JCAD deficiency delayed liver regenerative repair through the Hippo-YAP signalling pathway.

BACKGROUND AND AIMS: Liver regeneration retardation post partial hepatectomy (PH) is a common clinical problem after liver transplantation. Identification of key regulators in liver regeneration post PH may be beneficial for clinically improving the prognosis of patients after liver transplantation. This study aimed to clarify the function of junctional protein-associated with coronary artery disease (JCAD) in liver regeneration post PH and to reveal the underlying mechanisms. METHODS: JCAD knockout (JCAD-KO), liver-specific JCAD-KO (Jcad△Hep) mice and their control group were subjected to 70% PH. RNA sequencing was conducted to unravel the related signalling pathways. Primary hepatocytes from KO mice were treated with epidermal growth factor (EGF) to evaluate DNA replication. Fluorescent ubiquitination-based cell cycle indicator (FUCCI) live-imaging system was used to visualise the phases of cell cycle. RESULTS: Both global and liver-specific JCAD deficiency postponed liver regeneration after PH as indicated by reduced gene expression of cell cycle transition and DNA replication. Prolonged retention in G1 phase and failure to transition over the cell cycle checkpoint in JCAD-KO cell line was indicated by a FUCCI live-imaging system as well as pharmacologic blockage. JCAD replenishment by adenovirus reversed the impaired DNA synthesis in JCAD-KO primary hepatocyte in exposure to EGF, which was abrogated by a Yes-associated protein (YAP) inhibitor, verteporfin. Mechanistically, JCAD competed with large tumour suppressor 2 (LATS2) for WWC1 interaction, leading to LATS2 inhibition and thereafter YAP activation, and enhanced expression of cell cycle-associated genes. CONCLUSION: JCAD deficiency led to delayed regeneration after PH as a result of blockage in cell cycle progression through the Hippo-YAP signalling pathway. These findings uncovered novel functions of JCAD and suggested a potential strategy for improving graft growth and function post liver transplantation. KEY POINTS: JCAD deficiency leads to an impaired liver growth after PH due to cell division blockage. JCAD competes with LATS2 for WWC1 interaction, resulting in LATS2 inhibition, YAP activation and enhanced expression of cell cycle-associated genes. Delineation of JCADHippoYAP signalling pathway would facilitate to improve prognosis of acute liver failure and graft growth in living-donor liver transplantation.

Single-cell profiling and functional screening reveal crucial roles for lncRNAs in the epidermal re-epithelialization of human acute wounds.

Objectives: Re-epithelialization is an important physiological process for repairing skin barrier function during wound healing. It is primarily mediated by coordinated migration, proliferation, and differentiation of keratinocytes. Long noncoding RNAs (lncRNAs) are essential components of the noncoding genome and participate in various biological processes; however, their expression profiles and function in re-epithelialization during wound healing have not been established. Methods: We investigated the distribution of lncRNAs during wound re-epithelialization by comparing the genomic profiles of uninjured skin and acute wound (AW) from healthy donors. We performed functional screening of differentially expressed lncRNAs to identify the important lncRNAs for re-epithelialization. Results: The expression of multiple lncRNAs is changed during human wound re-epithelialization process. We identified VIM-AS1, SMAD5-AS1, and LINC02581 as critical regulators involved in keratinocyte migration, proliferation, and differentiation, respectively. Conclusion: LncRNAs play crucial regulatory roles in wound re-epithelialization. We established lncRNA expression profile in human acute wounds compared with intact skin, offering valuable insights into the physiological mechanisms underlying wound healing and potential therapeutic targets.

Cancer screening in hospitalized ischemic stroke patients: a multicenter study focused on multiparametric analysis to improve management of occult cancers.

Background/aims: The reciprocal promotion of cancer and stroke occurs due to changes in shared risk factors, such as metabolic pathways and molecular targets, creating a "vicious cycle." Cancer plays a direct or indirect role in the pathogenesis of ischemic stroke (IS), along with the reactive medical approach used in the treatment and clinical management of IS patients, resulting in clinical challenges associated with occult cancer in these patients. The lack of reliable and simple tools hinders the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) approach. Therefore, we conducted a multicenter study that focused on multiparametric analysis to facilitate early diagnosis of occult cancer and personalized treatment for stroke associated with cancer. Methods: Admission routine clinical examination indicators of IS patients were retrospectively collated from the electronic medical records. The training dataset comprised 136 IS patients with concurrent cancer, matched at a 1:1 ratio with a control group. The risk of occult cancer in IS patients was assessed through logistic regression and five alternative machine-learning models. Subsequently, select the model with the highest predictive efficacy to create a nomogram, which is a quantitative tool for predicting diagnosis in clinical practice. Internal validation employed a ten-fold cross-validation, while external validation involved 239 IS patients from six centers. Validation encompassed receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and comparison with models from prior research. Results: The ultimate prediction model was based on logistic regression and incorporated the following variables: regions of ischemic lesions, multiple vascular territories, hypertension, D-dimer, fibrinogen (FIB), and hemoglobin (Hb). The area under the ROC curve (AUC) for the nomogram was 0.871 in the training dataset and 0.834 in the external test dataset. Both calibration curves and DCA underscored the nomogram's strong performance. Conclusions: The nomogram enables early occult cancer diagnosis in hospitalized IS patients and helps to accurately identify the cause of IS, while the promotion of IS stratification makes personalized treatment feasible. The online nomogram based on routine clinical examination indicators of IS patients offered a cost-effective platform for secondary care in the framework of PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00354-8.

TGF-ß1/SMAD3-driven GLI2 isoform expression contributes to aggressive phenotypes of hepatocellular carcinoma.

Hedgehog signaling is activated in response to liver injury, and modulates organogenesis. However, the role of non-canonical hedgehog activation via TGF-ß1/SMAD3 in hepatic carcinogenesis is poorly understood. TGF-ß1/SMAD3-mediated non-canonical activation was found in approximately half of GLI2-positive hepatocellular carcinoma (HCC), and two new GLI2 isoforms with transactivating activity were identified. Phospho-SMAD3 interacted with active GLI2 isoforms to transactivate downstream genes in modulation of stemness, epithelial-mesenchymal transition, chemo-resistance and metastasis in poorly-differentiated hepatoma cells. Non-canonical activation of hedgehog signaling was confirmed in a transgenic HBV-associated HCC mouse model. Inhibition of TGF-ß/SMAD3 signaling reduced lung metastasis in a mouse in situ hepatic xenograft model. In another cohort of 55 HCC patients, subjects with high GLI2 expression had a shorter disease-free survival than those with low expression. Moreover, co-positivity of GLI2 with SMAD3 was observed in 87.5% of relapsed HCC patients with high GLI2 expression, indicating an increased risk of post-resection recurrence of HCC. The findings underscore that suppressing the non-canonical hedgehog signaling pathway may confer a potential strategy in the treatment of HCC.

JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis.

BACKGROUND/AIMS: Cholestatic liver diseases including primary biliary cholangitis (PBC) are associated with active hepatic fibrogenesis, which ultimately progresses to cirrhosis. Activated hepatic stellate cells (HSCs) are the main fibrogenic effectors in response to cholangiocyte damage. JCAD regulates cell proliferation and malignant transformation in nonalcoholic steatoheaptitis-associated hepatocellular carcinoma (NASH-HCC). However, its participation in cholestatic fibrosis has not been explored yet. METHODS: Serial sections of liver tissue of PBC patients were stained with immunofluorescence. Hepatic fibrosis was induced by bile duct ligation (BDL) in wild-type (WT), global JCAD knockout mice (JCAD-KO) and HSC-specific JCAD knockout mice (HSC-JCAD-KO), and evaluated by histopathology and biochemical tests. In situ-activated HSCs isolated from BDL mice were used to determine effects of JCAD on HSC activation. RESULTS: In consistence with staining of liver sections from PBC patients, immunofluorescent staining revealed that JCAD expression was identified in smooth muscle α-actin (α-SMA)-positive fibroblast-like cells and was significantly up-regulated in WT mice with BDL. JCAD deficiency remarkably ameliorated BDL-induced hepatic injury and fibrosis, as documented by liver hydroxyproline content, when compared to WT mice with BDL. Histopathologically, collagen deposition was dramatically reduced in both JCAD-KO and HSC-JCAD-KO mice compared to WT mice, as visualized by Trichrome staining and semi-quantitative scores. Moreover, JCAD deprivation significantly attenuated in situ HSC activation and reduced expression of fibrotic genes after BDL. CONCLUSION: JCAD deficiency effectively suppressed hepatic fibrosis induced by BDL in mice, and the underlying mechanisms are largely through suppressed Hippo-YAP signaling activity in HSCs.

Toward Class-Agnostic Tracking Using Feature Decorrelation in Point Clouds.

Single object tracking in point clouds has been attracting more and more attention owing to the presence of LiDAR sensors in 3D vision. However, existing methods based on deep neural networks mainly focus on training different models for different categories, which makes them unable to perform well in real-world applications when encountering classes unseen during the training phase. In this work, we investigate a more challenging task in LiDAR point clouds, namely class-agnostic tracking, where a general model is supposed to be learned to handle targets of both observed and unseen categories. In particular, we first investigate the class-agnostic performance of state-of-the-art trackers by exposing the unseen categories to them during testing. It is found that as the distribution shifts from observed to unseen classes, how to constrain the fused features between the template and the search region to maintain generalization is a key factor in class-agnostic tracking. Therefore, we propose a feature decorrelation method to address this problem, which eliminates the spurious correlations of the fused features through a set of learned weights, and further makes the search region consistent among foreground points and distinctive between foreground and background points. Experiments on KITTI and NuScenes demonstrate that the proposed method can achieve considerable improvements by benchmarking against the advanced trackers P2B and BAT, especially when tracking unseen objects.

Helicobacter pylori vacA affects the expression of COX-2 in the duodenal mucosa of patients with duodenitis.

Duodenitis refers to inflammation that occurs in the duodenum. Helicobacter pylori (Hp) is a known risk factor for duodenitis. This paper attempted to analyze the correlation between Hp virulence genotypes and the initiation and development of duodenal bulbar inflammation (DBI) to lay the foundation for the management of duodenitis induced by Hp infection. Total RNA was extracted from duodenal samples of 156 Hp-positive patients [70 with DBI and 86 with duodenal bulbar ulcer (DBU)] and 80 Hp-free DBI patients, followed by RT-qPCR detection of COX-2 mRNA expression and the presence of virulence factors. The cagA positive (62.2%), vacAs1 (21.79%), vacAm2 (23.72%), vacAs1m2 (19.87%) and iceA1 (55.80%) genotypes were dominant in 156 Hp-positive samples. Statistical difference was observed in vacAs and vacA mixtures between DBI and DBU patients. Gastric metaplasia had an association with vacA allelotypes, and its occurrence had strong correlations with vacAs1 and vacAs1m2 genotypes. The vacAs1 and vacAs1m2 genotypes were correlated with gastric metaplasia occurrence (all p<0.05). There were significant correlations between vacAs and vacA mixtures with cagA genotypes, and between iceA genotypes with vacA mixtures (all p<0.05). COX-2 was strongly expressed in Hp-infected duodenal mucosa and showed correlations with vacA genotype. COX-2 was differentially expressed in vacAs1- and vacAs2-positive patients. COX-2 was more highly upregulated in vacAs1m1- and vacAs1m2-positive patients than vacAs2m2-positive patients. Overall, Hp virulence genotype vacA was correlated with DBI and DBU initiation and development.

Determinants of photochemical characteristics of the photosynthetic electron transport chain of maize.

Introduction: The photosynthetic electron transport chain (ETC) is the bridge that links energy harvesting during the photophysical reactions at one end and energy consumption during the biochemical reactions at the other. Its functioning is thus fundamental for the proper balance between energy supply and demand in photosynthesis. Currently, there is a lack of understanding regarding how the structural properties of the ETC are affected by nutrient availability and plant developmental stages, which is a major roadblock to comprehensive modeling of photosynthesis. Methods: Redox parameters reflect the structural controls of ETC on the photochemical reactions and electron transport. We conducted joint measurements of chlorophyll fluorescence (ChlF) and gas exchange under systematically varying environmental conditions and growth stages of maize and sampled foliar nutrient contents. We utilized the recently developed steady-state photochemical model to infer redox parameters of electron transport from these measurements. Results and discussion: We found that the inferred values of these photochemical redox parameters varied with leaf macronutrient content. These variations may be caused either directly by these nutrients being components of protein complexes on the ETC or indirectly by their impacts on the structural integrity of the thylakoid and feedback from the biochemical reactions. Also, the redox parameters varied with plant morphology and developmental stage, reflecting seasonal changes in the structural properties of the ETC. Our findings will facilitate the parameterization and simulation of complete models of photosynthesis.

Association of KRAS, NRAS, BRAF and PIK3CA gene mutations with clinicopathological features, prognosis and ring finger protein 215 expression in patients with colorectal cancer.

The relationships of KRAS, NRAS, BRAF and PIK3CA gene mutations with the clinicopathological features and prognosis of colorectal cancer (CRC) in patient are lacking. Furthermore, the role of ring finger protein 215 (RNF215) in CRC patients with KRAS, NRAS, BRAF and PIK3CA mutations remains unclear. In the present study, 182 surgical resection specimens from patients with primary CRC for retrospective analysis, were collected. KRAS/NRAS/BRAF/PIK3CA gene mutations were confirmed by an amplification-refractory mutation system. Immunohistochemistry (IHC) was conducted to confirm KRAS, NRAS, BRAF and PIK3CA protein expression. RNF215 expression in patients with CRC was evaluated using TIMER 2.0 database and IHC. The individual mutation rates of KRAS, NRAS, BRAF and PIK3CA were 40.7% (74/182), 4.4% (8/182), 4.4% (8/182) and 3.3% (6/182), respectively. The KRAS exon 2 mutation rate was the highest (61.5%, 64/104), and these mutations mainly occurred at codons 12 and 13. KRAS/NRAS/BRAF/PIK3CA wild-type CRC patients had significantly longer overall survival and disease-free survival than mutated KRAS/NRAS/BRAF/PIK3CA CRC patients (P<0.05). Overall, 45.4% (5/11) of patients with PIK3CA mutations had concomitant KRAS mutations. The KRAS/NRAS/BRAF/PIK3CA gene mutation rate in patients with lymph node metastasis (76.1%, 35/46) was significantly higher than that in patients without lymph node metastasis (50.8%, 69/136) (P=0.0027). There were no significant differences in IHC expression between patients with and without KRAS, NRAS, BRAF and PIK3CA mutations (P>0.05). The TIMER 2.0 analysis showed that RNF215 expression was significantly higher in the mutated BRAF group than in the wild-type BRAF group in CRC (P<0.05). In conclusion, KRAS is the most commonly mutated gene, and KRAS mutations may be a poor prognostic factor for patients with CRC. KRAS wild-type patient resistance may be related to PIK3CA gene mutations, although this needs further verification in larger cohorts. BRAF mutations may be associated with RNF215 expression in patients with CRC.

Ultrasound-based horizontal ranging in the localization of fetal conus medullaris.

BACKGROUND: Currently, there are a variety of methods for ultrasound to localize the conus medullaris. A concern is that measured values can be influenced by variations in spinal flexion and extension. OBJECTIVE: To overcome this limitation, the present study measures the horizontal distance (HD) between the end of the conus medullaris and the caudal edge of last vertebral body ossification in normal fetus at different gestational weeks, and analyzes the relationship between the measured value and fetal growth, as well as the utility of these measurements in assessing the position of the conus medullaris. METHODS: A total of 655 fetuses at gestational weeks 18-40, who underwent routine prenatal ultrasound, were selected in the study. We measured the distance between the end of the cone of the fetal spinal cord and the caudal end of the final vertebral ossification center (Distance1, D1), the distance between the end of the spinal cord cone and the intersection of the extension of D1 with the caudal skin (Distance2, D2), and HD. We analyzed the correlation between the measurements and gestational weeks, established normal reference values, the ratio of D1, D2 and HD to the commonly used growth parameters was calculated. The ratios of D1, D2, HD and the application value of each ratio phase were analyzed, and the reliability analysis of repeated measurement results among physicians was performed. RESULTS: D1, D2 and HD exhibited strong linear correlations with gestational weeks. Among the ratios of D1, D2 and HD to common growth parameters, D2/FL stabilized after 20 weeks of gestation and consistently exceeded 1. Repeatability tests between D1, D2 and HD showed good reliability (P> 0.05). CONCLUSION: D1, D2 and HD are significantly correlated with gestational age. Horizontal distance measurement can effectively determine the position of fetal conus medullaris, enabling rapid prenatal evaluation of low position of conus medullaris and excluding the possibility of tethered cord.

An audit of autopsy-confirmed diagnostic errors in perinatal deaths: What are the most common major missed diagnoses.

Perinatal autopsies are essential to establish the cause of stillbirth or neonatal death and improve clinical practice. Limited studies have provided detailed major missed diagnoses of perinatal deaths in current clinical practice. In this retrospective audit of 177 perinatal autopsies including 99 stillbirths and 78 neonatal deaths with complete pathologic evaluation, 66 cases (21 Class I and 45 Class II diagnostic errors) were revealed as major discrepancies (37.3%), with complete agreements in 80 cases (45.2%). The difference in major discrepancies between stillbirth and neonatal death groups was significant (P < 0.001), with neonatal deaths being more prone to Class I errors. Various respiratory diseases (25/66, 37.9%) and congenital malformations (16/66, 24.2%) accounted for the majority of missed diagnoses (41/66, 62.1%). More importantly, neonatal respiratory distress syndrome (NRDS) was the most common type I missed diagnosis (7/8, 87.5%), markedly higher than the average 11.9% of all Class I errors. Our findings suggest that there are high disparities between clinical diagnoses and autopsy findings in perinatal deaths, and that various respiratory diseases are mostly inclined to cause major diagnostic errors. We first demonstrated that NRDS is the most common type I missed diagnosis in perinatal deaths, which clinicians should pay special attention to in practice.

Effects of information-knowledge-attitude-practice health education combined with cluster-based care in patients with gestational hypertension.

To analyze the impact of information-knowledge-attitude-practice (IKAP) health education incorporated with cluster-based care on blood pressure control, pregnancy outcome and life quality in those who have gestational hypertension, and to provide methodological backing for the care of patients. A total of 80 patients with pregnancy-induced hypertension were selected as the research objects and randomly divided into control and experimental groups, with 40 cases in each group. The control group received routine cluster care, which included providing individual and group health information through the distribution of health education manuals to hypertensive patients during pregnancy and their families. The experimental group received additional IKAP health education, including data collection, health knowledge imparted, concept change and behavior generation process. Blood pressure control status was measured and recorded. Adverse pregnancy outcomes include placenta previa, cesarean section, hyperamniotic fluid, fetal distress, and postpartum hemorrhage. Postpartum quality of life conditions, including physical activity, emotional awareness, physical discomfort, mental health, sleep quality, postpartum anxiety or depression, and general health were evaluated. Age, prepregnancy BMI, and educational level did not significantly vary between the 2 groups(P > .05). In comparison to the control group, the experimental group demonstrated healthier behavior. Blood pressure and weight control during pregnancy were better than control group. The frequency of adverse pregnancy was inferior to control group. The number of adverse neonatal conditions was inferior to control group. The postpartum quality of life score was higher in the experimental group compared to the control group. The combination of IKAP health education and cluster based care has a better effect on blood pressure control compared to the sole use of cluster based care. This approach can reduce the likelihood of experiencing adverse pregnancy outcomes and help improve the quality of life for patients after delivery.

Secondary succession of shrub-herb communities in the hilly area of Taihang Mountain.

Introduction: To document the successional processes of shrub-herb communities after large-scale human disturbance, and understand how changing environmental conditions affect species replacement in semi-humid hilly areas. Methods: Utilizing the established permanent plots in the hilly area of Taihang Mountain, we evaluated temporal patterns of vegetation and soil following grass-to-shrub succession. Results and Discussion: Along secondary succession, Vitex negundo var. heterophylla gradually dominated in dry sunny slope and shared the dominance with Leptodermis oblonga in shaded slope. Herbaceous dominant species in shrub-herb communities switched from Themeda japonica, Bothriochloa ischaemum, Artemisia sacrorum, and Cleistogenes chinensis in 1986 census to B. ischaemum and A. sacrorum in 2008 census, but herb was no longer dominant in 2020 census. As succession progresses, species dominance increased while richness decreased generally, and herb cover and aboveground biomass decreased, whereas shrub height, cover, and aboveground biomass increased significantly. Soil organic matter (SOM), total nitrogen (TN), total phosphorus (TP), and total potassium (TK) in topsoil increased significantly while pH declined by 1.04 units over the past three decades. Plant communities transitioned from perennial herbs to shrub-herb and then shrub communities, and V. negundo var. heterophylla dominated in the succession of shrub-herb communities. Climate and soil properties, combined with plant attributes, together drive post-disturbance secondary succession. From a management perspective, the tight coupling between vegetation and soil under local climatic conditions should be considered to improve the fragile ecosystem in the hilly area of Taihang Mountain.

Factors affecting gastrointestinal function recovery after cesarean section among Chinese mothers: A cross-sectional study.

This study was conducted to explore the influencing factors of gastrointestinal function recovery after cesarean section (CS), which could provide a reference for the enhanced recovery after surgery in obstetrics. This is a cross-sectional survey on Chinese mothers receiving CS. The participants's socio-demographic characteristics, perioperative diet, medical condition and gastrointestinal function after surgery were collected by a self-designed questionnaire. Binary logistic regression analysis was employed to explore the influencing factors of gastrointestinal function recovery after CS. A total of 1501 (94.76%) valid questionnaires were collected. The first borborygmus was 2.21 ± 0.63 hours, and the first anal exhaust was 35.73 ± 14.85 hours after the CS. The incidence of abdominal distension and intestinal obstruction were 15.1% and 0.7%, respectively. The parity, type of CS, 2-hours bleeding after surgery, time of first meal after surgery, whether taking peppermint water after surgery were the independent influencing factors for gastrointestinal function recovery after CS. We should pay more attention to the mothers with scarred uterus, manage the labor process strictly, and reduce 2-hours bleeding after surgery. The mothers with CS should also be encouraged to eat early and take peppermint water to promote intestinal peristalsis actively.

Retrospective analyses of routine preoperative blood testing in a tertiary eye hospital: could Choosing Wisely work in China?

AIMS: To explore the possibility of implementing Choosing Wisely on ocular patients in China by investigating the prevalence of abnormalities in routine preoperative blood tests (RPBTs) and its turnaround time (TAT). METHODS: Data from 102 542 ocular patients between January 2016 and December 2018, at Zhongshan Ophthalmic Center, were pooled from the laboratory information system. The test results were divided into normal and abnormal, including critical values. Ocular diseases were stratified into 11 subtypes based on the primary diagnosis. The TAT of 243 350 blood tests from January 2017 to December 2018 was categorised into transportation time and intralaboratory time. RESULTS: RPBT was grouped into complete blood count (CBC), blood biochemistry (BBC), blood coagulation (BCG) and blood-borne pathogens (BBP), completed for 97.22%, 87.66%, 94.41% and 95.35% of the recruited patients (male, 52 549 (51.25%); median(IQR) age, 54 (29-67) years), respectively. Stratified by the test items, 9.19% (95% CI 9.07% to 9.31%) were abnormal results, and 0.020% (95% CI 0.019% to 0.022%) were critical; most abnormalities were on the CBC, while glucose was the most common critical item. Classified by the patients' primary diagnosis, 76.97% (95% CI 76.71% to 77.23%) had at least one abnormal result, and 0.28% (95% CI 0.25% to 0.32%) were critical; abnormal findings were reported in 45.29% (95% CI 44.98% to 45.60%), 54.97% (95% CI 54.65% to 55.30%), 30.29% (95% CI 30.00% to 30.58%) and 11.32% (95% CI 11.12% to 11.52%) for the CBC, BBC, BCG and BBP tests, respectively. The median transportation time and intralaboratory TAT of the samples were 12 min and 78 min respectively. CONCLUSION: Blood abnormalities are common in ocular patients. With acceptable timelines, RPBT is still indispensable in China for patient safety.

Anti-miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response.

Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array analysis of PBMCs from patients with sepsis and control individuals, blood samples from 2 cohorts of patients with sepsis, and multiple animal models: mouse cecum ligation puncture-induced (CLP-induced) sepsis, mouse viral miRNA challenge, and baboon Gram+ and Gram- sepsis models. miR-93-5p met the criteria for a therapeutic target, as it was overexpressed in baboons that died early after induction of sepsis, was downregulated in patients who survived after sepsis, and correlated with negative clinical prognosticators for sepsis. Therapeutically, inhibition of miR-93-5p prolonged the overall survival of mice with CLP-induced sepsis, with a stronger effect in older mice. Mechanistically, anti-miR-93-5p therapy reduced inflammatory monocytes and increased circulating effector memory T cells, especially the CD4+ subset. AGO2 IP in miR-93-KO T cells identified important regulatory receptors, such as CD28, as direct miR-93-5p target genes. In conclusion, miR-93-5p is a potential therapeutic target in sepsis through the regulation of both innate and adaptive immunity, with possibly a greater benefit for elderly patients than for young patients.

Ring finger protein 215 is a potential prognostic biomarker involved in immune infiltration and angiogenesis in colorectal cancer.

The prognostic value of ring finger protein 215 (RNF215) in colorectal cancer (CRC) is unclear. Herein, the present study aimed to investigate the precise value of RNF215 based on CRC datasets from The Cancer Genome Atlas (TCGA) and clinical cases. CRC patient data was collected from TCGA and clinical samples from the Department of Pathology, Shanghai Fifth People's Hospital, Fudan University (Shanghai, China). Logistic regression analysis was used to investigate the correlations between RNF215 and clinicopathological characteristics. The predictive value of RNF215 for the clinical outcome of CRC was determined using Kaplan-Meier curves and Cox regression. Gene set enrichment analysis (GSEA), single-sample GSEA (ssGSEA), and angiogenesis analysis were also conducted to investigate the biological role of RNF215. Immunohistochemistry was conducted to validate the results. The results of the present study confirmed that RNF215 protein expression was significantly associated with age, lymphatic invasion, and overall survival (OS). Univariate analysis showed that upregulation of RNF215 in CRC was significantly associated with age and lymphatic invasion. Kaplan-Meier survival analysis revealed that high RNF215 expression predicted poorer OS and disease-specific survival. A total of nine experimentally detected RNF215-binding proteins were identified with the STRING tool and Cytoscape software. GSEA suggested that RNF215 was associated with several important pathways involved in tumor occurrence, including the Kyoto Encyclopedia of Genes and Genomes MAPK signaling pathway and the WikiPathway RAS signaling pathway. ssGSEA confirmed that RNF215 was significantly expressed in natural killer cells, CD8 T cells and T helper cells. Angiogenesis analysis revealed that numerous angiogenesis-related genes had the same expression trend as RNF215 in CRC. The immunostaining results indicated that RNF215 expression was significantly higher in CRC tissues than in corresponding normal tissues. In conclusion, increased RNF215 expression may be a potential molecular marker predictive of poor survival and a treatment target in CRC. In addition, RNF215 may participate in the formation of CRC through a variety of signaling pathways.

A giant breast malignant solitary fibrous tumor: A rare case report and brief review.

Solitary fibrous tumors (SFTs), which were first identified in the pleura and later at multiple anatomical locations, are rare mesenchymal neoplasms. The characteristics of SFTs include well-circumscribed margins, intense vascularity and a relatively indolent clinical course. SFTs originating from the breast are rare. To the best of our knowledge, only 33 cases of breast SFTs, including five malignant tumors, have been reported to date. In the present study, a rare case of complete resection of a giant malignant SFT is reported. A 48-year-old female patient who visited Weifang People's Hospital (Weifang, China) had a 2-year history of a right palpable breast lesion. The patient reported no other symptoms, such as skin changes or nipple discharge. An ultrasound examination revealed a giant, well-circumscribed, heterogeneous and hypoechoic lesion with central and peripheral blood flow. Owing to the large size of the lesion, mammography and magnetic resonance imaging were not feasible. Core needle biology showed that the lesion was a malignant spindle cell tumor. Following this, mastectomy and sentinel lymph node biopsy were performed. The sentinel lymph nodes exhibited metastasis. A definitive diagnosis of malignant SFT was made by microscopic examination with immunohistochemistry. The treatment strategy for benign breast SFTs should be complete surgical excision, whereas for malignant SFTs, it should include radical resection along with radiotherapy and chemotherapy. Owing to the indolent nature and late recurrence and metastasis of malignant breast SFTs, regular patient follow-up for a longer duration is essential.

The Association of Experienced Long Working Hours and Depression, Anxiety, and Suicidal Ideation Among Chinese Medical Residents During the COVID-19 Pandemic: A Multi-Center Cross-Sectional Study.

Background: Long working hours are common among medical residents and may increase the risk of mental disorders. We aimed to investigate the association between experienced long working hours and depression, anxiety, and suicidal ideation among Chinese medical residents during the COVID-19 pandemic. Methods: This study was conducted in September 2022; 1343 residents from three center in Northeastern China were included in the final analysis (effective response rate: 87.61%). The data were collected from participants via online self-administered questionnaires. Depression and anxiety were measured by the Patient Health Questionnaire (PHQ-9) and the General Anxiety Disorder (GAD-7) scale, respectively. Adjusted odds ratios and 95% confidence intervals were determined after adjusting for potential confounders by binary unconditional logistic regression. Results: The effective response rate was 87.61%. Among the 1343 participants, 12.88% (173), 9.90% (133), and 9.68% (130) had experienced major depression, major anxiety, and suicidal ideation, respectively. We found that longer weekly worktime increased the risk of major depression, particularly in those who worked for more than 60 hours per week (≥ 61 hours vs ≤ 40 hours, OR=1.87, P for trend = 0.003). However, this trend was not observed for either major anxiety or suicidal ideation (P for trend > 0.05 for both). Conclusion: This study revealed that there was a considerable incidence of poor mental health among medical residents; furthermore, the longer weekly worktime was associated with a higher risk of major depression, especially for those who worked more than 60 hours per week, but this association was not observed in either major anxiety or suicidal ideation. This may help policymakers to develop targeted interventions.

Alpha-Tocopherol Significantly Improved Squalene Production Yield of Aurantiochytrium sp. TWZ-97 through Lowering ROS levels and Up-Regulating Key Genes of Central Carbon Metabolism Pathways.

Media supplementation has proven to be an effective technique for improving byproduct yield during microbial fermentation. This study explored the impact of different concentrations of bioactive compounds, namely alpha-tocopherol, mannitol, melatonin, sesamol, ascorbic acid, and biotin, on the Aurantiochytrium sp. TWZ-97 culture. Our investigation revealed that alpha-tocopherol was the most effective compound in reducing the reactive oxygen species (ROS) burden, both directly and indirectly. Adding 0.7 g/L of alpha-tocopherol led to an 18% improvement in biomass, from 6.29 g/L to 7.42 g/L. Moreover, the squalene concentration increased from 129.8 mg/L to 240.2 mg/L, indicating an 85% improvement, while the squalene yield increased by 63.2%, from 19.82 mg/g to 32.4 mg/g. Additionally, our comparative transcriptomics analysis suggested that several genes involved in glycolysis, pentose phosphate pathway, TCA cycle, and MVA pathway were overexpressed following alpha-tocopherol supplementation. The alpha-tocopherol supplementation also lowered ROS levels by binding directly to ROS generated in the fermentation medium and indirectly by stimulating genes that encode antioxidative enzymes, thereby decreasing the ROS burden. Our findings suggest that alpha-tocopherol supplementation can be an effective method for improving squalene production in Aurantiochytrium sp. TWZ-97 culture.