Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Mechanisms and clinical landscape of N6-methyladenosine (m6A) RNA modification in gastrointestinal tract cancers.

Epigenetics encompasses reversible and heritable chemical modifications of non-nuclear DNA sequences, including DNA and RNA methylation, histone modifications, non-coding RNA modifications, and chromatin rearrangements. In addition to well-studied DNA and histone methylation, RNA methylation has emerged as a hot topic in biological sciences over the past decade. N6-methyladenosine (m6A) is the most common and abundant modification in eukaryotic mRNA, affecting all RNA stages, including transcription, translation, and degradation. Advances in high-throughput sequencing technologies made it feasible to identify the chemical basis and biological functions of m6A RNA. Dysregulation of m6A levels and associated modifying proteins can both inhibit and promote cancer, highlighting the importance of the tumor microenvironment in diverse biological processes. Gastrointestinal tract cancers, including gastric, colorectal, and pancreatic cancers, are among the most common and deadly malignancies in humans. Growing evidence suggests a close association between m6A levels and the progression of gastrointestinal tumors. Global m6A modification levels are substantially modified in gastrointestinal tumor tissues and cell lines compared to healthy tissues and cells, possibly influencing various biological behaviors such as tumor cell proliferation, invasion, metastasis, and drug resistance. Exploring the diagnostic and therapeutic potential of m6A-related proteins is critical from a clinical standpoint. Developing more specific and effective m6A modulators offers new options for treating these tumors and deeper insights into gastrointestinal tract cancers.

Negative expression of CD117 predicted inferior OS and PFS in acute promyelocytic leukemia.

INTRODUCTION: In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the clinical significance of CD117 antigen in acute promyelocytic leukemia (APL). The aim of this study was to retrospectively analyze the clinical features and prognostic significance of CD117 in APL. METHODS: In this study, we retrospectively investigated the clinicopathological characteristics, outcome, and prognostic impact of negative CD117 expression (CD117-) in 169 APL patients treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) containing regimen. RESULTS: The median follow-up period was 63.0 months. CD117- was detected in 13 APL patients (7.7%). No significant differences were found in baseline characteristics between CD117+ and CD117- subgroups. However, compared to CD117+ APL, the incidence of early death (ED) was significantly higher in CD117- APL (p = 0.023). By multivariate analysis, CD117- was an independent adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) (p = 0.022 and p = 0.014, respectively). CONCLUSIONS: To sum up, CD117- is associated with greater risk of ED and has the statistical power to predict inferior OS and PFS, this marker may be considered to build prognostic scores for risk-adapted therapeutic strategies in APL management.

Evaluating the clinical impact of resuscitative endovascular balloon occlusion of the aorta in patients with blunt trauma with hemorrhagic shock and coexisting traumatic brain injuries: a retrospective cohort study.

BACKGROUND: The impact of resuscitative endovascular balloon occlusion of the aorta (REBOA) on traumatic brain injuries remains uncertain, with potential outcomes ranging from neuroprotection to exacerbation of the injury. The study aimed to evaluate consciousness recovery in patients with blunt trauma with shock and traumatic brain injuries. MATERIAL AND METHODS: Data were obtained from the American College of Surgeons Trauma Quality Improvement Program from 2017-2019. During the study period, 3,138,896 trauma registries were examined, and 16,016 adult patients with blunt trauma, shock, and traumatic brain injuries were included. Among these, 172 (1.1%) underwent REBOA. Comparisons were conducted between patients with and without REBOA after implementing 1:3 propensity score matching to mitigate disparities. The primary outcome was the highest Glasgow Coma Scale score during admission. The secondary outcomes encompassed the volume of blood transfusion, the necessity for hemostatic interventions and therapeutic neurosurgery, and mortality rate. RESULTS: Through well-balanced propensity score matching, a notable difference in mortality rate was observed, with 59.7% in the REBOA group and 48.7% in the non-REBOA group (P=0.015). In the REBOA group, the median 4-hour red blood cell transfusion was significantly higher (2800 mL [1500, 4908] vs. 1300 mL [600, 2500], P<0.001). The REBOA group required lesser hemorrhagic control surgeries (31.8% vs. 47.7%, P<0.001) but needed more transarterial embolization interventions (22.2% vs 15.9%, P=0.076). The incidence of therapeutic neurosurgery was 5.1% in the REBOA group and 8.7% in the non-REBOA group (P=0.168). Among survivors in the REBOA group, the median highest Glasgow Coma Scale score during admission was significantly greater for both total (11 [8, 14] vs. 9 [6, 12], P=0.036) and motor components (6 [4, 6] vs. 5 [3, 6], P=0.037). The highest GCS score among the survivors with predominant pelvic injuries was not different between the two groups (11 [8, 13] vs. 11 [7, 14], P=0.750). CONCLUSIONS: Patients experiencing shock and traumatic brain injury have high mortality rates, necessitating swift resuscitation and prompt hemorrhagic control. The use of REBOA as an adjunct for bridging definitive hemorrhagic control may correlate with enhanced consciousness recovery.

Crowd-sourced benchmarking of single-sample tumor subclonal reconstruction.

Subclonal reconstruction algorithms use bulk DNA sequencing data to quantify parameters of tumor evolution, allowing an assessment of how cancers initiate, progress and respond to selective pressures. We launched the ICGC-TCGA (International Cancer Genome Consortium-The Cancer Genome Atlas) DREAM Somatic Mutation Calling Tumor Heterogeneity and Evolution Challenge to benchmark existing subclonal reconstruction algorithms. This 7-year community effort used cloud computing to benchmark 31 subclonal reconstruction algorithms on 51 simulated tumors. Algorithms were scored on seven independent tasks, leading to 12,061 total runs. Algorithm choice influenced performance substantially more than tumor features but purity-adjusted read depth, copy-number state and read mappability were associated with the performance of most algorithms on most tasks. No single algorithm was a top performer for all seven tasks and existing ensemble strategies were unable to outperform the best individual methods, highlighting a key research need. All containerized methods, evaluation code and datasets are available to support further assessment of the determinants of subclonal reconstruction accuracy and development of improved methods to understand tumor evolution.

Influence of preoperative urine culture and bacterial species on urogenital sepsis after ureteral flexible lithotripsy in patients with upper urinary tract stones.

Objective: This retrospective study aims to identify risk factors for urogenic sepsis in patients with upper urinary tract stones following ureteral flexible lithotripsy (FURL). Additionally, we analyze the clinical characteristics of bacterial infections post-surgery. Methods: A total of 759 patients who underwent FURL at the Urology Department of Zunyi Medical University were included. Univariate and multivariate Logistic regression analyses were conducted to identify independent risk factors for urogenic sepsis post-FURL. The distribution of bacteria based on preoperative urine cultures was also analyzed. Statistical analysis was performed using R4.2.2 software. Results: Of the 759 patients, positive preoperative urine culture, urine nitrite positivity, urine white blood cell count (WBC) ≥ 200 cells/µL, residual stones, and neutrophil-to-lymphocyte ratio (NLR) were found to be independent risk factors for urogenic sepsis after FURL. Among the 164 patients with positive preoperative urine cultures, 32 developed urogenic sepsis post-surgery, with 68.75% having positive preoperative cultures. The leading pathogens causing postoperative urogenic sepsis were Escherichia coli (E. coli), Enterococcus faecium, Proteus mirabilis, and Klebsiella pneumoniae. The probabilities of progression to urogenic sepsis were as follows: E. coli 19% (n = 12), Enterococcus faecium 43% (n = 3), Proteus mirabilis 33.3% (n = 1), and Klebsiella pneumoniae 33.3% (n = 1). The ages of affected patients were 47.17 ± 13.2, 53.7, 41, and 79 years, respectively. Rates of comorbid diabetes were 36.4, 66.7, 50, 100%, with nitrite positivity rates at 72.7, 33.3, 50, 0%. Ten female patients were infected with E. coli, while patients infected with Klebsiella pneumoniae had an NLR of 7.62. Conclusion: Positive preoperative urine culture, urine nitrite positivity, urine WBC ≥ 200 cells/µL, residual stones, and NLR are independent risk factors for urogenic sepsis after FURL. Escherichia coli is the predominant pathogen post-FURL, with notable female prevalence and nitrite-positive urine in infections. Enterococcus faecium infections are associated with diabetes.

Multiple Spinal Epidural Abscesses with Concomitant Multifocal Systemic Abscesses and Multi-joint Septic Arthritis:, A Case Report.

Introduction: Multiple spinal epidual abscesses with multifocal systemic abscess and multiple joint septic arthritis present with a large infective burden resulting in sepsis, systemic inflammatory dysregulation, and multi-organ failure. This requires pre-operative resuscitation and surgery of greater complexity, longer operative duration, and blood loss, creating challenges to surgical management. Case Report: A 69-year-old Chinese female presented with multilevel discrete spinal epidural abscesses along the cervical, thoracic, and lumbar spine, alongside concomitant multifocal systemic abscesses and multiple small joint septic arthritis. She received pre-operative resuscitation to restore organ function, reverse acidosis, and coagulopathy, prior tobefore surgical decompression of selected abscesses and joints under a multidisciplinary team. Remaining sites of infection without significant compression were undrained. The patient recovered well with no residual neurological deficits. Conclusion: Multifocal infections in critically ill patients require a multidisciplinary team for preoperative resuscitation, joint surgical planning, and prioritiszing surgical interventions to prevent excessive surgical stress to the patient.

CD276 enhances sunitinib resistance in clear cell renal cell carcinoma by promoting DNA damage repair and activation of FAK-MAPK signaling pathway.

OBJECTIVE: This study aimed to explore the effect of CD276 expression on the sunitinib sensitivity of clear cell renal cell carcinoma (ccRCC) cell and animal models and the potential mechanisms involved. METHODS: CD276 expression levels of ccRCC and normal samples were analyzed via online databases and real-time quantitative PCR (RT-qPCR). CD276 was knocked down in ccRCC cell models (sunitinib-resistant 786-O/R cells and sunitinib-sensitive 786-O cells) using shRNA transfection, and the cells were exposed to a sunitinib (2 µM) environment. Cells proliferation was then analyzed using MTT assay and colony formation experiment. Alkaline comet assay, immunofluorescent staining, and western blot experiments were conducted to assess the DNA damage repair ability of the cells. Western blot was also used to observe the activation of FAK-MAPK pathway within the cells. Finally, a nude mouse xenograft model was established and the nude mice were orally administered sunitinib (40 mg/kg/d) to evaluate the in vivo effects of CD276 knockdown on the therapeutic efficacy of sunitinib against ccRCC. RESULTS: CD276 was significantly upregulated in both ccRCC clinical tissue samples and cell models. In vitro experiments showed that knocking down CD276 reduced the survival rate, IC50 value, and colony-forming ability of ccRCC cells. Knocking down CD276 increased the comet tail moment (TM) values and γH2AX foci number, and reduced BRCA1 and RAD51 protein levels. Knocking down CD276 also decreased the levels of p-FAK, p-MEK, and p-ERK proteins. CONCLUSION: Knocking down CD276 effectively improved the sensitivity of ccRCC cell and animal models to sunitinib treatment.

Single-structure 3-axis Lorentz force magnetometer based on an AlN-on-Si MEMS resonator.

This work presents a single-structure 3-axis Lorentz force magnetometer (LFM) based on an AlN-on-Si MEMS resonator. The operation of the proposed LFM relies on the flexible manipulation of applied excitation currents in different directions and frequencies, enabling the effective actuation of two mechanical vibration modes in a single device for magnetic field measurements in three axes. Specifically, the excited out-of-plane drum-like mode at 277 kHz is used for measuring the x- and y-axis magnetic fields, while the in-plane square-extensional mode at 5.4 MHz is used for measuring the z-axis magnetic field. The different configurations of applied excitation currents ensure good cross-interference immunity among the three axes. Compared to conventional capacitive LFMs, the proposed piezoelectric LFM utilizes strong electromechanical coupling from the AlN layer, which allows it to operate at ambient pressure with a high sensitivity. To understand and analyze the measured results, a novel equivalent circuit model for the proposed LFM is also reported in this work, which serves to separate the effect of Lorentz force from the unwanted capacitive feedthrough. The demonstrated 3-axis LFM exhibits measured magnetic responsivities of 1.74 ppm/mT, 1.83 ppm/mT and 6.75 ppm/mT in the x-, y- and z-axes, respectively, which are comparable to their capacitive counterparts.

Chirality-Driven Orbital Angular Momentum and Circular Dichroism in CoSi.

Chiral crystals and molecules were recently predicted to form an intriguing platform for unconventional orbital physics. Here, we report the observation of chirality-driven orbital textures in the bulk electronic structure of CoSi, a prototype member of the cubic B20 family of chiral crystals. Using circular dichroism in soft x-ray angle-resolved photoemission, we demonstrate the formation of a bulk orbital-angular-momentum texture and monopolelike orbital-momentum locking that depends on crystal handedness. We introduce the intrinsic chiral circular dichroism, icCD, as a differential photoemission observable and a natural probe of chiral electron states. Our findings render chiral crystals promising for spin-orbitronics applications.

Hybrid Microneedle-Mediated Transdermal Delivery of Atorvastatin Calcium-Loaded Polymeric Micelles for Hyperlipidemia Therapy.

Hyperlipidemia has been a huge challenge to global health, leading to the cardiovascular disease, hypertension, and diabetes. Atorvastatin calcium (AC), a widely prescribed drug for hyperlipidemia, faces huge challenges with oral administration due to poor water solubility and hepatic first-pass effects, resulting in low therapeutic efficacy. In this work, we designed and developed a hybrid microneedle (MN) patch system constructed with soluble poly(vinyl alcohol) (PVA) and AC-loaded polymeric micelles (AC@PMs) for transdermal delivery of AC to enhance the hyperlipidemia therapy. We first prepared various AC@PM formulations self-assembled from mPEG-PLA and mPEG-PLA-PEG block copolymers using a dialysis method and evaluated the physicochemical properties in combination with experiment skills and dissipative particle dynamics (DPD) simulations. Then, we encapsulated the AC@PMs into the PVA MN patch using a micromold filling method, followed by characterizing the performances, especially the structural stability, mechanical performance, and biosafety. After conducting in vivo experiments using a hyperlipidemic rat model, our findings revealed that the hybrid microneedle-mediated administration exhibited superior therapeutic efficacy when compared to oral delivery methods. In summary, we have successfully developed a hybrid microneedle (MN) patch system that holds promising potential for the efficient transdermal delivery of hydrophobic drugs.

Comprehensive analysis of fibroblast activation protein expression across 23 tumor indications: insights for biomarker development in cancer immunotherapies.

Introduction: Fibroblast activation protein (FAP) is predominantly upregulated in various tumor microenvironments and scarcely expressed in normal tissues. Methods: We analyzed FAP across 1216 tissue samples covering 23 tumor types and 70 subtypes. Results: Elevated FAP levels were notable in breast, pancreatic, esophageal, and lung cancers. Using immunohistochemistry and RNAseq, a correlation between FAP gene and protein expression was found. Evaluating FAP's clinical significance, we assessed 29 cohorts from 12 clinical trials, including both mono and combination therapies with the PD-L1 inhibitor atezolizumab and chemotherapy. A trend links higher FAP expression to poorer prognosis, particularly in RCC, across both treatment arms. However, four cohorts showed improved survival with high FAP, while in four others, FAP had no apparent survival impact. Conclusions: Our results emphasize FAP's multifaceted role in therapy response, suggesting its potential as a cancer immunotherapy biomarker.

Associations between postoperative anaemia and unplanned readmission to hospital after major surgery: a retrospective cohort study†.

BACKGROUND: Anaemia following major surgery may be associated with unplanned readmission to hospital. However, the severity-response relationship between the degree of anaemia at discharge and the risk of unplanned readmission is poorly defined. We aimed to describe the severity-response relationship between haemoglobin concentration at the time of discharge and the risk of unplanned readmission in a cohort of patients undergoing different types of major surgery. METHODS: We performed a retrospective cohort study in a single tertiary health service, including all patients who underwent major surgery (orthopaedic, abdominal, cardiac or thoracic) between 1 May 2011 and 1 February 2022. The primary outcome was unplanned readmission to hospital in the 90 days following discharge after the index surgical procedure. These complex, non-linear relationships were modelled with restricted cubic splines. RESULTS: We identified 22,134 patients and included 14,635 in the primary analysis, of whom 1804 (12%) experienced at least one unplanned readmission. The odds of unplanned readmission rose when the discharge haemoglobin concentration was < 100 g.l-1 (p < 0.001). On subgroup analysis, the haemoglobin threshold below which odds of readmission began to increase appeared to be higher in patients undergoing emergency surgery (110 g.l-1; p < 0.001) compared with elective surgery. Declining discharge haemoglobin concentration was associated with increased odds ratios (95%CI) of unplanned readmission in patients undergoing orthopaedic (1.08 (1.01-1.15), p = 0.03), abdominal (1.13 (1.07-1.19), p < 0.001) and thoracic (1.12 (1.01-1.24), p = 0.03) procedures, but not cardiac surgery (1.09 (0.99-1.19), p = 0.07). CONCLUSIONS: Our findings suggest that a haemoglobin concentration < 100 g.l-1 following elective procedures and < 110 g.l-1 following emergency procedures, at the time of hospital discharge after major surgery, was associated with unplanned readmission. Future interventional trials that aim to treat postoperative anaemia and reduce unplanned readmission should include patients with discharge haemoglobin below these thresholds.

Mendelian randomization of circulating proteome identifies IFN-γ as a druggable target in aplastic anemia.

BACKGROUND: Aplastic anemia (AA) is a kind of bone marrow failure (BMF) characterized by pancytopenia with hypoplasia/aplasia of bone marrow. Immunosuppressive therapy and bone marrow transplantation are effective methods to treat severe aplastic anemia. However, the efficacy is limited by complications and the availability of suitable donors. This study aimed to determine whether any circulating druggable protein levels may have causal effects on AA and provide potential novel drug targets for AA. METHODS: Genetic variants strongly associated with circulating druggable protein levels to perform Mendelian randomization (MR) analyses were used. The effect of these druggable protein levels on AA risk was measured using the summary statistics from a large-scale proteomic genome-wide association study (GWAS) and FinnGen database ( https://www.finngen.fi/en/access_results ). Multivariable MR analyses were performed to statistically adjust for potential confounders, including platelet counts, reticulocyte counts, neutrophil counts, and proportions of hematopoietic stem cells. RESULTS: The data showed that higher level of circulating IFN-γ levels was causally associated with AA susceptibility. The causal effects of circulating IFN-γ levels on the AA were broadly consistent, when adjusted for platelet counts, reticulocyte counts, neutrophil counts and proportions of hematopoietic stem cells. CONCLUSIONS: High levels of circulating IFN-γ levels might increase the risk of AA and might provide a potential novel target for AA.

Protein degradation of Lsd1 is mediated by Bre1 yet opposed by Lsd1-interacting lncRNAs during fly follicle development.

Tissue development, homeostasis, and repair all require efficient progenitor expansion. Lysine-specific demethylase 1 (Lsd1) maintains plastic epigenetic states to promote progenitor proliferation while overexpressed Lsd1 protein causes oncogenic gene expression in cancer cells. However, the precise regulation of Lsd1 protein expression at the molecular level to drive progenitor differentiation remains unclear. Here, using Drosophila melanogaster oogenesis as our experimental system, we discovered molecular machineries that modify Lsd1 protein stability in vivo. Through genetic and biochemical analyses, an E3 ubiquitin ligase, Bre1, was identified as required for follicle progenitor differentiation, likely by mediating Lsd1 protein degradation. Interestingly, specific Lsd1-interacting long non-coding RNAs (LINRs) were found to antagonize Bre1-mediated Lsd1 protein degradation. The intricate interplay discovered among the Lsd1 complex, LINRs and Bre1 provides insight into how Lsd1 protein stability is fine-tuned to underlie progenitor differentiation in vivo.

The Epidemiology, Management and Therapeutic Outcomes of Subdural Empyema in Neonates with Acute Bacterial Meningitis.

Background: Subdural empyema is one of the more serious complications of bacterial meningitis and therapeutic challenges to clinicians. We aimed to evaluate the clinical characteristics, treatment, and outcome of subdural empyema in neonates with bacterial meningitis. Methods: A retrospective cohort study was conducted in two medical centers in Taiwan that enrolled all cases of neonates with subdural empyema after bacterial meningitis between 2003 and 2020. Results: Subdural empyema was diagnosed in 27 of 153 (17.6%) neonates with acute bacterial meningitis compared with cases of meningitis without subdural empyema. The demographics and pathogen distributions were comparable between the study group and the controls, but neonates with subdural empyema were significantly more likely to have clinical manifestations of fever (85.2%) and seizure (81.5%) (both p values < 0.05). The cerebrospinal fluid results of neonates with subdural empyema showed significantly higher white blood cell counts, lower glucose levels and higher protein levels (p = 0.011, 0.003 and 0.006, respectively). Neonates with subdural empyema had a significantly higher rate of neurological complications, especially subdural effusions and periventricular leukomalacia. Although the final mortality rate was not increased in neonates with subdural empyema when compared with the controls, they were often treated much longer and had a high rate of long-term neurological sequelae. Conclusions: Subdural empyema is not uncommon in neonates with acute bacterial meningitis and was associated with a high risk of neurological complications, although it does not significantly increase the final mortality rate. Close monitoring of the occurrence of subdural empyema is required, and appropriate long-term antibiotic treatment after surgical intervention may lead to optimized outcomes.

Improving SLAM Techniques with Integrated Multi-Sensor Fusion for 3D Reconstruction.

Simultaneous Localization and Mapping (SLAM) poses distinct challenges, especially in settings with variable elements, which demand the integration of multiple sensors to ensure robustness. This study addresses these issues by integrating advanced technologies like LiDAR-inertial odometry (LIO), visual-inertial odometry (VIO), and sophisticated Inertial Measurement Unit (IMU) preintegration methods. These integrations enhance the robustness and reliability of the SLAM process for precise mapping of complex environments. Additionally, incorporating an object-detection network aids in identifying and excluding transient objects such as pedestrians and vehicles, essential for maintaining the integrity and accuracy of environmental mapping. The object-detection network features a lightweight design and swift performance, enabling real-time analysis without significant resource utilization. Our approach focuses on harmoniously blending these techniques to yield superior mapping outcomes in complex scenarios. The effectiveness of our proposed methods is substantiated through experimental evaluation, demonstrating their capability to produce more reliable and precise maps in environments with variable elements. The results indicate improvements in autonomous navigation and mapping, providing a practical solution for SLAM in challenging and dynamic settings.

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In the clinical diagnosis and treatment of children with short stature, mental health issues merit special attention. It is widely acknowledged that the psychological well-being of children with short stature is lower than that of their peers with normal height. Therefore, during the diagnosis, treatment, and care of short stature, it is crucial to actively monitor the mental health of these children, promptly identify potential psychological and behavioral issues, and intervene accordingly. Such measures play a positive role in enhancing the quality of life of these children and improving their physical and mental health. This article analyses and discusses the current state of psychological assessment and psycho-behavioral interventions for children with short stature, aiming to provide insights for improving their mental health.

Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.

Genetic interactions reveal distinct biological and therapeutic implications in breast cancer.

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53mut-AURKAamp and endocrine therapy resistance, germline BRCA1mut-MYCamp and improved sensitivity to PARP inhibitors, and TP53mut-MYBamp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations.