Mining Real-World Big Data to Characterize Adverse Drug Reaction Quantitatively: Mixed Methods Study.

BACKGROUND: Adverse drug reactions (ADRs), which are the phenotypic manifestations of clinical drug toxicity in humans, are a major concern in precision clinical medicine. A comprehensive evaluation of ADRs is helpful for unbiased supervision of marketed drugs and for discovering new drugs with high success rates. OBJECTIVE: In current practice, drug safety evaluation is often oversimplified to the occurrence or nonoccurrence of ADRs. Given the limitations of current qualitative methods, there is an urgent need for a quantitative evaluation model to improve pharmacovigilance and the accurate assessment of drug safety. METHODS: In this study, we developed a mathematical model, namely the Adverse Drug Reaction Classification System (ADReCS) severity-grading model, for the quantitative characterization of ADR severity, a crucial feature for evaluating the impact of ADRs on human health. The model was constructed by mining millions of real-world historical adverse drug event reports. A new parameter called Severity_score was introduced to measure the severity of ADRs, and upper and lower score boundaries were determined for 5 severity grades. RESULTS: The ADReCS severity-grading model exhibited excellent consistency (99.22%) with the expert-grading system, the Common Terminology Criteria for Adverse Events. Hence, we graded the severity of 6277 standard ADRs for 129,407 drug-ADR pairs. Moreover, we calculated the occurrence rates of 6272 distinct ADRs for 127,763 drug-ADR pairs in large patient populations by mining real-world medication prescriptions. With the quantitative features, we demonstrated example applications in systematically elucidating ADR mechanisms and thereby discovered a list of drugs with improper dosages. CONCLUSIONS: In summary, this study represents the first comprehensive determination of both ADR severity grades and ADR frequencies. This endeavor establishes a strong foundation for future artificial intelligence applications in discovering new drugs with high efficacy and low toxicity. It also heralds a paradigm shift in clinical toxicity research, moving from qualitative description to quantitative evaluation.

PhosMap: An ensemble bioinformatic platform to empower interactive analysis of quantitative phosphoproteomics.

BACKGROUND: Liquid chromatography-mass spectrometry (LC-MS)-based quantitative phosphoproteomics has been widely used to detect thousands of protein phosphorylation modifications simultaneously from the biological specimens. However, the complicated procedures for analyzing phosphoproteomics data has become a bottleneck to widening its application. METHODS: Here, we develop PhosMap, a versatile and scalable tool to accomplish phosphoproteomics data analysis. A standardized phosphorylation data format was created for data analyses, from data preprocessing to downstream bioinformatic analyses such as dimension reduction, differential phosphorylation analysis, kinase activity, survival analysis, and so on. For better usability, we distribute PhosMap as a Docker image for easy local deployment upon any of Windows, Linux, and Mac system. RESULTS: The source code is deposited at https://github.com/BADD-XMU/PhosMap. A free PhosMap webserver (https://huggingface.co/spaces/Bio-Add/PhosMap), with easy-to-follow fashion of dashboards, is curated for interactive data analysis. CONCLUSIONS: PhosMap fills the technical gap of large-scale phosphorylation research by empowering researchers to process their own phosphoproteomics data expediently and efficiently, and facilitates better data interpretation.

Chemotherapy re-use versus anti-angiogenic monotherapy as the third-line treatment of patients with metastatic colorectal cancer: a real-world cohort study.

BACKGROUND: There are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use in third-line setting is a common option in clinical practice. This study aimed to investigate the efficacy of third-line chemotherapy re-use by the comparison with that of anti-angiogenic monotherapy, and further find the population more suitable for third-line chemotherapy. METHODS: Using electronic medical records of patients with mCRC, a retrospective cohort study was conducted. A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting as control group were retrospectively collected. Baseline characteristics were analyzed using the χ² test or the Fisher's exact test. ROC curve and surv_cutpoint function of 'survminer' package in R software were used to calculate the cut-off value. Survival curves were plotted with the Kaplan-Meier method and were compared using the log-rank test. The Cox proportional hazard regression model was used to analyze the potential risk factors. RESULTS: A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting were retrospectively collected. Chemotherapy rechallenge was recorded in 93 patients (93/143, 65.0%), and the remaining patients chose new chemotherapeutic drugs that had not been previously used, including irinotecan-based (22/50), oxaliplatin-based (9/50), raltitrexed (9/50), gemcitabine (5/50) and other agents (5/50). The ORR and DCR of third-line chemotherapy reached 8.8%, 61.3%, respectively (anti-angiogenic monotherapy group: ORR 2.6%, DCR 47.4%). The mPFS and mOS of patients receiving chemotherapy were 4.9 and 12.0 m, respectively (anti-angiogenic monotherapy group: mPFS 2.7 m, mOS 5.2 m). Subgroup analyses found that patients with RAS/RAF mutation, longer PFS (greater than 10.6 m) in front-line treatment or larger tumor burden had better prognosis with third-line chemotherapy rather than anti-angiogenic monotherapy. CONCLUSIONS: Third-line chemotherapy re-use was effective in mCRC. Those with more aggressive characteristics (RAS/RAF mutant, larger tumor burden) or better efficacy of previous chemotherapy (longer PFS) were more appropriate for third-line chemotherapy, rather than anti-angiogenic monotherapy.

Wearable Electrochemical Sensor for Sweat-Based Potassium Ion and Glucose Detection in Exercise Health Monitoring.

The increasing prevalence of wearable devices has sparked a growing interest in real-time health monitoring and physiological parameter tracking. This study focuses on the development of a cost-effective sweat analysis device, utilizing microfluidic technology and selective electrochemical electrodes for non-invasive monitoring of glucose and potassium ions. The device, through real-time monitoring of glucose and potassium ion levels in sweat during physical activity, issues a warning signal when reaching experimentally set thresholds (K+ concentration at 7.5 mM, glucose concentrations at 60 µM and 120 µM). This alerts users to potential dehydration and hypoglycemic conditions. Through the integration of microfluidic devices and precise electrochemical analysis techniques, the device enables accurate and real-time monitoring of glucose and potassium ions in sweat. This advancement in wearable technology holds significant potential for personalized health management and preventive care, promoting overall well-being, and optimizing performance during physical activities.

Discovery of N-benzyl-6-methylpicolinamide as a potential scaffold for bleaching herbicides.

BACKGROUND: In pesticide research, bleaching herbicides have always been a hot topic. Our previous research showed that N-(4-fluorobenzyl)-2-methoxybenzamide is an innovative lead compound for bleaching herbicides. RESULTS: A total of 40 derivatives of picolinamides were prepared and evaluated for their herbicidal activity by Petri dish tests and postemergence trials. The structure-activity relationship (SAR) revealed that introducing electron-withdrawing groups at the 3- or 4-positions of the benzyl significantly enhances herbicidal activity. Furthermore, ZI-04 induced similar symptoms such as bleaching effect in treated weeds and accumulation of biosynthetic precursors for carotenoids as observed with diflufenican. ZI-04 also exhibited significant cross-resistance to diflufenican and had a lower resistance risk than diflufenican. CONCLUSION: N-benzyl-6-methylpicolinamides were discovered as a novel scaffold for bleaching herbicides. The accumulation of phytoene, phytofluene and ζ-Carotene in radish cotyledons, and cross-resistance observed with diflufenican, showed that title compounds can interfere with carotenoid biosynthesis. © 2024 Society of Chemical Industry.

Combined score based on plasma fibrinogen and platelet-lymphocyte ratio as a prognostic biomarker in esophageal squamous cell carcinoma.

BACKGROUND: Increasing evidence has showed that inflammatory biomarkers, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and fibrinogen can be used as predictors in the prognosis of esophageal squamous cell carcinoma (ESCC). The aim of this study was to explore prognostic value of these biomarkers and evaluate the clinicopathological and prognostic significance of combined score based on plasma fibrinogen and platelet-lymphocyte ratio (F-PLR score). METHODS: A total of 506 patients with ESCC were enrolled in this study. Harrell's concordance index (c-index) was used to determine the optimal cut-off values of these markers and evaluate their prognostic significance. The relationship between factors with survival rates (including overall survival [OS] and disease-free survival [DFS]) was explored by Kaplan-Meier curve, univariate analysis and multivariate cox hazard analysis. RESULTS: Our result indicated that high F-PLR score was significantly associated with longer tumor length and deeper depth of tumor invasion (p < 0.01). The result of Cox multivariable analysis showed that F-PLR score was an independent prognostic factor for OS (p = 0.002) and DFS (p = 0.003). In addition, F-PLR score presented the greater c-index values for OS and DFS compared with NLR, PLR and fibrinogen level. Our result also showed that the c-index values for OS and DFS were both greater in TNM + F-PLR than those in TNM stage alone. CONCLUSIONS: In conclusion, F-PLR score is a predictive biomarker for prognosis in patients with ESCC.

Identification of key genes in chronic intermittent hypoxia-induced lung cancer progression based on transcriptome sequencing.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased risk of lung cancer mortality. Nevertheless, little is known about the underlying molecular mechanisms. This research aimed to investigate differentially expressed genes (DEGs) and explore their function in Lewis lung carcinoma (LLC)-bearing mice exposed to chronic intermittent hypoxia (CIH) by transcriptome sequencing. METHODS: Lung cancer tissues in LLC-bearing mice exposed to CIH or normoxia were subjected for transcriptome sequencing to examine DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were employed to explore the function of DEGs. To evaluate the prognostic value of DEGs, the Kaplan-Meier survival analysis in combination with Cox proportional hazard model were applied based on The Cancer Genome Atlas. RESULTS: A total of 388 genes with 207 up-regulated and 181 down-regulated genes were differentially expressed between the CIH and normoxia control groups. Bioinformatics analysis revealed that the DEGs were related to various signaling pathways such as chemokine signaling pathway, IL-17 signaling pathway, TGF-ß signaling pathway, transcriptional misregulation in cancer, natural killer cell mediated cytotoxicity, PPAR signaling pathway. In addition, the DEGs including APOL1, ETFB, KLK8, PPP1R3G, PRL, SPTA1, PLA2G3, PCP4L1, NINJ2, MIR186, and KLRG1 were proven to be significantly correlated with poorer overall survival in lung adenocarcinoma. CONCLUSIONS: CIH caused a significant change of gene expression profiling in LLC-bearing mice. The DEGs were found to be involved in various physiological and pathological processes and correlated with poorer prognosis in lung cancer.

Electronanofiltration Membranes with a Bilayer Charged Structure Enable High Li+/Mg2+ Selectivity.

Achieving separation of lithium and magnesium with similar radii is crucial for the current lithium extraction technology from salt lakes, which usually possess a high lithium-to-magnesium ratio. Herein, we proposed the facile sequential interfacial polymerization (SIP) approach to construct electronanofiltration membranes (ENFMs) with a bilayer charged structure consisting of a high positively charged surface and a negatively charged sublayer. The trimesoyl chloride (TMC) concentration was adjusted to enhance the -COOH content and negative charge of the polyamide sublayer to promote Li+ migration, and then the quaternized polyethylenimine was introduced to the membrane surface by the SIP process to increase the positive charge density on the surface of the ENFMs, which would block the migration of Mg2+ and enhance the Li+/Mg2+ selectivity of the ENFMs. The optimal quaternary-modified ENFMs achieved outstanding selectivity for Li+/Mg2+ (49.85) and high Li+ flux (4.10 × 10-8 mol cm-2 s-1) at a current density of 10 mA cm-2. Moreover, in simulated brines with low lithium concentration and high Mg2+/Li+ ratio, the optimal ENFMs also displayed elevated Li+/Mg2+ selectivity (>45), highlighting the substantial promise of the membranes for practical applications.

ROS-induced oxidative stress is a major contributor to sperm cryoinjury.

STUDY QUESTION: What is the mechanism behind cryoinjury in human sperm, particularly concerning the interplay between reactive oxygen species (ROS) and autophagy, and how does it subsequently affect sperm fate? SUMMARY ANSWER: The freeze-thaw operation induces oxidative stress by generating abundant ROS, which impairs sperm motility and activates autophagy, ultimately guiding the sperm toward programmed cell death such as apoptosis and necrosis, as well as triggering premature capacitation. WHAT IS KNOWN ALREADY: Both ROS-induced oxidative stress and autophagy are thought to exert an influence on the quality of frozen-thawed sperm. STUDY DESIGN, SIZE, DURATION: Overall, 84 semen specimens were collected from young healthy fertile males, with careful quality evaluation. The specimens were split into three groups to investigate the ROS-induced cryoinjury: normal control without any treatment, sperm treated with 0.5 mM hydrogen peroxide (H2O2) for 1 h, and sperm thawed following cryopreservation. Samples from 48 individuals underwent computer-assisted human sperm analysis (CASA) to evaluate sperm quality in response to the treatments. Semen samples from three donors were analyzed for changes in the sperm proteome after H2O2 treatment, and another set of samples from three donors were analyzed for changes following the freeze-thaw process. The other 30 samples were used for fluorescence-staining and western blotting. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm motility parameters, including progressive motility (PR %) and total motility (PR + NP %), were evaluated using the CASA system on a minimum of 200 spermatozoa. The proteomic profiles were determined with label-free mass spectrometry (MS/MS) and protein identification was performed via ion search against the NCBI human database. Subsequently, comprehensive bioinformatics was applied to detect significant proteomic changes and functional enrichment. Fluorescence-staining and western blot analyses were also conducted to confirm the proteomic changes on selected key proteins. The ROS level was measured using 2',7'-dichlorodihydrofluorescein diacetate labeling and the abundance of bioactive mitochondria was determined by evaluating the inner mitochondrial membrane potential (MMP) level. Molecular behaviors of sequestosome-1 (p62 or SQSTM1) and microtubule-associated proteins 1A/1B light chain 3 (LC3) were monitored to evaluate the state of apoptosis in human sperm. Fluorescent probes oxazole yellow (YO-PRO-1) and propidium iodide (PI) were utilized to monitor programmed cell death, namely apoptosis and necrosis. Additionally, gradient concentrations of antioxidant coenzyme Q10 (CoQ10) were introduced to suppress ROS impacts on sperm. MAIN RESULTS AND THE ROLE OF CHANCE: The CASA analysis revealed a significant decrease in sperm motility for both the H2O2-treatment and freeze-thaw groups. Fluorescence staining showed that high ROS levels were produced in the treated sperm and the MMPs were largely reduced. The introduction of CoQ10 at concentrations of 20 and 30 µM resulted in a significant rescue of progressive motility (P < 0.05). The result suggested that excessive ROS could be the major cause of sperm motility impairment, likely by damaging mitochondrial energy generation. Autophagy was significantly activated in sperm when they were under oxidative stress, as evidenced by the upregulation of p62 and the increased conversion of LC3 as well as the upregulation of several autophagy-related proteins, such as charged multivesicular body protein 2a, mitochondrial import receptor subunit TOM22 homolog, and WD repeat domain phosphoinositide-interacting protein 2. Additionally, fluorescent staining indicated the occurrence of apoptosis and necrosis in both H2O2-treated sperm and post-thaw sperm. The cell death process can be suppressed when CoQ10 is introduced, which consolidates the view that ROS could be the major contributor to sperm cryoinjury. The freeze-thaw process could also initiate sperm premature capacitation, demonstrated by the prominent increase in tyrosine phosphorylated proteins, verified with anti-phosphotyrosine antibody and immunofluorescence assays. The upregulation of capacitation-related proteins, such as hyaluronidase 3 and Folate receptor alpha, supported this finding. LARGE SCALE DATA: The data underlying this article are available in the article and its online supplementary material. LIMITATIONS, REASONS FOR CAUTION: The semen samples were obtained exclusively from young, healthy, and fertile males with progressive motility exceeding 60%, which might overemphasize the positive effects while possibly neglecting the negative impacts of cryoinjury. Additionally, the H2O2 treatment conditions in this study may not precisely mimic the oxidative stress experienced by sperm after thawing from cryopreservation, potentially resulting in the omission of certain molecular alterations. WIDER IMPLICATIONS OF THE FINDINGS: This study provides substantial proteomic data for a comprehensive and deeper understanding of the impact of cryopreservation on sperm quality. It will facilitate the design of optimal protocols for utilizing cryopreserved sperm to improve applications, such as ART, and help resolve various adverse situations caused by chemotherapy, radiotherapy, and surgery. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the Major Innovation Project of Research Institute of National Health Commission (#2022GJZD01-3) and the National Key R&D Program of China (#2018YFC1003600). All authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

PEDF Prevents Mitochondrial Function Decay and ER Stress Induced by Rotenone in Aging RPE Cells.

BACKGROUND: Neurodegenerative diseases, including age-related macular degeneration (AMD), may be linked to mitochondrial dysfunction and endoplasmic reticulum (ER) stress. We examined whether Pigment epithelium-derived factor (PEDF) could prevent changes in the structure and function of these organelles by accelerating by rotenone (ROT), a mitochondrial inhibitor, in human retinal pigment epithelium (RPE) cells of chronological age. METHODS: RPE cells from 9-20, 50-55, 60-70, and >70-year-old donors were isolated, grown as primary cultures, harvested, and treated with ROT and PEDF for electron microscope (EM), western blot analysis, and polymerase chain reaction (PCR). Reactive oxygen species (ROS) and cytoplasmic calcium [Ca2+]c and mitochondrial calcium [Ca2+]m levels were measured by flow cytometry using 2',7'-dichlorodihydrofluorescin diacetate (H2-DCF-DA), fluo-3/AM, and Rhod-2/AM, and ATP levels were measured using a luciferin/luciferase-based assay. Mitochondrial membrane potential (ΔΨm) was detected using 5,5',6,6'-tetrachloro1,1',3,3'-tetraethylbenzimid azolocarbocyanine iodide (JC-1), and susceptibility of the cells to ROT toxicity and PEDF-protective effect was determined by propidium iodide (PI) staining and lactate dehydrogenase (LDH) assay. The expression of ER stress-related genes was detected using real-time (RT)-PCR. RESULTS: We observed decay in the mitochondria of aged RPE cells, including matrix abnormalities, elongation, loss of cristae, and disruption of membrane integrity after ROT treatment. We also observed lower [Ca2+]c, higher ROS and [Ca2+]m levels, decreased ΔΨm after ROT treatment, and greater susceptibility to ROT toxicity in aged RPE cells. PEDF can protect the cristae and integrity of the mitochondrial membrane, increase ATP levels and ΔΨm, and lower ROS, [Ca2+]c, and [Ca2+]m in aged RPE cells induced by ROT. In addition, there was an increase in RDH expression in RPE cells with increasing age after PEDF treatment. Similarly, PEDF decreased the expression of ROT-induced ER stress-related genes. CONCLUSIONS: Our study provides evidence that PEDF can reduce bioenergetic deficiencies, mitochondrial decay, and ER stress in aging RPE, a condition that may trigger the onset of retinal diseases such as AMD.

Nomogram for predicting early complications after distal gastrectomy.

BACKGROUND: Reducing or preventing postoperative morbidity in patients with gastric cancer (GC) is particularly important in perioperative treatment plans. AIM: To identify risk factors for early postoperative complications of GC post-distal gastrectomy and to establish a nomogram prediction model. METHODS: This retrospective study included 131 patients with GC who underwent distal gastrectomy at the Second Hospital of Shandong University between January 2019 and February 2023. The factors influencing the development of complications after distal gastrectomy in these patients were evaluated using univariate and multivariate logistic regression analysis. Based on the results obtained, a predictive nomogram was established. The nomogram was validated using internal and external (n = 45) datasets. Its sensitivity and specificity were established by receiver operating characteristic curve analysis. Decision curve (DCA) analysis was used to determine its clinical benefit and ten-fold overfitting was used to establish its accuracy and stability. RESULTS: Multivariate logistic regression analysis showed that hypertension, diabetes, history of abdominal surgery, and perioperative blood transfusion were independent predictors of postoperative complications of distal gastrectomy. The modeling and validation sets showed that the area under the curve was 0.843 [95% confidence interval (CI): 0.746-0.940] and 0.877 (95%CI: 0.719-1.000), the sensitivity was 0.762 and 0.778, respectively, and the specificity was 0.809 and 0.944, respectively, indicating that the model had good sensitivity and specificity. The C-indexes of the modeling and validation datasets were 0.843 (95%CI: 0.746-0.940) and 0.877 (95%CI: 0.719-1.000), respectively. The calibration curve (Hosmer Lemeshow test: χ2 = 7.33) showed that the model had good consistency. The results of the DCA analysis indicated that this model offered good clinical benefits. The accuracy of 10-fold cross-validation was 0.878, indicating that the model had good accuracy and stability. CONCLUSION: The nomogram prediction model based on independent risk factors related to postoperative complications of distal gastrectomy can facilitate perioperative intervention for high-risk populations and reduce the incidence of postoperative complications.

[Effect of Neodymium-Doped Yttrium Aluminum Garnet Laser Combined With Desensitizing Toothpaste on Dentinal Tubule Occlusion Against Acid Challenge].

Objective To assess the effects of different application sequences of neodymium-doped yttrium aluminum garnet(Nd∶YAG)laser and the desensitizing toothpaste containing stannous fluoride on dentinal tubule occlusion.Methods Twelve intact third molars freshly extracted from human were selected and prepared into dentin slices with a thickness of 0.8 mm.Each dentin slice was subdivided into four small slices,three of which were etched with 6% citric acid and randomly assigned to the following three groups(n=12):(1)control group:no treatment;(2)Nd∶YAG+toothbrushing(TB)group:first irradiated with Nd∶YAG laser and then brushed with desensitizing toothpaste;(3)TB+Nd∶YAG group:first brushed with desensitizing toothpaste and then irradiated with Nd∶YAG laser.The Nd∶YAG laser irradiation were carried out at 1 W,15 pulses/s,and the pulse width of 150 µs for 10 s(for a total of 6 cycles).After the above treatment,the 12 dentin slices from the Nd∶YAG+TB and TB+Nd∶YAG groups were randomly assigned to four subgroups(n=3)and subjected to acid etching in the Coca-Cola solution for 0,5,10,and 15 min.A scanning electron microscope was used to observe and photograph the dentin slices in each group,and eight single-blinded examiners scored the slices according to uniform criteria.The analysis of variance was carried out to compared the scores between groups.Results Before acid etching,the dentin tubule occlusion scores of the Nd∶YAG+TB and TB+Nd∶YAG groups were(4.83±0.09) scores and(3.85±0.66) scores,respectively,which had no significant difference between each other(P=0.0590)and were higher than that[(0.10±0.07)scores]of the control group(both P<0.0001).The dentin tubule occlusion scores of the Nd∶YAG+TB group after acid etching for 5,10,and 15 min were(4.33±0.60)scores,(4.27±0.24)scores,and(3.63±0.07)scores,respectively,which were not significantly different from those[(4.04±0.10)scores,(3.76±0.59)scores,and(3.17±0.29)scores,respectively]of the TB+Nd∶YAG group(all P>0.05).In the Nd∶YAG+TB subgroup,the dentin tubule occlusion score after acid etching for 15 min was significantly lower than that before acid etching(P=0.0011).In the TB+Nd∶YAG group,there was no statistically significant difference in the score between before and after acid etching(P>0.05).Conclusions Nd∶YAG laser irradiation with appropriate parameters combined with the use of desensitizing toothpaste could produce an excellent occluding effect on dentinal tubules regardless of the sequence.However,brushing with desensitizing toothpaste followed by Nd∶YAG laser irradiation produced more consistent dentin sealing after acid etching.

TransIntegrator: capture nearly full protein-coding transcript variants via integrating Illumina and PacBio transcriptomes.

Genes have the ability to produce transcript variants that perform specific cellular functions. However, accurately detecting all transcript variants remains a long-standing challenge, especially when working with poorly annotated genomes or without a known genome. To address this issue, we have developed a new computational method, TransIntegrator, which enables transcriptome-wide detection of novel transcript variants. For this, we determined 10 Illumina sequencing transcriptomes and a PacBio full-length transcriptome for consecutive embryo development stages of amphioxus, a species of great evolutionary importance. Based on the transcriptomes, we employed TransIntegrator to create a comprehensive transcript variant library, namely iTranscriptome. The resulting iTrancriptome contained 91 915 distinct transcript variants, with an average of 2.4 variants per gene. This substantially improved current amphioxus genome annotation by expanding the number of genes from 21 954 to 38 777. Further analysis manifested that the gene expansion was largely ascribed to integration of multiple Illumina datasets instead of involving the PacBio data. Moreover, we demonstrated an example application of TransIntegrator, via generating iTrancriptome, in aiding accurate transcriptome assembly, which significantly outperformed other hybrid methods such as IDP-denovo and Trinity. For user convenience, we have deposited the source codes of TransIntegrator on GitHub as well as a conda package in Anaconda. In summary, this study proposes an affordable but efficient method for reliable transcriptomic research in most species.

Third-line treatment patterns and clinical outcomes for metastatic colorectal cancer: a retrospective real-world study.

Background: There are multiple recommendations on the third-line therapy of metastatic colorectal cancer (mCRC); however, no consensus has been reached. Objectives: This study aimed to explore the patient demographics and the real-world third-line treatment landscape of mCRC. Design: A retrospective real-world cohort study. Methods: Electronic medical records of mCRC patients from Tianjin Medical University Cancer Institute and Hospital between 2013 and 2020 were collected. Upon descriptive, comparative, and survival analyses, a retrospective study was conducted to describe demographics and clinical outcomes of mCRC patients receiving third-line treatment. Results: Among 218 mCRC patients receiving third-line therapy, 65.5% received chemotherapy combined with or without targeted drugs, followed by anti-angiogenic monotherapy (18.4%), anti-epidermal growth factor receptor drugs (6.9%) and immunotherapy (6.4%). The overall response rate and disease control rate reached 10.2% and 59.2%, respectively; and median progression-free survival (PFS) and overall survival were 4.0 m and 10.7 m, respectively. After Cox multivariate analysis, we found that therapeutic regime was an independent prognostic factor. Compared to patients receiving anti-angiogenic monotherapy, those receiving chemotherapy combined with or without targeted drugs exhibited better prognosis. For patients whose PFS were longer in the front-line treatment, the PFS of third-line therapy was also relatively longer (p = 0.023). Multiple types of therapies (>3, p = 0.002) or multiple drugs (>5, p = 0.024) in the whole-course management of mCRC are indicators of longer survival. Conclusion: Chemotherapy combined with or without targeted therapy remained dominated third-line choice and showed favorable efficacy compared with anti-angiogenic monotherapy. With the application of more types and quantities of effective drugs, patients would achieve better survival.

An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development.

Macrophages are heterogeneous and play critical roles in development and disease, but their diversity, function, and specification remain inadequately understood during human development. We generated a single-cell RNA sequencing map of the dynamics of human macrophage specification from PCW 4-26 across 19 tissues. We identified a microglia-like population and a proangiogenic population in 15 macrophage subtypes. Microglia-like cells, molecularly and morphologically similar to microglia in the CNS, are present in the fetal epidermis, testicle, and heart. They are the major immune population in the early epidermis, exhibit a polarized distribution along the dorsal-lateral-ventral axis, and interact with neural crest cells, modulating their differentiation along the melanocyte lineage. Through spatial and differentiation trajectory analysis, we also showed that proangiogenic macrophages are perivascular across fetal organs and likely yolk-sac-derived as microglia. Our study provides a comprehensive map of the heterogeneity and developmental dynamics of human macrophages and unravels their diverse functions during development.

Repetitive transcranial magnetic stimulation in the treatment of middle-aged and elderly major depressive disorder: A randomized controlled trial.

BACKGROUND: Studies have reported the use of repetitive transcranial magnetic stimulation (rTMS) in patients with major depressive disorder (MDD). However, most studies focus on antidepressant effect of rTMS, but few on cognitive aspects. The present study aimed to explore the effect of rTMS on BDNF levels and cognitive function in the treatment of middle-aged and elderly MDD. METHODS: This was a randomized controlled trial. A total of 120 elderly patients with MDD treated in The Second Affiliated Hospital of Xi'an Medical University from January 2021 to January 2023 were selected as research subjects. The patients were randomly divided into control group (n = 60, patients received simple oral treatment with escitalopram and sham rTMS) and study group (n = 60, patients received oral treatment with escitalopram combined with rTMS) according to the random number table method. We compared the clinical efficacy, serum BDNF levels, and cognitive function between the 2 groups. RESULTS: After treatment, the HAMD-17 score in the study group was lower than that in the control group [13.00 (12.00-16.00) vs 17.00 (15.00-19.00), P < .05], and the RBANS score was higher than that in the control group [166.00 (161.25-171.75) vs 133.00 (130.00-136.75), P < .05]. The total effective rate of the research group was 95.0%, which was higher than the 82.0% of the control group (P < .05). The serum BDNF levels [36.00 (33.00-38.00) vs 30.00 (28.00-32.00), P < .05] and MoCA scores [24.00 (22.00-26.75) vs 23.00 (21.00-25.00), P < .05] of the study group were higher than those of the control group. There were no significant adverse reactions during the treatment of both groups. CONCLUSIONS: Compared with oral escitalopram alone, repeated transcranial magnetic stimulation in the treatment of middle-aged and elderly patients with major depressive disorder can further improve the efficacy, and can more effectively improve the BDNF level and cognitive function, with ideal safety.

Circ_0001666 upregulation promotes intestinal epithelial cell fibrosis in pediatric Crohn's disease via the SRSF1/BMP7 axis.

The epithelial-mesenchymal transition (EMT) is closely associated with Crohn's disease (CD) related intestinal fibrosis, a condition whose prevalence is increasing annually among children. Recently, the CD marker gene microarray screening revealed an upregulation of circ_0001666 in the colon tissues of CD patients, but its underlying mechanisms remain unclear. In this study, we explored the molecular mechanism of circ_0001666 in regulating EMT-mediated fibrosis in CD in vitro. The levels of circ_0001666 and EMT-associated proteins were assessed in CD clinical samples, and a CD cell model was established using TGF-ß1 to induce human intestinal epithelial cells (HIECs). Additionally, the expression levels of genes and proteins related to EMT and fibrosis were analyzed by quantitative real-time PCR and western blot, cell migration, and invasion were assessed via wound healing assay and transwell, respectively, and RNA pull-down and RNA immunoprecipitation assays were performed to verify the relationship between SRSF1 and BMP7 or circ_0001666. Circ_0001666 was overexpressed in the intestinal mucosal tissues of CD patients and was positively correlated with EMT. Silencing circ_0001666 inhibited the migration, invasion, EMT, and fibrosis of HIECs induced by TGF-ß1. Mechanistically, circ_0001666 regulated BMP7 expression by interacting with SRSF1. Furthermore, the effects of inhibiting circ_0001666 on HIECs could be partially reversed by overexpressing SRSF1 or silencing BMP7. Collectively, circ_0001666 regulates TGF-ß1-induced HIEC migration, invasion, EMT, and fibrosis. Circ_0001666 also promoted EMT-mediated fibrosis by interacting with SRSF1 to accelerate BMP7 mRNA decay. These findings provide new insights into the pathogenesis of CD and suggest that circ_0001666 might be a potential therapeutic target for CD.

The Use of 810 and 1064 nm Lasers on Dental Implants: In Vitro Analysis of Temperature, Surface Alterations, and Biological Behavior in Human Gingival Fibroblasts.

Objective: The primary objective of this study was to evaluate the safety of 810 and 1064 nm laser treatment on dental implants. Background: Peri-implantitis is a challenge for clinicians and researchers. Methods: A pig mandible model was used to evaluate temperature increases during laser irradiation. Surface alterations on processed pure titanium discs were analyzed via scanning electron microscopy and measurement of surface contact angles. Processed titanium discs were cocultured in vitro with human gingival fibroblasts; subsequently, cell proliferation was measured. Results: The maximum temperature and time to reach each threshold were comparable. No surface alterations were detected after 810 nm laser irradiation, whereas surface cracks were observed after 1064 nm laser irradiation under the parameter setting of 31.84 W/cm2. Compared with unaltered processed pure titanium discs, the proliferation of human gingival fibroblasts was significantly greater on altered processed pure titanium discs. Conclusions: The use of either 810 or 1064 nm laser treatments may increase the risk of thermal damage in terms of increased temperature if the parameter setting is not warranted. In addition, the use of 1064 nm laser treatment could lead to changes in pure titanium discs that do not negatively affect cell proliferation. Further investigations of laser-assisted therapy are necessary to improve guidelines concerning the treatment of peri-implantitis. Clinical trial registration number: 2021-P2-098-01.

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OBJECTIVES: To evaluate the clinical effectiveness of integrated management during the perinatal period for fetuses diagnosed with total anomalous pulmonary venous connection (TAPVC) by prenatal echocardiography. METHODS: Clinical data of 64 cases of TAPVC fetuses diagnosed by prenatal echocardiography and managed with integrated perinatal care in Qingdao Women and Children's Hospital from January 2017 to December 2021 were retrospectively analyzed. Integrated perinatal care included multidisciplinary collaboration among obstetrics, fetal medicine, ultrasound, pediatric cardiology, pediatric anesthesia, and neonatology. RESULTS: Among the 64 TAPVC fetuses, there were 29 cases of supracardiac type, 27 cases of intracardiac type, 2 cases of infracardiac type, and 6 cases of mixed type. Chromosomal analysis was performed in 42 cases, and no obvious abnormalities were found. Among the 64 TAPVC fetuses, 37 were induced labor, and 27 were followed up until term birth. Among the 27 TAPVC cases, 2 cases accepted palliative care, 2 cases were referred to another hospital for treatment and lost to follow-up, while the remaining 23 cases underwent primary repair surgery. One case died within 6 months after the operation due to low cardiac output syndrome, while the other 22 cases were followed up for (2.1±0.3) years with good outcomes (2 cases underwent a second surgery within 1 year after the first operation due to anastomotic stenosis or pulmonary vein stenosis). CONCLUSIONS: TAPVC fetuses can achieve good outcomes with integrated management during the perinatal period.