The metabolic crosstalk of cancer-associated fibroblasts and tumor cells: Recent advances and future perspectives.

Tumor cells grow in a microenvironment with a lack of nutrients and oxygen. Cancer-associated fibroblasts (CAFs) as one major component of tumor microenvironment have strong ability to survive under stressful conditions through metabolic remodelling. Furthermore, CAFs are educated by tumor cells and help them adapt to the hostile microenvironment through their metabolic communication. By inducing catabolism, CAFs release nutrients into the microenvironment which are taken up by tumor cells to satisfy their metabolic requirements. Furthermore, CAFs can recycle toxic metabolic wastes produced by cancer cells into energetic substances, allowing cancer cells to undergo biosynthesis. Their metabolic crosstalk also enhances CAFs' pro-tumor phenotype and reshape the microenvironment facilitating tumor cells' metastasis and immune escape. In this review, we have analyzed the effect and mechanisms of metabolic crosstalk between tumor cells and CAFs. We also analyzed the future perspectives in this area from the points of CAFs heterogeneity, spatial metabonomics and patient-derived tumor organoids (PDOs). These information may deepen the knowledge of tumor metabolism regulated by CAFs and provide novel insights into the development of metabolism-based anti-cancer strategies.

A multi-task deep learning approach for real-time view classification and quality assessment of echocardiographic images.

High-quality standard views in two-dimensional echocardiography are essential for accurate cardiovascular disease diagnosis and treatment decisions. However, the quality of echocardiographic images is highly dependent on the practitioner's experience. Ensuring timely quality control of echocardiographic images in the clinical setting remains a significant challenge. In this study, we aimed to propose new quality assessment criteria and develop a multi-task deep learning model for real-time multi-view classification and image quality assessment (six standard views and "others"). A total of 170,311 echocardiographic images collected between 2015 and 2022 were utilized to develop and evaluate the model. On the test set, the model achieved an overall classification accuracy of 97.8% (95%CI 97.7-98.0) and a mean absolute error of 6.54 (95%CI 6.43-6.66). A single-frame inference time of 2.8 ms was achieved, meeting real-time requirements. We also analyzed pre-stored images from three distinct groups of echocardiographers (junior, senior, and expert) to evaluate the clinical feasibility of the model. Our multi-task model can provide objective, reproducible, and clinically significant view quality assessment results for echocardiographic images, potentially optimizing the clinical image acquisition process and improving AI-assisted diagnosis accuracy.

The function and mechanism of Human nasal mucosa-derived mesenchymal stem cells in allergic rhinitis in mice.

PURPOSE: To investigate the immunomodulatory effects and potential mechanisms of human nasal mucosa-derived mesenchymal stem cells(hNMSCs) on mouse allergic rhinitis, and to compare them with human umbilical cord-derived mesenchymal stem cells (hUCMSCs). METHOD: hNMSCs and hUCMSCs were isolated and cultured for identification from human nasal mucosa and umbilical cord tissues. A co-culture system of LPS-stimulated RAW264.7 cells/mouse peritoneal macrophages and MSCs was employed.Changes in inflammatory factors in RAW264.7 cells and the culture medium as well as the expression of NF-κB signaling pathway in RAW264.7 cells were detected. Forty-eight BALB/c mice were randomly divided into control, OVA, hNMSCs, and hUCMSCs groups. An allergic rhinitis (AR) model was established through ovalbumin (OVA) stimulation and treated with hNMSCs and hUCMSCs. Subsequent assessments included related symptoms, biological changes, and the expression of the NF-κB signaling pathway in the nasal mucosa of mice. RESULTS: MSCs can be successfully isolated from human nasal mucosa. Both hNMSCs and hUCMSCs interventions significantly reverseed the inflammation induced by LPS and suppressed the upregulation of the NF-κB signaling pathway in RAW264.7 cells. Treatment with hNMSCs and hUCMSCs alleviated mouse allergic symptoms, reduced levels of total IgE, OVA-specific IgE and IgG1 in mouse serum, TH2-type cytokines and chemokines in mouse nasal mucosa, and TH2-type cytokines in mouse spleen culture medium, while also inhibiting the expression of the NF-κB signaling pathway in the nasal mucosa of mice. moreover, the hNMSCs group showed a more significant reduction in OVA-specific IgG1 in serum and IL-4 expression levels in mouse spleen culture medium compared to the hUCMSCs group. CONCLUSION: Our findings suggest that hNMSCs can ameliorate allergic rhinitis in mice, with a certain advantage in anti-inflammatory effects compared to hUCMSCs. The NF-κB pathway is likely involved in the anti-inflammatory regulation process by hNMSCs.Therefore, hNMSCs might represent a novel therapeutic approach for allergic rhinitis.

Genome-Wide Characterization of the BTB Gene Family in Poplar and Expression Analysis in Response to Hormones and Biotic/Abiotic Stresses.

The BTB (Broad-complex, tramtrack, and bric-a-brac) gene family, characterized by a highly conserved BTB domain, is implicated in a spectrum of biological processes, encompassing growth and development, as well as stress responses. Characterization and functional studies of BTB genes in poplar are still limited, especially regarding their response to hormones and biotic/abiotic stresses. In this study, we conducted an HMMER search in conjunction with BLASTp and identified 95 BTB gene models in Populus trichocarpa. Through domain motif and phylogenetic relationship analyses, these proteins were classified into eight families, NPH3, TAZ, Ankyrin, only BTB, BACK, Armadillo, TPR, and MATH. Collinearity analysis of poplar BTB genes with homologs in six other species elucidated evolutionary relationships and functional conservations. RNA-seq analysis of five tissues of poplar identified BTB genes as playing a pivotal role during developmental processes. Comprehensive RT-qPCR analysis of 11 BTB genes across leaves, roots, and xylem tissues revealed their responsive expression patterns under diverse hormonal and biotic/abiotic stress conditions, with varying degrees of regulation observed in the results. This study marks the first in-depth exploration of the BTB gene family in poplar, providing insights into the potential roles of BTB genes in hormonal regulation and response to stress.

Diagnosis of light­chain deposition disease after renal transplantation: A case report and literature review.

Light chain deposition disease (LCDD) is a rare, clonal plasma cell proliferative condition. The deposition of nonamyloid monoclonal immunoglobulin light chains predominantly affects the kidneys, which may lead to end-stage renal disease, eventually requiring renal replacement therapy. The present study reported a rare case of LCDD that was confirmed after renal transplantation. A 49-year-old man initially presented with heavy proteinuria, hypoproteinemia, hyperlipidemia and renal insufficiency. The patient was diagnosed with nephrotic syndrome and pathological examination revealed fibrillary glomerulonephritis in 2014. Treatment was started with prednisolone. About 5 years later, the patient began to receive continuous hemodialysis due to worsening serum creatinine levels. Renal allograft transplantation was performed in 2020 and dialysis independence was achieved. Laboratory findings before renal transplantation revealed that serum and urine immunofixation electrophoresis was negative. Allograft kidney biopsy established the pathological diagnosis of LCDD at >1 year after renal transplantation for renal dysfunction. The treatment is challenging due to the lack of generally accepted standard treatment practices. Administration of bortezomib combined with dexamethasone was started. As anemia and renal failure developed progressively, the treatment was switched to anti-CD38 antibody and continuous hemodialysis was restarted. The best response achieved was hematological partial response and relief of anemia. However, the patient's renal function did not improve and he remains to have end-stage kidney disease. LCDD is easily missed in cases in which serum and urine immunofixation electrophoresis is negative. Hence, early recognition of LCCD based on kidney biopsy is important. To the best of our knowledge, the use of anti-CD38 antibody therapy in patients with LCDD is rarely reported. Anti-CD38 antibody is effective in treating LCDD, but it may not reverse the marked deterioration of renal function.

The density of the inner cell mass is a new indicator of the quality of a human blastocyst: a valid supplement to the Gardner scoring system.

STUDY QUESTION: Can the density of the inner cell mass (ICM) be a new indicator of the quality of the human blastocyst? SUMMARY ANSWER: The densification index (DI) developed in this study can quantify ICM density and provide positive guidance for ploidy, pregnancy, and live birth. WHAT IS KNOWN ALREADY: In evaluating the quality of ICM, reproductive care clinics still use size indicators without further evaluation. The main disadvantage of this current method is that the evaluation of blastocyst ICM is relatively rough and cannot meet the needs of clinical embryologists, especially when multiple blastocysts have the same ICM score, which makes them difficult to evaluate further. STUDY DESIGN, SIZE, DURATION: This observational study included data from 2272 blastocysts in 1991 frozen-thawed embryo transfer (FET) cycles between January 2018 to November 2021 and 1105 blastocysts in 430 preimplantation genetic testing cycles between January 2019 and February 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: FET, ICSI, blastocyst culture, trophectoderm biopsy, time-lapse (TL) monitoring, and next-generation sequencing were performed. After preliminary sample size selection, the 11 focal plane images captured by the TL system were normalized and the spatial frequency was used to construct the DI of the ICM. MAIN RESULTS AND THE ROLE OF CHANCE: This study successfully constructed a quantitative indicator DI that can reflect the degree of ICM density in terms of fusion and texture features. The higher the DI value, the better the density of the blastocyst ICM, and the higher the chances that the blastocyst was euploid (P < 0.001) and that pregnancy (P < 0.001) and live birth (P = 0.005) were reached. In blastocysts with ICM graded B and blastocysts graded 4BB, DI was also positively associated with ploidy, pregnancy, and live birth (P < 0.05). ROC analysis showed that combining the Gardner scoring system with DI can more effectively predict pregnancy and live births, when compared to using the Gardner scoring system alone. LIMITATIONS, REASONS FOR CAUTION: Accurate calculation of the DI value places high demands on image quality, requiring manual selection of the clearest focal plane and exposure control. Images with the ICM not completely within the field of view cannot be used. The association between the density of ICM and chromosomal mosaicism was not evaluated. The associations between the density of ICM and different assisted reproductive technologies and different culture conditions in embryo laboratories were also not evaluated. Prospective studies are needed to further investigate the impact of ICM density on clinical outcomes. WIDER IMPLICATIONS OF THE FINDINGS: ICM density assessment is a new direction in blastocyst assessment. This study explores new ways of assessing blastocyst ICM density and develops quantitative indicators and a corresponding qualitative evaluation scheme for ICM density. The DI of the blastocyst ICM developed in this study is easy to calculate and requires only TL equipment and image processing, providing positive guidance for clinical outcomes. The qualitative evaluation scheme of ICM density can assist embryologists without TL equipment to manually evaluate ICM density. ICM density is a simple indicator that can be used in practice and is a good complement to the blastocyst scoring systems currently used in most centers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Research & Development Program of China (2021YFC2700603). The authors report no financial or commercial conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Comparative study on emotional behavior and parental job stress of only-child and non-only-child preschool children.

BACKGROUND: Studies have revealed that Children's psychological, behavioral, and emotional problems are easily influenced by the family environment. In recent years, the family structure in China has undergone significant changes, with more families having two or three children. AIM: To explore the relationship between emotional behavior and parental job stress in only preschool and non-only preschool children. METHODS: Children aged 3-6 in kindergartens in four main urban areas of Shijiazhuang were selected by stratified sampling for a questionnaire and divided into only and non-only child groups. Their emotional behaviors and parental pressure were compared. Only and non-only children were paired in a 1:1 ratio by class and age (difference less than or equal to 6 months), and the matched data were compared. The relationship between children's emotional behavior and parents' job stress before and after matching was analyzed. RESULTS: Before matching, the mother's occupation, children's personality characteristics, and children's rearing patterns differed between the groups (P < 0.05). After matching 550 pairs, differences in the children's parenting styles remained. There were significant differences in children's gender and parents' attitudes toward children between the two groups. The Strengths and Difficulties Questionnaire (SDQ) scores of children in the only child group and the Parenting Stress Index-Short Form (PSI-SF) scores of parents were significantly lower than those in the non-only child group (P < 0.05). Pearson's correlation analysis showed that after matching, there was a positive correlation between children's parenting style and parents' attitudes toward their children (r = 0.096, P < 0.01), and the PSI-SF score was positively correlated with children's gender, parents' attitudes toward their children, and SDQ scores (r = 0.077, 0.193, 0.172, 0.222). CONCLUSION: Preschool children's emotional behavior and parental pressure were significantly higher in multi-child families. Parental pressure in differently structured families was associated with many factors, and preschool children's emotional behavior was positively correlated with parental pressure.

The genomic and immunogenomic landscape of mechanics pathway informs clinical prognosis and response to mechanotherapy.

Mechanics shape cell and tissue plasticity and maintain their homeostasis. In cancers, mechanical signals regulate cancer hallmarks via mechanotransduction pathways, such as proliferation, metastasis and metabolic reprogramming. However, comprehensive characterization of mechanotransduction pathway genes and their clinical relevance across different cancer types remains untouched. Herein, we systematically portrayed the alterations of mechanotransduction pathway genes across 31 cancer types using The Cancer Genome Atlas (TCGA) databases. All the cancer types could be categorized into 6 subtypes based upon the transcriptional pattern of mechanics pathway genes. Each subtype has its own unique molecular expression pattern, mutation landscapes, immune infiltrates, and patient clinical outcome. We further found that the responses of two subtypes of cancers, one with the optimal outcome and the other with the worst prognosis, to a classical mechanotherapeutic agent (Fasudil, RhoA/ROCK inhibitor) were totally different, indicating that our cancer stratification system based upon mechanotransduction pathway genes could inform clinical responses of patients to mechanotherapeutic agents. Collectively, our study provides a novel pan-cancer landscape of the mechanotransduction pathways and underscores its potential clinical significance in the prediction of clinical prognosis and therapeutic responses to mechanotherapy among cancer patients.

Modified traditional TNM staging of pyriform sinus and hypopharyngeal and laryngeal cancer based on lymph node ratio and its clinical significance: a population-based study combined with external validation.

BACKGROUND: To evaluate the application value of a new TLNRM staging prediction model based on lymph node ratio (LNR) in patients with Pyriform Sinus and Hypopharyngeal and Laryngeal cancer (PHLC). METHODS: A total of 2,257 patients with pathologically diagnosed PHLC from 2004 through 2019 were collected from the SEE database for analysis. The N staging of AJCC was replaced by LNR, and we compared the differences in patient prognosis and judgment ability between the new TLNRM staging and the 8th edition TNM staging. At the same time, data from 1,094 people in our hospital were included for external verification and validation. RESULTS: We selected four cutoff points based on LNR and reclassified N staging into five groups (LNR1-5). Compared to the traditional TNM staging (8th edition), the new TLNRM staging showed a statistically significant 5-year OS difference. The decision curve showed that the new TLNRM staging had a higher net benefit for different decision thresholds than the traditional TNM staging system's prediction line. The smaller AIC and BIC suggested that the new staging system had a higher sensitivity to prognosis evaluation compared to the traditional staging system. TLNRM stage III patients can benefit from radiotherapy, while TLNRM IVA and IVB patients can benefit from chemoradiotherapy. The same conclusion has been drawn from external validation data from our center. CONCLUSIONS: Compared with the traditional 8th edition AJCC staging system, the new TLNRM staging system has advantages in predicting the staging and prognosis of PHLC patients, and can independently guide postoperative chemoradiotherapy in patients.

The effect of systematic couple group therapy on families with depressed juveniles: a pilot trial.

Background: Depression is a primary cause of illness and disability among teenagers, and the incidence of depression and the number of untreated young people have increased in recent years. Effective intervention for those youths could decrease the disease burden and suicide or self-harm risk during preadolescence and adolescence. Objective: To verify the short efficacy of the systemic couple group therapy (SCGT) on youths' depression changes and families with depressed adolescents. Methods: The study was a self-control trial; only within-group changes were evaluated. Participants were couples with a depressed child who was resistant to psychotherapy; they were recruited non-randomly through convenient sampling. The paired-sample t-test and Wilcoxon signed-rank test were used to compare differences before and after interventions. The effect sizes were also estimated using Cohen's d. Spearman's correlation analysis was used to examine associations between changes. Results: A downward trend was seen in depressive symptoms after treatment, and Cohen's d was 0.33 (p = 0.258). The adolescents perceived fewer interparental conflicts, and the effect sizes were medium for perceived conflict frequency (0.66, p = 0.043), conflict intensity (0.73, p = 0.028), conflict solutions (0.75, p = 0.025), coping efficacy (0.68, p = 0.038), and perceived threat (0.57, p = 0.072). For parents, global communication quality, constructive communication patterns, and subjective marital satisfaction significantly improved after interventions, with large effect sizes (1.11, 0.85, and 1.03, respectively; all p < 0.001). Other destructive communication patterns such as demand/withdraw (p = 0.003) and mutual avoidance (p = 0.018) and communication strategies like verbal aggression (p = 0.012), stonewalling (p = 0.002), avoidance-capitulation (p = 0.036), and child involvement (p = 0.001) also reduced, with medium effect sizes (0.69, 0.52, 0.55, 0.71, 0.46, and 0.79, respectively). Meanwhile, the associations between depression changes and changes in interparental conflicts (p < 0.001) and marital satisfaction (p = 0.001) were significant. Conclusions and clinical relevance: The SCGT offers the possibility for the treatment of families with depressed children who are unwilling to seek treatment. Helping parents improve communication and marital quality may have benefits on children's depressive symptoms.

Efficacy Analysis of Bortezomib Combined with Lenalidomide in Newly Diagnosed Multiple Myeloma with 1q21 Gain/Amp.

OBJECTIVE: 1q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in patients with newly diagnosed multiple myeloma (NDMM). To explore the optimal induction treatment, we analyzed and compared the efficacy of combinations of bortezomib-lenalidomide-dexamethasone (VRD) and only bortezomib-based triplet regimens without lenalidomide (only bortezomib-based) as induction therapy in patients with NDMM with 1q21 gain/Amp. METHODS: Seventy-six NDMM patients with 1q21 gain/Amp who were admitted to our center from 2016 to 2022 were retrospectively analyzed in this study. The progression and efficacy of the patients were observed. RESULTS: Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients with 1q21 gain/Amp. The best outcome assessment was that 17.1% achieved complete response (CR) and 44.7% achieved very good partial response (VGPR). Patients in the VRD group had a deeper response (VGPR: 63.6% vs 37.0%, P = 0.034), lower disease progression rate (31.8% vs 70.3%, P = 0.002), longer sustained remission (median 49.7 months vs 18.3 months, P = 0.030), and longer PFS (median 61.9 months vs 22.9 months, P = 0.032) than those treated with only bortezomib-based induction therapy. No significant differences were found among patients with partial response or better (86.4% vs 77.8%, P = 0.532) or CR (27.3% vs 13.0%, P = 0.180). Multivariate analysis showed that only bortezomib-based induction therapy (P = 0.003, HR 0.246, 95% CI 0.097-0.620), International Staging System stage III (P = 0.003, HR 3.844, 95% CI 1.588-9.308) and LMR <3.6 (P = 0.032, HR 0.491, 95% CI 0.257-0.940) were significantly associated with adverse PFS. CONCLUSIONS: When compared with the sequential administration of bortezomib and lenalidomide or only bortezomib-based protocols, NDMM patients with 1q21 gain/Amp may benefit more from VRD as initial treatments.

The multifaceted mechanisms of Dihydrotanshinone I in the treatment of tumors.

The morbidity and mortality of malignant tumors are progressively rising on an annual basis. Traditional Chinese Medicine (TCM) holds promise as a possible therapeutic agent for the avoidance or therapy of malignant tumors. Salvia miltiorrhiza Bunge (Danshen), a traditional Asian functional food, has therapeutic characteristics in application for the treatment of malignant tumors. Dihydrotanshinone I (DHTS) is the principal lipophilic phenanthraquinone compound found in Salvia miltiorrhiza Bunge, whose anti-tumor effect has attracted widespread attention. The anti-tumor effects include inhibiting cancer cell proliferation, triggering apoptosis of tumor cells, inducing ferroptosis in tumor cells, inhibiting tumor cell invasion and metastasis, and improving drug resistance of tumor cells. In this paper, we summarized and analyzed the mechanisms and targets of anti-tumor effect of DHTS, providing new ideas and establishing a solid theoretical basis for the future advancement and clinical treatment of DHTS.

Research progress of traditional Chinese medicine in the treatment of allergic rhinitis.

Allergic rhinitis, one of the common diseases in otolaryngology, has shown an increasing incidence under the influence of various geographical, cultural and economic factors, making it a common and serious global public health problem. Modern medicine uses medication as the primary therapy for allergic rhinitis, but poor symptom control and easy relapse are the disadvantages of this treatment. However, Traditional Chinese medicine, with its long history, has treated allergic rhinitis by symptomatic treatment according to pattern differentiation with its unique insights and methods, which are effective and safe in numerous clinical studies. Therefore, this paper describes TCM decoction, acupuncture, moxibustion, acupoint application, catgut-embedding therapy and ear acupuncture in the treatment of AR. This study aims to provide more personalized and precise treatment for allergic rhinitis patients by investigating the mechanism of action, clinical research and development of traditional Chinese medicine treatments.

Establishment of self-reported hearing cut-off value on the Chinese version of short form of speech, spatial and qualities of hearing scale (SSQ12).

OBJECTIVE: The aim of this study was to evaluate the efficacy of the Chinese version of Speech, Spatial and Qualities of Hearing Scale (C-SSQ12) in the Chinese Mandarin-speaking population and to determine its screening cut-off value by comparing measured pure-tone average (PTA), the Hearing Handicap Inventory for the Elderly-Screening Version (HHIE-S) scores and C-SSQ12 scores. DESIGN: All participants completed the C-SSQ12 questionnaire and underwent the pure-tone audiometry. Older subjects aged ≧ 60 years completed the HHIE-S questionnaire. The optimal cut-off value for the C-SSQ12 as a hearing screening tool was calculated by comparing different cut-offs and hearing thresholds. STUDY SAMPLE: A total of 300 subjects were recruited. RESULTS: There was a negative correlation between C-SSQ12 scores and HHIE-S scores (r = -0.749). C-SSQ12 scores were negatively correlated with PTA (r = -0.507; r = -0.542). The best cut-off value for the C-SSQ12 was 6.0, with a sensitivity of 78.2%, specificity of 80.3%, positive predictive value of 63.7% and negative predictive value of 97.0% (PTA > 40dBHL for bilateral ears). CONCLUSIONS: Compared to mild hearing loss, the C-SSQ12 is a reliable and validated hearing screening tool with increased sensitivity for detecting moderate-to-severe hearing loss.

Knowledge, Attitude, and Practice About Antibiotic Use and Antimicrobial Resistance Among Nursing Students in China: A Cross Sectional Study.

Purpose: The knowledge, attitude, and practices (KAP) concerning antibiotics by healthcare students have the potential impact on controlling antibiotic abuse and antimicrobial resistance (AMR) growth. This study aims to evaluate the levels and explore the associated factors with KAP on antibiotic use and AMR in Chinese nursing students. Methods: A cross-sectional survey using a self-administered questionnaire consisting of demographics and selected features and KAP on antibiotic use and AMR was conducted to measure KAP levels among nursing students at various universities in Hubei Province, China. The logistic regression analyses were performed to analyze the potential factors associated with the KAP. Results: The survey eventually included a total of 1959 nursing students. The mean scores for KAP were 57.89 ±26.32, 55.00 ±12.50, and 71.88 ±15.63, respectively. Regarding knowledge, 54.3% of participants were unaware that antibiotic was ineffective against viral infections. Regarding attitude, 36% of participants agreed that current antibiotic abuse existed; 96.2% of participants thought it necessary to set up a special course on antibiotics. Regarding practice, only 48.4% of participants usually purchased antibiotics with a prescription. Multivariable analyses indicated that lack of discussion on AMR in school courses was an independent risk factor against KAP, respectively. The main knowledge sources of antibiotic being outside the classroom was an independent risk factor related to knowledge and practice. The average score >80 points was an independent protective factor related to knowledge and practice. Conclusion: The KAP level on antibiotic use and AMR among Hubei nursing students was general and required further strengthening. Nursing students with risk factors should be prioritized in educational interventions. The findings of our study pointed out some directions for tailored interventions to improve the training on antibiotics.

Activation of ERß hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor ß (ERß) in TNBC, but the detailed molecular mechanisms downstream ERß activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERß agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp439 and Lys443 of ERß were critical for the binding between U2AF1 and ERß. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase (OPLAH) could affect its enzymatic activity and is essential for ERß-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERß activation in TNBC, which provides rationale for ERß activation-based single or combined therapy for patients with TNBC.

N6-methyladenosine (m6A) modification in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers of human, the tumor-related death of which ranks third among the common malignances. N6-methyladenosine (m6A) methylation, the most abundant internal modification of RNA in mammals, participates in the metabolism of mRNA and interrelates with ncRNAs. In this paper, we overviewed the complex function of m6A regulators in HCC, including regulating the tumorigenesis, progression, prognosis, stemness, metabolic reprogramming, autophagy, ferroptosis, drug resistance and tumor immune microenvironment (TIME). Furthermore, we elucidated the interplay between m6A modification and non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). Finally, we summarized the potential of m6A regulators as diagnostic biomarkers. What's more, we reviewed the inhibitors targeting m6A enzymes as promising therapeutic targets of HCC. We aimed to help understand the function of m6A methylation in HCC systematically and comprehensively so that more effective strategies for HCC treatment will be developed.

Knowledge, attitudes and practices towards the diagnosis and management of paediatric sepsis among paediatric physicians and nurses: a cross-sectional study of 21 hospitals in Hubei Province, China.

OBJECTIVES: To evaluate the knowledge, attitudes and practices towards diagnosing and managing paediatric sepsis among paediatric physicians and nurses. DESIGN: A cross-sectional, questionnaire-based study. SETTING: 21 hospitals in Hubei Province between February 2023 and March 2023. PARTICIPANTS: Paediatric physicians and nurses. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOME MEASURES: The questionnaire contained 35 items across four dimensions (demographic information, knowledge, attitude and practice). RESULTS: The study included 295 participants (173 women). The average knowledge, attitude and practice scores were 10.93±2.61 points (possible range, 0-20 points), 32.22±2.65 points (possible range, 7-35 points) and 36.54±5.24 points (possible range, 9-45 points), respectively. Knowledge had a direct influence on both attitude (ß=0.240, 95% CI 0.136 to 0.365, p=0.009) and practice (ß=0.278, 95% CI 0.084 to 0.513, p=0.010), which also indirectly influenced practice through attitude (ß=0.162, 95% CI 0.078 to 0.290, p=0.007). Attitude directly influenced practice (ß=0.677, 95% CI 0.384 to 0.902, p=0.025). A higher attitude score was associated with good practice (OR=1.392; 95% CI 1.231 to 1.576; p<0.001), while not working in a tertiary hospital reduced the odds of good practice (OR=0.443; 95% CI 0.2390.821; p=0.010). CONCLUSIONS: The knowledge regarding paediatric sepsis, especially knowledge about sepsis management, is poor among paediatric physicians and nurses in Hubei Province. The findings of this study may facilitate the development and implementation of training programmes to improve the diagnosis and management of paediatric sepsis.

Recurrent miscarriage and low-titer antiphospholipid antibodies.

OBJECTIVE: To evaluate the clinical features and pregnancy outcomes in patients experiencing recurrent miscarriage (RM) with either low-titer or medium-high titer positivity of antiphospholipid antibodies (aPL). METHODS: A retrospective review of medical records was conducted for patients with aPL positivity and recurrent miscarriage between 2018 and 2022. The clinical features, treatment strategies, outcomes were compared between the patients with low (n = 92) and medium (n = 32) titer of aPL. RESULTS: A total of 118 patients, resulting in 124 obstetric episodes (pregnancies), with a mean age of 33. 15 ± 4.56 and 31.47 ± 4.41 years between the two groups. The low-titer group exhibited a higher frequency of anti-cardiolipin antibodies IgM (P < 0.001), whereas the medium-high titer group demonstrated a higher frequency of anti-ß2-glycoprotein 1 antibodies IgG (P < 0.001) and IgM (P = 0.032). Moreover, the medium-high titer group displayed a significantly elevated erythrocyte sedimentation rate compared to the low-titer group (P < 0.05). In the low-titer group, 71 patients (77.2%) received appropriate treatment, resulting in 48 live births (67.6%) and 23 repeat abortions (32.4%). In the medium-high titer group, 29 patients (90.6%) received relevant treatment, leading to 23 live births (79.3%) and 6 repeat abortions (20.7%). No significant differences were observed in live births or maternal-fetal complications between the two groups (all P > 0.05). CONCLUSION: Noteworthy distinctions in laboratory parameters were identified between the low-titer and medium-high titer groups. However, when appropriately treated, the fetal-maternal outcomes were comparable in both groups. Timely intervention by clinicians is imperative to enhance pregnancy outcomes in patients experiencing recurrent miscarriage with low levels of aPL. Key Points • This study challenges the conventional belief that only the higher antiphospholipid antibodies (aPL) titers directly correlated with worse pregnancy outcomes, which emphasized the importance of patients with low titer positive aPL-positive RM. • The results underscore the need for timely intervention in women with low titer aPL-positive RM, as it leads to favorable maternal-fetal outcomes.