and sex hormone binding globulin for mediation analysis. Inverse-variance weighted (IVW) regression, weighted median, MR-Egger regression, and MR-PRESSO were performed in the main MR analysis. Multivariable MR was used to identify potential mediators and genetic colocalization analysis was performed to assess any shared genetic basis between two traits of interest. We found that genetically proxied metformin effects (1-SD HbA1c reduction, equivalent to 6.75 mmol/mol) were associated with higher risk of prostate cancer (odds ratioIVW [ORIVW]: 1.55, 95% confidence interval, CI: 1.23-1.96, p = 3.0 × 10-3). Two metformin targets, mitochondrial complex I (ORIVW: 1.48, 95% CI: 1.07-2.03, p = 0.016) and gamma-secretase complex (ORIVW: 2.58, 95%CI :1.47-4.55, p = 0.001), showed robust associations with prostate cancer risk, and their effects were partly mediated through BMI (16.4%) and total testosterone levels (34.3%), respectively. These results were further supported by colocalization analysis that expressions of NDUFA13 and BMI, APH1A, and total testosterone may be influenced by shared genetic factors, respectively. In summary, our study indicated that genetically proxied metformin effects may be associated with an increased risk of prostate cancer. Repurposing metformin for prostate cancer prevention in general populations is not supported by our findings.

Steric and energetic studies on the influence of cellulose on the adsorption effectiveness of Mg trapped hydroxyapatite for enhanced remediation of chlorpyrifos and omethoate pesticides.

Magnesium-trapped hydroxyapatite (Mg.HP) was hybridized with cellulose fiber to produce a bio-composite (CLF/HP) with enhanced adsorption affinities for two types of toxic pesticides (chlorpyrifos (CF) and omethoate (OM)). The enhancement influence of the hybridized cellulose on the adsorption performances of Mg.HP was illustrated based on the determined steric and energetic factors. The computed CF and OM adsorption performances of CLF/HP during the saturation phases are 279.8 mg/g and 317.9 mg/g, respectively, which are significantly higher than the determined values using Mg/HP (143.4 mg/g (CF) and 145.3 mg/g (OM)). The steric analysis demonstrates a strong impact of the hybridization process on the reactivity of the surface of the composite. While CLF/HP reflects effective uptake site densities (Nm) of 93.3 mg/g (CF) and 135.3 mg/g (OM), the estimated values for Mg.HP are 51.2 mg/g (CF) and 46.11 mg/g (OM), which explain the reported enhancement in the adsorption performances of the composite. The capacity of each uptake site to be occupied with more than one molecule (n (CF) = 3-3.74 and n (OM) = 2.35-3.54) suggests multimolecular uptake. The energetic factors suggested physical mechanistic processes of spontaneous and exothermic behaviors either during the uptake of CF or OM.

[Effect of Preserving the Pulmonary Branch of Vagus Nerve on Postoperative Cough 
in Patients with Stage I Peripheral Lung Adenocarcinoma].

BACKGROUND: Cough is one of the main complications after pulmonary surgery, which seriously affects the postoperative quality of life. Preserving the pulmonary branch of vagus nerve may reduce the incidence of postoperative cough. Therefore, the aim of this study was to investigate whether preserving the pulmonary branch of the vagus nerve could reduce the incidence of postoperative chronic cough in patients with stage I peripheral lung adenocarcinoma. METHODS: A total of 125 patients who underwent single-port thoracoscopic radical resection for lung cancer in the Department of Thoracic Surgery, The First Affiliated Hospital of University of Science and Technology of China from June 2022 to June 2023 were retrospectively selected, and divided into two groups according to whether the vagopulmonary branch was preserved during the operation, namely, the vagopulmonary branch group (n=61) and the traditional group (n=64). The general clinical data, perioperative conditions, lymph node dissection, Mandarin Chinese version of The Leicester Cough Questionnaire (LCQ-MC) scores before and 8 weeks after operation were recorded in the two groups. Both the two groups were divided into tamponade group and non-tamponade group according to whether autologous fat or gelatin sponge was tamponade after lymph node dissection. LCQ-MC scores and postoperative chronic cough of both groups were calculated. RESULTS: The LCQ-MC score of the traditional group was significantly lower than that of the vagopulmonary branch group in physiological, psychological, social and total scores at 8 weeks after surgery, and the difference was statistically significant (P<0.05). There were more cough patients in the traditional group than the vagopulmonary branch group at 8 weeks after surgery, with significant difference (P=0.006). Subgroup analysis was conducted separately for the vagopulmonary branch group and the traditional group. Among the patients in the vagopulmonary branch group and the traditional group, the LCQ-MC scores of the non-tamponade group 8 weeks after surgery were lower than those of the tamponade group (P<0.05). There were more patients with cough in the group 8 weeks after surgery than in the tamponade group (P=0.001, P=0.024). CONCLUSIONS: For patients with stage I peripheral lung adenocarcinoma, the preservation of the pulmonary branch of vagus nerve is safe and effective, which can reduce the incidence of postoperative chronic cough and improve the postoperative quality of life of the patients.

Association between famine exposure during infancy and childhood and the risk of chronic kidney disease in adulthood.

BACKGROUND: Famine exposure in childhood is proven to be associated with multiple chornic disease in adult but has not been studied with chronic kidney disease (CKD). AIMS: This study was conducted to identify the relationship between famine exposure during infancy and childhood - specifically, the Chinese famine of 1959-1961 - and the risk of adult-onset chronic kidney disease (CKD) among Chinese individuals. METHODS: This study included 2937 individuals from the Qingdao Diabetes Prevention Program. They were stratified by birth year into infancy-exposed (1956-1958), childhood-exposed (1950-1955) and unexposed (1963-1971) groups. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. CKD was defined as an eGFR of <90 mL/min/1.73 m2 . RESULTS: The mean eGFR values for the infancy-exposed and childhood-exposed groups were 107.23 ± 12.53 and 103.23 ± 12.44 mL/min/1.73 m2 , respectively, both of which were lower than that of the unexposed group (114.82 ± 13.39 mL/min/1.73 m2 ; P < 0.05). In the crude model, the odds ratio (OR) for CKD was 2.00 (95% confidence interval (CI): 1.39-2.88) in the infancy-exposed group and 2.92 (95% CI: 2.17-3.93) in the childhood-exposed group. Further adjustments for urban/rural residence, body mass index, age, current smoking, type 2 diabetes, systolic blood pressure, diastolic blood pressure and total cholesterol did not significantly alter the association between famine exposure and CKD. The corresponding ORs were 1.71 (95% CI: 1.17-2.50) and 2.48 (95% CI: 1.81-3.40) for the infancy-exposed and childhood-exposed groups respectively. CONCLUSIONS: Famine exposure during infancy and childhood is associated with a long-term decline in eGFR and an increased adult-onset CKD risk. Early intervention for high-risk individuals may mitigate the risk of adult-onset CKD.

Targeting Large-Conductance Calcium-Activated Potassium Channels to Ameliorate Lipopolysaccharide-Induced Depressive-Like Behavior in Mice.

Neuroinflammation plays crucial role in the development and progression of depression. Large conductance calcium- and voltage-dependent potassium (BK) channels mediate the activation of microglia. Herein, we investigated whether BK channels could serve as a target for the treatment of inflammation-associated depression. Lipopolysaccharide (LPS, 0.83 mg/kg) was injected intraperitoneally (i.p.) to induce neuroinflammation and depressive-like behavior in 6-8 week ICR mice. Adeno-associated virus (AAV) constructs (AAV9-Iba1p-BK shRNA-EGFP (BK shRNA-AAV) or AAV9-Iba1p-NC shRNA-EGFP (NC shRNA-AAV)) were unilaterally injected intracerebroventricularly to selectively knock down BK channels in microglia. The tail suspension test (TST) and forced-swim test (FST) were used to evaluate depressive-like behavior in mice 24 h after LPS challenge. The morphology of microglia, expression of BK channels, levels of cytokines, and expression and activity of indoleamine 2,3-dioxygenase (IDO) were measured by immunohistochemistry, western blot, quantitative real time PCR, and enzyme-linked immunosorbent assay (ELISA), respectively. Either paxilline (i.p.), a specific BK channel blocker, or BK shRNA-AAV effectively inhibited the activation of microglia, reduced the production of IL-1ß in the hippocampus and suppressed the expression and activity of IDO in the hippocampus and prefrontal cortex, resulting in the amelioration of depressive-like behavior in mice. These data suggest for the first time that BK channels are involved in LPS-induced depressive-like behaviors. Thus, microglia BK channels may be a potential drug target for the depression treatment.

Discovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53.

Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation.

A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study.

BACKGROUND: Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. FINDINGS: We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated. CONCLUSIONS: The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

NRF2 promotes radiation resistance by cooperating with TOPBP1 to activate the ATR-CHK1 signaling pathway.

Background: Radiation resistance is the main limitation of the application of radiotherapy. Ionizing radiation (IR) kills cancer cells mainly by causing DNA damage, particularly double-strand breaks (DSBs). Radioresistant cancer cells have developed the robust capability of DNA damage repair to survive IR. Nuclear factor erythroid 2-related factor 2 (NRF2) has been correlated with radiation resistance. We previously reported a novel function of NRF2 as an ATR activator in response to DSBs. However, little is known about the mechanism that how NRF2 regulates DNA damage repair and radiation resistance. Methods: The TCGA database and tissue microarray were used to analyze the correlation between NRF2 and the prognosis of lung cancer patients. The radioresistant lung cancer cells were constructed, and the role of NRF2 in radiation resistance was explored by in vivo and in vitro experiments. Immunoprecipitation, immunofluorescence and extraction of chromatin fractions were used to explore the underlying mechanisms. Results: In this study, the TCGA database and clinical lung cancer samples showed that high expression of NRF2 was associated with poor prognosis in lung cancer patients. We established radioresistant lung cancer cells expressing NRF2 at high levels, which showed increased antioxidant and DNA repair abilities. In addition, we found that NRF2 can be involved in the DNA damage response independently of its antioxidant function. Mechanistically, we demonstrated that NRF2 promoted the phosphorylation of replication protein A 32 (RPA32), and DNA topoisomerase 2-binding protein 1 (TOPBP1) was recruited to DSB sites in an NRF2-dependent manner. Conclusion: This study explored the novel role of NRF2 in promoting radiation resistance by cooperating with RPA32 and TOPBP1 to activate the ATR-CHK1 signaling pathway. In addition, the findings of this study not only provide novel insights into the molecular mechanisms underlying the radiation resistance of lung cancer cells but also validate NRF2 as a potential target for radiotherapy.

ß-eudesmol inhibits cell proliferation and induces ferroptosis via regulating MAPK signaling pathway in breast cancer.

The aim of this study was to explore the influences and underlying mechanisms of ß-eudesmol on breast cancer (BC). Different concentrations of ß-eudesmol (0, 10, 20, and 40 µM) were taken to treat BC cells. Cell Counting Kit-8, colony formation assay, and flow cytometry were performed to evaluate the influences of ß-eudesmol on cell viability, proliferation, and apoptosis. To assess the influences of ß-eudesmol on cell ferroptosis, the change of ROS, SOD, MDA, and intracellular iron and Fe2+ were determined. The protein changes of apoptosis, ferroptosis, and MAPK pathway (Bcl-2, Bax, cleaved caspase-3, SLC7A11, GPX4, SLC40A1, Transferrin, MEK1, and ERK1/2) were checked utilizing Western blot. In a concentration-dependent manner, ß-eudesmol restrained cell viability and proliferation. ß-eudesmol promoted cell apoptosis, as evidenced by the decline level of Bcl-2 and the raised level of Bax and cleaved caspase-3. ß-eudesmol enhanced the level of ROS, MDA, iron, Fe2+, and Transferrin, and lessened SOD activity and the protein expression of SLC7A11, GPX4, SLC40A1, MEK1, and ERK1/2. Moreover, ferroptosis inhibitor Fer-1 and MEK1 overexpression both reversed the changes on cell proliferation, apoptosis, and ferroptosis induced by ß-eudesmol. ß-eudesmol inhibited cell proliferation and promoted cell apoptosis and ferroptosis via regulating MAPK pathway in BC.

The impact of outpatient versus inpatient management on health-related quality of life outcomes for patients with malignant pleural effusion: the OPTIMUM randomised clinical trial.

BACKGROUND: The principal aim of malignant pleural effusion (MPE) management is to improve health-related quality of life (HRQoL) and symptoms. METHODS: In this open-label randomised controlled trial, patients with symptomatic MPE were randomly assigned to either indwelling pleural catheter (IPC) insertion with the option of talc pleurodesis or chest drain and talc pleurodesis. The primary end-point was global health status, measured with the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) at 30 days post-intervention. 142 participants were enrolled from July 2015 to December 2019. RESULTS: Of participants randomly assigned to the IPC (n=70) and chest drain (n=72) groups, primary outcome data were available in 58 and 56 patients, respectively. Global health status improved in both groups at day 30 compared with baseline: IPC (mean difference 13.11; p=0.001) and chest drain (mean difference 10.11; p=0.001). However, there was no significant between-group difference at day 30 (mean intergroup difference in baseline-adjusted global health status 2.06, 95% CI -5.86-9.99; p=0.61), day 60 or day 90. No significant differences were identified between groups in breathlessness and chest pain scores. All chest drain arm patients were admitted (median length of stay 4 days); seven patients in the IPC arm required intervention-related hospitalisation. CONCLUSIONS: While HRQoL significantly improved in both groups, there were no differences in patient-reported global health status at 30 days. The outpatient pathway using an IPC was not superior to inpatient treatment with a chest drain.

Circulating levels of cytokines and risk of inflammatory bowel disease: evidence from genetic data.

Background: Prior epidemiological studies have established a correlation between inflammatory cytokines and inflammatory bowel disease (IBD). However, the nature of this relationship remains uncertain. Mendelian randomization (MR) study has the advantages of avoiding confounding and reverse causality compared with traditional observational research. Objective: We aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of IBD by using the MR approach. Materials and methods: We selected genetic variants associated with circulating levels of 28 cytokines at the genome-wide significance level from a genome-wide association study (GWAS) including 8,293 individuals. Summary-level data for IBD (including Crohn's disease and ulcerative colitis) were obtained from the International Inflammatory Bowel Disease Genetics Consortium and UK Biobank. We performed the primary analysis using the inverse-variance weighted method, as well as sensitivity analyses to test the stability of our results. We subsequently replicated the results of IBD in the UK Biobank dataset. A reverse MR analysis was also conducted to evaluate the possibility of reverse causation. Results: Genetically predicted elevated levels of interleukin-17 (IL-17) and monokine induced by interferon-gamma (MIG) were associated with an increased risk of IBD[odds ratio (OR): 1.52, 95% confidence interval (CI):1.10-2.08, P =0.010 for IL-17 and OR: 1.58, 95% CI: 1.24-2.00, P = 1.60×10-4 for MIG]. Moreover, we observed suggestive associations between ß-NGF and MIP-1ß with the risk of Crohn's disease (OR: 0.71, 95% CI: 0.52-0.98, P = 0.039) and ulcerative colitis (OR: 1.08, 95% CI: 1.01-1.15, P= 0.019). In the reverse MR study, there was no evidence of causal effects of IBD and these cytokines. Conclusion: Our study suggests the potential causal associations of IL-17 and MIG with IBD. Further studies are needed to determine whether IL-17 and MIG or their downstream effectors could be useful in the management of IBD.

Prevalence and risk factors of emergence agitation among pediatric patients undergo ophthalmic and ENT Surgery: a cross-sectional study.

BACKGROUND: Some studies reported that pediatric patients undergoing otorhinolaryngology (ENT) and ophthalmic surgeries have higher incidences of emergence agitation (EA). Children with EA tend to carry the risk of self-harm, have longer periods of recovery and delayed hospital discharge. Consequently, EA needs to be monitored and risk factors ought to be emphasized to implement preventative measures. The objective of this study was to describe EA and to identify risk factors after pediatric ophthalmic or ENT surgery. METHODS: Between September 2021 and December 2021, a cross-sectional study was conducted in 100 children aged of 0-12 years who underwent ophthalmic or ENT surgery. The Watcha scale was used to observe and record EA, which was defined at levels of 3 or 4 at any time in the post-anesthesia care unit (PACU). The pain intensity was graded with the Face, Legs, Activity, Cry, Consolability (FLACC) Scale after surgery. Patient and surgery-related characteristics, the behavioral criteria of EA, the pharmacologic and non-pharmacologic interventions and recovery outcomes were objectively recorded. A binary logistic regression model was constructed to identify the associated factors of EA. RESULTS: From the 100 analyzed children, 58 were males and 42 were females, and 44 patients received ophthalmic surgery and 56 ENT surgery. The median age was 6 (IQR 4-7) years. The overall incidence of EA among pediatrics was 30% (34.5% for ENT and 24.4% for ophthalmic surgery). High preoperative modified Yale Preoperative Anxiety scale (m-YPAS) grade (OR = 1.19, 95%CI 1.06-1.33, P = 0.003) and high postoperative FLACC score (OR = 3.36, 95%CI 1.88-6.02, P < 0.001) were risk factors for EA. CONCLUSIONS: This study identified that preoperative anxiety and postoperative pain are associated with EA in children after ophthalmic or ENT surgery. Preoperative anxiety assessment and management, and administration of adjunct analgesic treatments should be considered in the routine care.

MtDNA Copy Number in Oral Epithelial Cells Serves as a Potential Biomarker of Mitochondrial Damage by Neonicotinoid Exposure: A Cross-Sectional Study.

As the mitochondrial DNA copy number (mtDNAcn) has been reported to be a biomarker for mtDNA damage in honeybees when exposed to sublethal neonicotinoids, the feasibility of using human mitochondria as a predictor upon neonicotinoid exposure remains elusive. This study investigated the association between the urinary neonicotinoid and the relative mtDNAcn (RmtDNAcn) of oral epithelial cells collected in a cross-sectional study with repeated measurements over 6 weeks. The molecular mechanism underlying neonicotinoid-caused mitochondrial damage was also examined by in vitro assay. Herein, the average integrated urinary neonicotinoid (IMIRPF) concentration ranged from 8.01 to 13.70 µg/L (specific gravity-adjusted) during the sampling period. Concomitantly, with an increase in the urinary IMIRPF, the RmtDNAcn significantly increased from 1.20 (low group) to 1.93 (high group), indicating potential dose-dependent mitochondrial damage. Furthermore, the linear regression analysis confirmed the significant correlation between the IMIRPF and RmtDNAcn. Results from in vitro assays demonstrated that neonicotinoid exposure led to the inhibition of the genes encoding mitochondrial oxidative phosphorylation (OXPHOS) complexes I and III (e.g., ND2, ND6, CytB, and CYC1), accompanied by increased reactive oxygen species production in SH-SY5Y cells. Conjointly, neonicotinoid exposure led to mitochondrial dysfunction and a resulting increase in the RmtDNAcn, which may serve as a plausible biomarker in humans.

Escin avoids hemorrhagic transformation in ischemic stroke by protecting BBB through the AMPK/Cav-1/MMP-9 pathway.

BACKGROUND: Hemorrhagic transformation (HT) seriously affects the clinical application of recombinant tissue plasminogen activator (rt-PA). The main strategy for combating HT is to keep the blood-brain barrier (BBB) stable. Escin is the active ingredient of Aesculus hippocastanum and a natural mixture of triterpene saponins, and may play a part in mitigation of HT. PURPOSE: This study sought to investigate the effect of Escin in improving rt-PA-induced HT, explore possible mechanisms, and provide new ideas for the treatment of clinical HT. STUDY DESIGN AND METHODS: In in vivo experiments, transient middle cerebral artery occlusion (tMCAO) was undertaken in 6-week-old and 12-month-old mice, and rt-PA was administered to induce HT injury. The inhibitory effect of Escin on HT and its protective effect on neurobehavior, the BBB, and cerebrovascular endothelial cells was determined. In in vitro experiments, bEnd.3 cells were injured by oxygen-glucose deprivation/reperfusion (OGD/R) and rt-PA. The protective effect of Escin was measured by the CCK8 assay, release of lactate dehydrogenase (LDH), and expression of tight junction (TJ) proteins. In mechanistic studies, the effect of Escin on the adenosine monophosphate-activated kinase / caveolin-1 / matrix metalloprotease-9 (AMPK/Cav-1/MMP-9) pathway was investigated by employing AMPK inhibitor and Cav-1 siRNA. RESULTS: In mice suffering from ischemia, rt-PA caused HT as well as damage to the BBB and cerebrovascular endothelial cells. Escin reduced the infarct volume, cerebral hemorrhage, improved neurobehavioral deficits, and maintained BBB integrity in rt-PA-treated tMCAO mice while attenuating bEnd.3 cells damage caused by rt-PA and OGD/R injury. Under physiological and pathological conditions, Escin increased the expression of p-AMPK and Cav-1, leading to decreased expression of MMP-9, which further attenuated damage to cerebrovascular endothelial cells, and these effects were verified with AMPK inhibitor and Cav-1 siRNA. CONCLUSION: We revealed important details of how Escin protects cerebrovascular endothelial cells from HT, these effects were associated with the AMPK/Cav-1/MMP-9 pathway. This study provides experimental foundation for the development of new drugs to mitigate rt-PA-induced HT and the discovery of new clinical application for Escin.

Ethyl Acetate Fraction from Hedyotis Diffusa Plus Scutellaria Barbata Inhibits the Progression of Breast Cancer via Targeting LMO1 and AKT/Mtor Signaling Pathway

BACKGROUND: Traditional Chinese medicines are widely used in cancer treatment. Scutellaria barbata and Hedyotis diffusa herb pair (SH) has an anticancer effects in various tumors. However, the specific mechanism of SH in breast cancer remains unclear. METHODS: In the present research, we investigated the effect and regulatory network of SH in in breast cancer. CCK8, colony formation, transwell, wound healing and flow cytometry analysis were used for the detection of cell function. RESULTS: Ethyl acetate fraction from SH at an equal weight ratio (EA11) could inhibit the proliferation, migration and invasion of MCF7 and MDA-MB-231 cells. It also induced apoptosis in these two cell lines by downregulating Bcl2 and upregulating Bax and Cleaved-Caspase3. SH reduced the activation of the AKT/mTOR signaling pathway and the expression of p70S6K. Sequencing results showed that LMO1 was significantly downregulated in SH-treated cells compared with control cells. Importantly, overexpression of LMO1 attenuated the inhibitory effect of SH on cell proliferation and invasion and induced inflammatory tumor microenvironment. CONCLUSION: In conclusion, the SH herb pair inhibited the proliferation and metastasis through downregulating LMO1 expression and reducing the activation of the AKT/mTOR signaling pathway. LMO1 has the potential as a new target in the treatment of breast cancer.

Subsecond periodic radio oscillations in a microquasar.

Powerful relativistic jets are one of the ubiquitous features of accreting black holes in all scales1-3. GRS 1915 + 105 is a well-known fast-spinning black-hole X-ray binary4 with a relativistic jet, termed a 'microquasar', as indicated by its superluminal motion of radio emission5,6. It has exhibited persistent X-ray activity over the last 30 years, with quasiperiodic oscillations of approximately 1-10 Hz (refs. 7-9) and 34 and 67 Hz in the X-ray band10. These oscillations probably originate in the inner accretion disk, but other origins have been considered11. Radio observations found variable light curves with quasiperiodic flares or oscillations with periods of approximately 20-50 min (refs. 12-14). Here we report two instances of approximately 5-Hz transient periodic oscillation features from the source detected in the 1.05- to 1.45-GHz radio band that occurred in January 2021 and June 2022. Circular polarization was also observed during the oscillation phase.