Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial.

BACKGROUND: Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a programmed cell death protein 1 monoclonal antibody) has shown potential clinical activity for locally advanced rectal cancer (LARC) in a phase II trial. This study aimed to further confirm the efficacy and safety of SCRT followed by CAPOX and camrelizumab compared to long-course chemoradiotherapy (LCRT) followed by CAPOX alone as neoadjuvant treatment for LARC. PATIENTS AND METHODS: In this randomized, phase III trial, patients with T3-4/N+ rectal adenocarcinoma were randomly assigned (1 : 1) to receive SCRT or long-course chemoradiotherapy (LCRT), followed by two cycles of camrelizumab and CAPOX or CAPOX alone, respectively. After surgery, each arm underwent either six cycles of camrelizumab and CAPOX, followed by up to 17 doses of camrelizumab, or six cycles of CAPOX. The primary endpoint was pathological complete response (pCR) rate (ypT0N0) assessed by a blinded independent review committee. Key secondary endpoints tested hierarchically were 3-year event-free survival (EFS) rate and overall survival (OS). RESULTS: Between July 2021 and March 2023, the intention-to-treat population comprised 113 patients in the experimental arm and 118 patients in the control arm, with surgery carried out in 92% and 83.9%, respectively. At data cut-off (11 July 2023), the pCR rates were 39.8% [95% confidence interval (CI) 30.7% to 49.5%] in the experimental arm compared to 15.3% (95% CI 9.3% to 23.0%) in the control arm (difference, 24.6%; odds ratio, 3.7; 95% CI 2.0-6.9; P < 0.001). In each arm, surgical complication rates were 40.0% and 40.8%, and grade ≥3 treatment-related adverse events were 29.2% and 27.2%. Three-year EFS rate and OS continue to mature. CONCLUSIONS: In LARC patients, neoadjuvant SCRT followed by camrelizumab plus CAPOX demonstrated a significantly higher pCR rate than LCRT followed by CAPOX, with a well-tolerated safety profile. SCRT followed by camrelizumab and chemotherapy can be recommended as a neoadjuvant treatment modality for these patients.

Transcriptome analysis of long non-coding RNA associated with embryonic muscle development in chickens.

1. Skeletal muscle is an important component of chicken carcass. In chickens, the number of muscle fibres is fixed during the embryonic period, and muscle development during the embryonic period determines the muscle development potential after hatching.2. Beijing-You (BY) and Cornish (CN) chickens show completely different growth rates and body types, and two breeds were used in this study to explore the role of lncRNAs in muscle development during different chicken embryonic periods. A systematic analysis of lncRNAs and mRNAs were conducted in the pectoral muscle tissues of BY and CN chickens at embryonic days 11 (ED11), 13 (ED13), 15 (ED15), 17 (ED17), and 1-day-old (D1) using RNA-seq. A total of 4,104 differentially expressed transcripts (DETs) were identified among the five stages, including 2,359 lncRNAs and 1,745 mRNAs.3. The number of DETs between the two breeds at ED17 (1,658 lncRNAs and 1,016 mRNAs) was much higher than the total number of DET at all the other stages (692 lncRNAs and 729 mRNAs), indicating that the two breeds show the largest difference in gene regulation at ED17.4. Correlation analysis was performed for all differentially expressed lncRNAs and mRNAs during the five periods. Forty-three, cis interaction pairs of lncRNA-mRNA related to chicken muscle development were predicted. The expression of four pairs was verified, and the results showed MSTRG.12395.2-FGFBP2 and MSTRG.18590.6-FMOD were significantly up-regulated in CN at ED11 compared to BY and might be important candidate genes for embryonic muscle development.

[Constructing a cataplexy face prediction model for narcolepsy type 1 based on ResNet-18].

Objective: To establish a prediction model for the identifying of cataplexy facial features based on clinical shooting videos by using a deep learning image recognition network ResNet-18. Methods: A cross-sectional study. Twenty-five narcolepsy type 1 patients who were first diagnosed and never received treatment and 25 healthy controls recruited by advertisement in the Second Affiliated Hospital of Nanchang University from 2020 to 2023.After image preprocessing, a total of 1 180 images were obtained, including 583 cataplexy faces and 597 normal faces.90% were selected as the training set and validation set, and then expanded the data by 5 times.80% of the expanded data set was extracted as the training set and 20% as the validation set, that is, the number of the training set was (583+597)×0.9×0.8×5=4 248, the number of the validation set was (583+597)×0.9×0.2×5=1 062. The data sets for training and validation were used train parameters to establish the model and were trained through the five-fold cross-validation method, to establish the ResNet-18 cataplexy face recognition model via transfer learning.10% (118 images) of the original non-amplified images were extracted as the test set. The test set data did not participate in data enhancement and model training, and was only used to evaluate the final performance of the model. Finally, ResNet-18 was compared with VGG-16, ResNet-34 and Inception V3 deep learning models, and the receiver operating characteristic curve was used to evaluate the value of ResNet-18 image recognition network in cataplexy face recognition. Results: Among 25 patients with narcolepsy type 1, 15 were males and 10 were females, aged [M (Q1, Q3)] of 14.0(11.0, 20.5) years.Among 25 healthy controls, 14 were males and 11 were females, with a median age of 16.0(14.4, 23.0) years.The overall accuracy of ResNet-18 image recognition network in the test set was 90.9%, the sensitivity was 96.4% and the specificity was 85.2%. The area under the ROC curve was 0.99(95%CI:0.96-1.00). The ResNet-18 model parameter amount was 11.69 M, the floating point operation amount was 1 824.03 M, and the single image recognition time was 5.9 ms. Conclusions: The cataplexy face prediction model built based on the deep learning image recognition network ResNet-18 has a high accuracy in identifying cataplexy faces.

[Efficacy analysis of chemotherapy and endocrine therapy combined with targeted drugs after progression on cyclin-dependent kinase 4/6 inhibitor treatment in hormone receptor positive/human epidermal growth factor receptor 2-low metastatic breast cancer].

Objective: To evaluate the efficacy of chemotherapy and endocrine therapy combined with targeted drugs after progression on cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment in hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer. Methods: Patients with metastatic breast cancer diagnosed with HR positive/HER2 low expression at the Fifth Medical Center of PLA General Hospital from October 1, 2018 to September 30, 2023 were retrospectively included. All patients received sequential chemotherapy or sequential endocrine therapy combined with targeted drugs after progression on CDK4/6 inhibitor treatment.The median follow-up was 9 months, and the follow-up ended on October 31, 2023. The patients were divided into chemotherapy group (receiving sequential chemotherapy) and endocrine therapy group (receiving sequential endocrine therapy combined with targeted drugs), according to the treatment plan. Information on demographic data, clinical and pathological diagnosis, treatment regimen, and efficacy evaluation was collected. The basic conditions of patients who may affect the curative effect of different treatment schemes were preset as stratified subgroups, including age, progesterone receptor (PR) status, HER2 status, disease-free survival, number of previous endocrine therapy and chemotherapy, and visceral metastasis. The primary endpoint was progression-free survival (PFS), the secondary endpoints were objective response rate (ORR), clinical benefit rate(CBR) and PFS based on stratification factors. The survival curve was plotted by Kaplan-Meier method, the comparison of PFS between groups was performed by log-rank test, and the comparison of ORR and CBR between groups were performed by χ2 test. Results: A total of 188 patients were included, including 126 patients in the chemotherapy group [all females, aged 29-74 (51±10) years] and 62 patients in the endocrine therapy group [1 male and 61 female, aged 29-77 (51±12) years]. ORR of chemotherapy group was 23.0% (29/126), higher than that of endocrine treatment group [3.2% (2/62)] (P<0.001); The CBR of chemotherapy group and endocrine therapy group were 46.8% (59/126) and 33.9% (21/62), respectively, with no statistical significance (P=0.091). The median PFS of chemotherapy group and endocrine therapy group were 5.0 (95%CI: 4.3-5.7) and 4.0 (95%CI: 1.6-6.4) months, respectively, with no statistical significance (P=0.484). In the preset stratified subgroups, the median PFS of chemotherapy [6.0 (95%CI: 5.4-6.6) months] was longer than that of endocrine combined with targeted therapy [2.0 (95%CI: 1.8-2.2) months] (P<0.001) in PR negative patients; In patients who had progressed on over 2 previous endocrine treatments, the median PFS of chemotherapy [5.0 (95%CI: 3.8-6.2) months] was longer than that of endocrine combined with targeted therapy [2.0 (95%CI: 0.6-3.4) months] (P=0.045). Conclusions: After progression on treatment with CDK4/6 inhibitors for HR-positive/HER2-low expression metastatic breast cancer, both chemotherapy and endocrine therpy combined with targeted drugs are viable treatment options. However, for patients with PR negative or ≥2 lines of endocrine therapy previously, priority should be accorded to chemotherapy.

Effects of Bulleyaconitine A on Extracellular Matrix Secretion and Expression of Related Proteins in Acetaldehyde-Activated Hepatic Stellate Cells.

Activated hepatic stellate cells differentiate into myofibroblasts, which synthesize and secrete extracellular matrix (ECM) leading to liver fibrosis. It was previously demonstrated that bulleyaconitine A (BLA), an alkaloid from Aconitum bulleyanum, inhibits proliferation and promotes apoptosis of human hepatic Lieming Xu-2 (LX-2) cells. In this study, we analyzed the effect of BLA on the production of ECM and related proteins by LX-2 cells activated with acetaldehyde (AA). The cells were randomized into the control group, AA group (cells activated with 400 µM AA), and BLA+AA group (cells cultured in the presence of 400 µM AA and 18.75 µg/ml BLA). In the BLA+AA group, the contents of collagens I and III and the expression of α-smooth muscle actin and transforming growth factor-ß1 (TGF-ß1) were statistically significantly higher than in the control, but lower than in the AA group. Expression of MMP-1 in the BLA+AA group was also significantly higher than in the AA group, but lower than in the control. Expression of TIMP-1 in the BLA+AA group was significantly higher than in the control, but lower than in the AA group. Thus, BLA suppressed activation and proliferation of LX-2 cells by inhibiting TGF-ß1 signaling pathway and decreasing the content of collagens I and III by reducing the MMP-1/TIMP-1 ratio.

[Diagnosis and differential diagnosis of large B-cell lymphoma with IRF4 rearrangement].

Objective: To analyze the clinicopathological features and differential diagnosis of large B-cell lymphoma with IRF4 rearrangement, aiming enhance its recognition and prevent misdiagnosis. Methods: The clinicopathological features, immunophenotype, and fluorescence in situ hybridization (FISH) results of six cases diagnosed with IRF4 rearrangement-positive B-cell lymphoma at the Affiliated Hospital of Xuzhou Medical University from 2015 to 2023 were retrospectively analyzed. Additionally, a comprehensive review of the literature was conducted. Results: Six patients with IRF4 rearrangement-positive large B-cell lymphoma were included. Patients 1 to 5 included three males and two females with a median age of 19 years ranging from 11 to 34 years. Four patients presented with head and neck lesions, while the other one had a breast nodule; all were in clinical Ann Arbor stages I to Ⅱ. Morphologically, entirely diffuse pattern was present in two cases, purely follicular pattern in one case, and diffuse and follicular patterns in other two cases. The tumor cells, predominantly centroblasts mixed with some irregular centrocytes, were of medium to large size, with a starry sky appearance observed in two cases. Immunophenotyping revealed all cases were positive for bcl-6 and MUM1, with a Ki-67 index ranging from 70% to 90%, and CD10 was positive in two cases. IRF4 rearrangement was confirmed in all cases by FISH analysis, with dual IRF4/bcl-6 rearrangements identified in two cases, leading to a diagnosis of LBCL-IRF4. Case 6, a 39-year-old female with a tonsillar mass and classified as clinical Ann Arbor stage Ⅳ, displayed predominantly diffuse large B-cell lymphoma (DLBCL) morphology with 20% high-grade follicular lymphoma characteristics. Immunohistochemistry showed negative CD10 and positive bcl-6/MUM1, with a Ki-67 index of approximately 80%. Triple rearrangements of IRF4/bcl-2/bcl-6 were identified by FISH, leading to a diagnosis of DLBCL with 20% follicular lymphoma (FL). All six patients achieved complete remission after treatment, with no progression or relapse during a follow-up period of 31-100 months. Conclusions: Large B-cell lymphoma with IRF4 rearrangement is a rare entity with pathological features that overlap with those of FL and DLBCL. While IRF4 rearrangement is necessary for diagnosing LBCL-IRF4, it is not specific and requires differentiation from other aggressive B-cell lymphomas with IRF4 rearrangement.

[Q-value-guided femtosecond laser-assisted in situ keratomileusis for low-to-moderate myopia with age-related accommodation deficiency].

Objective: To evaluate clinical outcomes and visual quality after femtosecond laser-assisted in situ keratomileusis (FS-LASIK) performed with the Q-value-guided optimized monocular vision protocol (Custom-Q) for correction of low-to-moderate myopia and compensation for age-related accommodation deficiency. Methods: A prospective study was performed based on patients with myopia and age-related accommodation deficiency, who underwent Custom-Q FS-LASIK in the Peking University Third Hospital from October 2022 to October 2023. Monocular and binocular distance, intermediate, and near visual acuities, simulated whole-course visual acuity (binocular defocus curve), objective and subjective refractions, anterior corneal Q factor, anterior corneal higher-order aberrations and a subjective questionnaire assessing near visual acuity and visual quality were evaluated at 3 months postoperatively. Visual acuity was recorded using the logarithm of the minimum angle of resolution. The data were analyzed using the t-test and the Wilcoxon rank-sum test. Results: A total of 45 patients (90 eyes) who met the inclusion criteria and completed the 3-month follow-up were included in the study. The mean age of the 21 men (42 eyes) and 24 women (48 eyes) was (42.82±2.72) years. During the 3-month follow-up, all the patients achieved binocular uncorrected distance visual acuity not less than 0.00 and uncorrected near visual acuity not less than 0.20. Defocus curves revealed better results at 3 months postoperatively [0.00 (-0.08, 0.00), -0.08 (-0.08, 0.00)] at intermediate and near vergence (-1.50 to -1.00 D) compared to the preoperative values [0.00 (-0.08, 0.05), -0.08 (-0.08, 0.00)] (P<0.05). All the 45 patients maintained 0.10 or better vision at the defocus range from -2.50 to 0.00 D. The Q value in the dominant eyes was more positive postoperatively (0.01±0.26 vs.-0.15±0.14, P<0.05), while in the nondominant eyes, the Q value and corneal spherical aberration coefficient became more negative than those before surgery (-0.27±0.32 vs.-0.14±0.11, P<0.05; 0.08±0.05 vs. 0.12±0.03, P<0.05). The questionnaire demonstrated 42 (93.3%) patients were satisfied with near vision. The three most commonly reported visual discomforts after surgery were blurred vision, glare and halos. These symptoms were all mild to moderate in severity and did not interfere with daily life. Conclusion: For myopic patients with age-related accommodation deficiency, the Custom-Q algorithm proved to be a safe and effective way to achieve acceptable near vision and visual quality without compromising distance vision.

Drought priming-induced stress memory improves subsequent drought or heat tolerance via activation of γ-aminobutyric acid-regulated pathways in creeping bentgrass.

Recurrent drought can induce stress memory in plants to induce tolerance to subsequent stress, such as high temperature or drought. Drought priming (DP) is an effective approach to improve tolerance to various stresses; however, the potential mechanism of DP-induced stress memory has not been fully resoved. We examined DP-regulated subsequent drought tolerance or thermotolerance associated with changes in physiological responses, GABA and NO metabolism, heat shock factor (HSF) and dehydrin (DHN) pathways in perennial creeping bentgrass. Plants can recover after two cycle of DP, and DP-treated plants had significantly higher tolerance to subsequent drought or heat stress, with higher leaf RWC, Chl content, photochemical efficiency, and cell membrane stability. DP significantly alleviated oxidative damage through enhancing total antioxidant capacity in response to subsequent drought or heat stress. Endogenous GABA was significantly increased by DP through activating glutamic acid decarboxylase activity and inhibiting GABA transaminase activity. DP also enhanced accumulation of NO, depending on NOS activity, under subsequent drought or heat stress. Transcript levels of multiple transcription factors, heat shock proteins, and DHNs in the HSF and DHN pathways were up-regulated by DP under drought or heat stress, but there were differences between DP-regulated heat tolerance and drought tolerance in these pathways. The findings indicate that under recurrent moderate drought, DP improves subsequent tolerance to drought or heat stress in relation to GABA-regulated pathways, providing new insight into understanding of the role of stress memory in plant adaptation to complex environmental stresses.

[Screening of differentially expressed genes in gastric cancer based on GEO database and function and pathway enrichment analysis].

OBJECTIVE: To explore the core genes related to the diagnosis and prognosis of gastric cancer (GC) based on Gene Expression Omnibus (GEO) database and screen the molecular targets involved in the occurrence and development of GC. METHODS: GC microarray data GSE118916, GSE54129 and GSE79973 were downloaded from GEO database, and the differentially expressed genes (DEGs) were screened. Enrichment analysis of the signaling pathways and molecular functions were preformed and protein-protein interaction networks (PPI) were constructed to identify the hub genes, whose expression levels and diagnostic and prognostic values were verifies based on gastric adenocarcinoma data from TCGA. The expression levels of these core genes were also detected in different GC cell lines using qRT- PCR. RESULTS: Seventy-seven DEGs were identified, which encodes proteins located mainly in the extracellular matrix and basement membrane with activities of oxidoreductase and extracellular matrix receptor and ligand, involving the biological processes of digestion and hormone metabolism and the signaling pathways in retinol metabolism and gastric acid secretion. Nine hub genes were obtained, among which SPARC, TIMP1, THBS2, COL6A3 and THY1 were significantly up- regulated and TFF1, GKN1, TFF2 and PGC were significantly down-regulated in GC. The abnormal expressions of SPARC, TIMP1, THBS2, COL6A3, TFF2 and THY1 were significantly correlated with the survival time of GC patients. ROC curve analysis showed that aberrant expression of TIMP1 SPARC, THY1 and THBS2 had high diagnostic value for GC. High expressions of SPARC, TIMP1, THBS2 and COL6A3 were detected in GC tissues. In the GC cell lines, qRT- PCR revealed different expression patterns of these hub genes, but their expressions were largely consistent with those found in bioinformatics analyses. CONCLUSION: SPARC, TIMP1, THBS2 and other DEGs are probably involved in GC occurrence and progression and may serve as potential candidate molecular markers for early diagnosis and prognostic evaluation of GC.

Study on the construction of nomogram prediction model for prognostic assessment of heart failure patients based on serological markers and echocardiography.

OBJECTIVE: We aimed to construct a nomogram prediction model for prognostic assessment of patients with heart failure (HF) based on serological markers and echocardiography. PATIENTS AND METHODS: A total of 200 HF patients admitted to the Second Affiliated Hospital of Nanchang University from January 2018 to January 2020 were selected as the research objects. According to the New York Heart Association (NYHA) cardiac function classification, they were divided into 3 groups, including 65 cases of grade II, 97 cases of grade III, and 38 cases of grade IV. Three groups of echocardiographic parameters were compared [including left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular end-systolic volume (LVESV)], differences in serum markers brain natriuretic peptide (BNP), soluble growth-stimulating expression gene 2 (sST2) and the Modified Early Warning Score (MEWS). The patients were divided into two groups according to their clinical outcomes during the follow-up period, including 52 cases in the death group and 148 cases in the survival group. The clinical data of the two groups were compared, and multi-factor logistic regression analysis was performed to screen out the independent risk factors affecting the patient's death. A nomogram model of the patient's mortality risk was constructed based on the independent risk factors. Receiver operating characteristic (ROC) curves and calibration curves were used to evaluate the discrimination and accuracy of the nomogram model. RESULTS: As the cardiac function class of elderly chronic heart failure (CHF) patients increases, LVEDD, LVESD, sST2, and MEWS increase and LVEF decreases (p<0.05). Multifactor analysis results showed that LVEF, LVEDD, sST2, and MEWS were independent factors affecting the clinical outcome of patients. The AUCs predicted using LVEF, LVEDD, sST2, and MEWS alone were 0.738, 0.775, 0.717, 0.831, and 0.768, respectively. There is a certain degree of discrimination, and the model has extremely high accuracy. CONCLUSIONS: MEWS, LVEDD, and sST2 increase as the NYHA cardiac function grade of HF patients increases and LVEF decreases, which can reflect the severity of the disease to a certain extent. Additionally, the nomogram model established based on this has a high predictive value for the long-term prognosis of patients and can formulate effective intervention measures for quantitative values.

Author Correction: Phase I study of the pharmacokinetics and safety of single and multiple doses of intravenous N-acetylcysteine in healthy Chinese subjects.

Eur Rev Med Pharmacol Sci 2023; 27 (24): 12103-12111-DOI: 10.26355/eurrev_202312_34808-PMID: 38164872, published online on December 22, 2023. After publication, the authors found that Table III's legend was the same as that of Table II. Therefore, Table III's legend has been corrected as follows: Table III. Plasma PK parameters following repeat doses of IV NAC 600 mg (n = 24). There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34808.

Application and prognostic relevance of CD34 detection in immunophenotyping of pediatric acute B lymphoblastic leukemia.

OBJECTIVE: We aimed to investigate the application of CD34 detection in immunophenotypic discrimination and its prognostic relevance in children with acute B-lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS: A retrospective analysis was conducted on clinical follow-up data of 105 children with newly diagnosed B-ALL treated at our hospital from January 2022 to December 2023. Based on the expression of CD34 in the bone marrow, patients were divided into a CD34 positive group (positive cells ≥10%) and a CD34 negative group (positive cells <10%). The study compared the positive rates of common leukemia cell antigens, clinical characteristics, initial treatment responses, and long-term follow-up outcomes between the two groups. RESULTS: Among all 105 B-ALL cases, 87 children (82.9%) had bone marrow CD34 positive cells ≥10%, classified into the CD34 positive group, while the remaining 18 children (17.1%) had bone marrow CD34 positive cells <10%, classified into the CD34 negative group. The CD34 positive group exhibited significantly higher positive rates of CD13 expression, standard-risk B-ALL, and risk stratification than the CD34 negative group. In contrast, the proportions of early pre-B-ALL, E2A-PBX1 fusion gene, and MLL-AF4 fusion gene were significantly lower in the CD34 negative group, with statistically significant differences (p<0.05). No significant differences were found in the positive rates of leukemia cell antigens such as CD10, CD19, CD20, CD22, CD79a, CD13, CD33, and CD38 between the two groups (p>0.05). The occurrence rates of minimal residual disease (MRD) and relapse after induction chemotherapy in the CD34 positive group were significantly lower than those in the CD34 negative group (p<0.05). However, the sensitivity to the first prednisone treatment and bone marrow treatment efficacy on the 19th and 33rd days after chemotherapy showed no significant differences between the groups (p>0.05). CONCLUSIONS: A higher positive rate of bone marrow CD34 expression in children with B-ALL is associated with a favorable prognosis. Children with negative CD34 expression are relatively more prone to MRD and tumor relapse after chemotherapy.

Proof of Concept: Development of a Mitral Annuloplasty Ring With Crosshatch Net.

OBJECTIVE: Here we report our preclinical, proof-of-concept testing to assess the ability of a novel device to correct mitral regurgitation. The Milwaukee Heart device aims to enable any cardiac surgeon to perform high-quality mitral valve repair using a standard annuloplasty ring with a crosshatch of microporous, monofilament suture. METHODS: Hemodynamic, echocardiographic, and videographic data were collected at baseline, following induction of mitral regurgitation, and after repair using porcine hearts in an ex vivo biosimulator model. A commercially available cardiac prosthesis assessment platform was then used to assess the hydrodynamic characteristics of the study device. RESULTS: Porcine biosimulator pressure and flow metrics exhibited successful correction of mitral regurgitation following device implantation with similar values to baseline. Hydrodynamic results yielded pressure gradients and an effective orifice area comparable to currently approved prostheses. CONCLUSIONS: The study device effectively reduced mitral valve regurgitation and improved hemodynamics in our preclinical model with similar biophysical metrics to currently approved devices. Future in vivo trials are needed to evaluate the efficacy, biocompatibility, and freedom from the most likely adverse events, such as device thrombosis, embolic events, and hemolysis.

A Cholecystokinin Analogue Ameliorates Cognitive Deficits and Regulates Mitochondrial Dynamics via the AMPK/Drp1 Pathway in APP/PS1 Mice.

BACKGROUND: There are no drugs on the market that can reverse or slow Alzheimer's disease (AD) progression. A protease-resistant Cholecystokinin (CCK) analogue used in this study is based on the basic structure of CCK, which further increases the stability of the peptide fragment and prolongs its half-life in vivo. We observed a neuroprotective effect of CCK-8L in APPswe/PS1dE9 (APP/PS1) AD mice. However, its corresponding mechanisms still need to be elucidated. OBJECTIVE: This study examined CCK-8L's neuroprotective effects in enhancing cognitive impairment by regulating mitochondrial dynamics through AMPK/Drp1 pathway in the APP/PS1 AD mice. METHODS: Behavioural tests are applied to assess competence in cognitive functions. Transmission electron microscopy (TEM) was performed to observe the ultrastructure of mitochondria of hippocampal neurons, Immunofluorescent staining was employed to assay for Aß1-42, APP, Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and dynamin-related protein1 (Drp1). CRISPR/Cas9 was utilized for targeted knockout of the CCKB receptor (CCKBR) in the mouse APP/PS1 hippocampal CA1 region. A model of lentiviral vector-mediated overexpression of APP in N2a cells was constructed. RESULTS: In vivo, experiments revealed that CCK analogue and liraglutide significantly alleviated cognitive deficits in APP/PS1 mice, reduced Aß1-42 expression, and ameliorated l damage, which is associated with CCKBR activation in the hippocampal CA1 region of mice. In vitro tests showed that CCK inhibited mitochondrial fission and promoted fusion through AMPK/Drp1 pathway. CONCLUSIONS: CCK analogue ameliorates cognitive deficits and regulates mitochondrial dynamics by activating the CCKB receptor and the AMPK/Drp1 pathway in AD mice.

[Identification of oxidative stress-related biomarkers in chronic rhinosinusitis with nasal polyps using WGCNA combined with machine learning algorithms].

Objective: To identify diagnostic markers related to oxidative stress in chronic rhinosinusitis with nasal polyps (CRSwNP) by analyzing transcriptome sequencing data, and to investigate their roles in CRSwNP. Methods: Utilizing four CRSwNP sequencing datasets, differentially expressed genes (DEGs) analysis, weighted gene co-expression network analysis (WGCNA), and three machine learning methods for Hub gene selection were performed in this study. Subsequent validation was carried out using external datasets, as well as real-time quantitative polymerase chain reaction (Real-time qPCR), and immunofluorescence staining of clinical samples. Moreover, the diagnostic efficacy of the genes was assessed by receiver operating characteristic (ROC) curve, followed by functional and pathway enrichment analysis, immune-related analysis, and cell population localization. Additionally, a competing endogenous RNA (CeRNA) network was constructed to predict potential drug targets. Statistical analysis and plotting were conducted using SPSS 26.0 and Graphpad Prism9 software. Results: Through data analysis and clinical validation, CP, SERPINF1 and GSTO2 were identified among 4 138 DEGs as oxidative stress markers related to CRSwNP. Specifically, the expression of CP and SERPINF1 increased in CRSwNP, whereas that of GSTO2 decreased, with statistically significant differences (P<0.05). Additionally, an area under the curve (AUC)>0.7 indicated their effectiveness as diagnostic indicators. Importantly, functional analysis indicated that these genes were mainly related to lipid metabolism, cell adhesion migration, and immunity. Single-cell data analysis revealed that SERPINF1 was mainly distributed in epithelial cells, stromal cells, and fibroblasts, while CP was primarily located in epithelial cells, and GSTO2 was minimally present in the epithelial cells and fibroblasts of nasal polyps. Consequently, a CeRNA regulatory network was constructed for the genes CP and GSTO2. This construction allowed for the prediction of potential drugs that could target CP. Conclusion: This study successfully identifies CP, SERPINF1 and GSTO2 as diagnostic and therapeutic markers related to oxidative stress in CRSwNP.

Ambulatory facial feminization surgery: a comparative analysis of outcomes and complications.

BACKGROUND: To date, there are no studies investigating the safety and outcomes of facial feminization surgery (FFS) as an outpatient procedure. This is the first study of its kind analyzing the outcomes of ambulatory FFS based on a comparison of complications, post-operative emergency department or urgent care (ED/UC) visits, and readmissions between patients who underwent FFS with admission versus same-day surgery. METHODS: A retrospective analysis was conducted on all patients who underwent FFS in a single integrated healthcare system. Patient charts were reviewed for operative details, complications, post-operative ED/UC visits, readmission, and demographic factors. Major outcomes including complications, readmissions, and ED/UC visits were compared between groups with same-day discharge and post-operative hospital admission. RESULTS: Of 242 patients included in the study, ED/UC visits were comparable between patients discharged same-day (18.2%) and patients admitted post-operatively (21.6%, p = 0.52). Logistic regression showed no significant difference in the composite outcomes of minor complications, major complications, and readmissions (15.6% for ambulatory versus 19.3% for admission, p = 0.46). Temporary nerve palsy, infection, and hematoma were the most common post-operative complications. However, covariates of a lower face procedure and operative time were shown to have significant differences in the composite complication outcome (p = 0.04 and p = 0.045, respectively). CONCLUSION: Ambulatory FFS is a safe practice with no associated increase in adverse outcomes including complications, ED/UC visits, and readmission when compared to post-operative admission. Adoption of same-day FFS should be considered by high-volume gender health centers to potentially benefit from increased scheduling flexibility and efficiency, increased access to care, and lower healthcare costs.

A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors.

BACKGROUND: Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors. PATIENTS AND METHODS: Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response. CONCLUSIONS: The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.

[Multicenter evaluation of the diagnostic efficacy of jaundice color card for neonatal hyperbilirubinemia].

Objective: To evaluate the diagnostic efficacy and practicality of the Jaundice color card (JCard) as a screening tool for neonatal jaundice. Methods: Following the standards for reporting of diagnostic accuracy studies (STARD) statement, a multicenter prospective study was conducted in 9 hospitals in China from October 2019 to September 2021. A total of 845 newborns who were admitted to the hospital or outpatient department for liver function testing due to their own diseases. The inclusion criteria were a gestational age of ≥35 weeks, a birth weight of ≥2 000 g, and an age of ≤28 days. The neonate's parents used the JCard to measure jaundice at the neonate's cheek. Within 2 hours of the JCard measurement, transcutaneous bilirubin (TcB) was measured with a JH20-1B device and total serum bilirubin (TSB) was detected. The Pearson's correlation analysis, Bland-Altman plots and the receiver operating characteristic (ROC) curve were used for statistic analysis. Results: Out of the 854 newborns, 445 were male and 409 were female; 46 were born at 35-36 weeks of gestational age and 808 were born at ≥37 weeks of gestational age. Additionally, 432 cases were aged 0-3 days, 236 cases were aged 4-7 days, and 186 cases were aged 8-28 days. The TSB level was (227.4±89.6) µmol/L, with a range of 23.7-717.0 µmol/L. The JCard level was (221.4±77.0) µmol/L and the TcB level was (252.5±76.0) µmol/L. Both the JCard and TcB values showed good correlation (r=0.77 and 0.80, respectively) and agreements (96.0% (820/854) and 95.2% (813/854) of samples fell within the 95% limits of agreement, respectively) with TSB. The JCard value of 12 had a sensitivity of 0.93 and specificity of 0.75 for identifying a TSB ≥205.2 µmol/L, and a sensitivity of 1.00 and specificity of 0.35 for identifying a TSB ≥342.0 µmol/L. The TcB value of 205.2 µmol/L had a sensitivity of 0.97 and specificity of 0.60 for identifying TSB levels of 205.2 µmol/L, and a sensitivity of 1.00 and specificity of 0.26 for identifying TSB levels of 342.0 µmol/L. The areas under the ROC curve (AUC) of JCard for identifying TSB levels of 153.9, 205.2, 256.5, and 342.0 µmol/L were 0.96, 0.92, 0.83, and 0.83, respectively. The AUC of TcB were 0.94, 0.91, 0.86, and 0.87, respectively. There were both no significant differences between the AUC of JCard and TcB in identifying TSB levels of 153.9 and 205.2 µmol/L (both P>0.05). However, the AUC of JCard were both lower than those of TcB in identifying TSB levels of 256.5 and 342.0 µmol/L (both P<0.05). Conclusions: JCard can be used to classify different levels of bilirubin, but its diagnostic efficacy decreases with increasing bilirubin levels. When TSB level are ≤205.2 µmol/L, its diagnostic efficacy is equivalent to that of the JH20-1B. To prevent the misdiagnosis of severe jaundice, it is recommended that parents use a low JCard score, such as 12, to identify severe hyperbilirubinemia (TSB ≥342.0 µmol/L).

Phase I study of the pharmacokinetics and safety of single and multiple doses of intravenous N-acetylcysteine in healthy Chinese subjects.

OBJECTIVE: The aim of the study was to determine the pharmacokinetics (PK) and safety of single and repeat doses of intravenous (IV) N-acetylcysteine (NAC) in Chinese subjects. PATIENTS AND METHODS: A total of 24 healthy male and female Chinese subjects aged 19-40 years were enrolled in this open-label phase I study. All subjects received a single dose of NAC 600 mg IV on day 1 and, after a 3-day washout, received repeat doses of NAC 600 mg IV (twice daily on days 4 and 5 and once on day 6). RESULTS: Following a single dose, plasma NAC concentrations peaked rapidly, starting to fall at the end of the 5-minute infusion in a multiphasic manner. Mean Cmax was 83.30 µg/mL (CV% 30.7%), median Tmax was 0.083 h (range 0.08-0.25 h), and mean AUC(0-12 h) was 81.87 h*µg/mL (CV 14.0%). Following repeat dosing, Cmax was approximately 20% higher than after a single dose, with similar Tmax. Total exposure AUC(0-12) was 13% higher at steady state than after single dosing. The accumulation ratio was approximately 1.13, indicating only a slight accumulation with multiple dosing. NAC was eliminated with T1/2 of approximately 8 hours. Around 15% of the total NAC dose was excreted in the urine in the 32 hours post-dose, keeping with extensive NAC metabolism and transformation. Renal clearance of NAC was 995.2 mL/h (CV 50.2%). IV NAC was well tolerated after both single and multiple dosing. CONCLUSIONS: This is the first robust study evaluating the PK and safety of IV NAC 600 mg in Chinese subjects and provides important data if this agent is to be used IV as a mucolytic in this population.