-
BMC Cancer Jun 2024Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the...
OBJECTIVE
Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the expression of USP10 was negatively correlated with the depth of gastric wall invasion, lymph node metastasis, and prognosis in gastric cancer (GC) patients. However, it remains unclear whether USP10 can regulate the metastasis of GC cells through its de-ubiquitination function.
METHODS
In this study, proteome, ubiquitinome, and transcriptome analyses were conducted to comprehensively identify novel de-ubiquitination targets for USP10 in GC cells. Subsequently, a series of validation experiments, including in vitro cell culture studies, in vivo metastatic tumor models, and clinical sample analyses, were performed to elucidate the regulatory mechanism of USP10 and its de-ubiquitination targets in GC metastasis.
RESULTS
After overexpression of USP10 in GC cells, 146 proteins, 489 ubiquitin sites, and 61 mRNAs exhibited differential expression. By integrating the results of multi-omics, we ultimately screened 9 potential substrates of USP10, including TNFRSF10B, SLC2A3, CD44, CSTF2, RPS27, TPD52, GPS1, RNF185, and MED16. Among them, TNFRSF10B was further verified as a direct de-ubiquitination target for USP10 by Co-IP and protein stabilization assays. The dysregulation of USP10 or TNFRSF10B affected the migration and invasion of GC cells in vitro and in vivo models. Molecular mechanism studies showed that USP10 inhibited the epithelial-mesenchymal transition (EMT) process by increasing the stability of TNFRSF10B protein, thereby regulating the migration and invasion of GC cells. Finally, the retrospective clinical sample studies demonstrated that the downregulation of TNFRSF10B expression was associated with poor survival among 4 of 7 GC cohorts, and the expression of TNFRSF10B protein was significantly negatively correlated with the incidence of distant metastasis, diffuse type, and poorly cohesive carcinoma.
CONCLUSIONS
Our study established a high-throughput strategy for screening de-ubiquitination targets for USP10 and further confirmed that inhibiting the ubiquitination of TNFRSF10B might be a promising therapeutic strategy for GC metastasis.
Topics: Stomach Neoplasms; Humans; Ubiquitin Thiolesterase; Ubiquitination; Mice; Animals; Cell Line, Tumor; Cell Movement; Gene Expression Regulation, Neoplastic; Female; Male; Neoplasm Metastasis; Gene Expression Profiling; Epithelial-Mesenchymal Transition; Prognosis; Multiomics
PubMed: 38937694
DOI: 10.1186/s12885-024-12549-3 -
BMC Cancer Jun 2024Wilms tumor (WT) is the most common pediatric embryonal tumor. Improving patient outcomes requires advances in understanding and targeting the multiple genes and...
BACKGROUND
Wilms tumor (WT) is the most common pediatric embryonal tumor. Improving patient outcomes requires advances in understanding and targeting the multiple genes and cellular control pathways, but its pathogenesis is currently not well-researched. We aimed to identify the potential molecular biological mechanism of WT and develop new prognostic markers and molecular targets by comparing gene expression profiles of Wilms tumors and fetal normal kidneys.
METHODS
Differential gene expression analysis was performed on Wilms tumor transcriptomic data from the GEO and TARGET databases. For biological functional analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were utilized. Out of 24 hub genes identified, nine were found to be prognostic-related through univariate Cox regression analysis. These nine genes underwent LASSO regression analysis to enhance the predictive capability of the model. The key hub genes were validated in the GSE73209 datasets, and cell function experiments were conducted to identify the genes' functions in WiT-49 cells.
RESULTS
The enrichment analysis revealed that DEGs were significantly involved in the regulation of angiogenesis and regulation of cell differentiation. 24 DEGs were identified through PPI networks and the MCODE algorithm, and 9 of 24 genes were related to WT patients' prognosis. EMCN and CCNA1 were identified as key hub genes, and related to the progression of WT. Functionally, over-expression of EMCN and CCNA1 knockdown inhibited cell viability, proliferation, migration, and invasion of Wilms tumor cells.
CONCLUSIONS
EMCN and CCNA1 were identified as key prognostic markers in Wilms tumor, suggesting their potential as therapeutic targets. Differential gene expression and enrichment analyses indicate significant roles in angiogenesis and cell differentiation.
Topics: Wilms Tumor; Humans; Computational Biology; Kidney Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Prognosis; Gene Regulatory Networks; Transcriptome; Cell Proliferation; Protein Interaction Maps; Gene Ontology; Cell Line, Tumor
PubMed: 38937666
DOI: 10.1186/s12885-024-12541-x -
Scientific Reports Jun 2024Although robotic radical resection for hilar cholangiocarcinoma (HCCA) has been reported in some large hepatobiliary centers, biliary-enteric reconstruction (BER)...
Although robotic radical resection for hilar cholangiocarcinoma (HCCA) has been reported in some large hepatobiliary centers, biliary-enteric reconstruction (BER) remains a critical step that hampers the operation's success. This study aimed to evaluate the feasibility and quality of BER in robotic radical resection of HCCA and propose technical recommendations. A retrospective study was conducted on patients with HCCA who underwent minimally invasive radical resection at Zhejiang Provincial People's Hospital between January 2016 and July 2023. A 1:2 propensity score matching (PSM), widely used to reduce selection bias, was performed to evaluate the outcomes, especially BER-related data, between the robotic and laparoscopic surgery. Forty-six patients with HCCA were enrolled; ten underwent robotic-assisted resection, while the others underwent laparoscopic surgery. After PSM at a ratio of 1:2, 10 and 20 patients were assigned to the robot-assisted and laparoscopic groups, respectively. The baseline characteristics of both groups were generally well-balanced. The average liver resection time was longer in the robotic group than in the laparoscopic group (139.5 ± 38.8 vs 108.1 ± 35.8 min, P = 0.036). However, the former had less intraoperative blood loss [200 (50-500) vs 310 (100-850) ml], despite no statistical difference (P = 0.109). The number of residual bile ducts was 2.6 ± 1.3 and 2.7 ± 1.2 (P = 0.795), and anastomoses were both 1.6 ± 0.7 in the two groups (P = 0.965). The time of BER was 38.4 ± 13.6 and 59.1 ± 25.5 min (P = 0.024), accounting for 9.9 ± 2.8% and 15.4 ± 4.8% of the total operation time (P = 0.001). Although postoperative bile leakage incidence in laparoscopic group (40%) was higher than that in robotic group (10%), there was no significant difference between the two groups (P = 0.204); 6.7 ± 4.4 and 12.1 ± 11.7 days were observed for tube drawing (P = 0.019); anastomosis stenosis and calculus rate was 10% and 30% (P = 0.372), 0% and 15% (P = 0.532), respectively. Neither group had hemorrhage- or bile leakage-related deaths. Robotic radical resection for HCCA may offer perioperative outcomes comparable to conventional laparoscopic procedures and tends to be advantageous in terms of anastomosis time and quality. We are optimistic about its wide application in the future with the improvement of surgical techniques and experience.
Topics: Humans; Male; Female; Middle Aged; Propensity Score; Robotic Surgical Procedures; Retrospective Studies; Laparoscopy; Aged; Bile Duct Neoplasms; Klatskin Tumor; Treatment Outcome; Plastic Surgery Procedures; Postoperative Complications
PubMed: 38937559
DOI: 10.1038/s41598-024-65875-8 -
Scientific Reports Jun 2024Accurate screening of COVID-19 infection status for symptomatic patients is a critical public health task. Although molecular and antigen tests now exist for COVID-19,... (Comparative Study)
Comparative Study
Accurate screening of COVID-19 infection status for symptomatic patients is a critical public health task. Although molecular and antigen tests now exist for COVID-19, in resource-limited settings, screening tests are often not available. Furthermore, during the early stages of the pandemic tests were not available in any capacity. We utilized an automated machine learning (ML) approach to train and evaluate thousands of models on a clinical dataset consisting of commonly available clinical and laboratory data, along with cytokine profiles for patients (n = 150). These models were then further tested for generalizability on an out-of-sample secondary dataset (n = 120). We were able to develop a ML model for rapid and reliable screening of patients as COVID-19 positive or negative using three approaches: commonly available clinical and laboratory data, a cytokine profile, and a combination of the common data and cytokine profile. Of the tens of thousands of models automatically tested for the three approaches, all three approaches demonstrated > 92% sensitivity and > 88 specificity while our highest performing model achieved 95.6% sensitivity and 98.1% specificity. These models represent a potential effective deployable solution for COVID-19 status classification for symptomatic patients in resource-limited settings and provide proof-of-concept for rapid development of screening tools for novel emerging infectious diseases.
Topics: Humans; COVID-19; Machine Learning; Cytokines; SARS-CoV-2; Mass Screening; Male; Female; Sensitivity and Specificity; Middle Aged; Adult; Aged
PubMed: 38937503
DOI: 10.1038/s41598-024-63707-3 -
Nature Communications Jun 2024Progressive lung fibrosis is associated with poorly understood aging-related endothelial cell dysfunction. To gain insight into endothelial cell alterations in lung...
Progressive lung fibrosis is associated with poorly understood aging-related endothelial cell dysfunction. To gain insight into endothelial cell alterations in lung fibrosis we performed single cell RNA-sequencing of bleomycin-injured lungs from young and aged mice. Analysis reveals activated cell states enriched for hypoxia, glycolysis and YAP/TAZ activity in ACKR1+ venous and TrkB+ capillary endothelial cells. Endothelial cell activation is prevalent in lungs of aged mice and can also be detected in human fibrotic lungs. Longitudinal single cell RNA-sequencing combined with lineage tracing demonstrate that endothelial activation resolves in young mouse lungs but persists in aged ones, indicating a failure of the aged vasculature to return to quiescence. Genes associated with activated lung endothelial cells states in vivo can be induced in vitro by activating YAP/TAZ. YAP/TAZ also cooperate with BDNF, a TrkB ligand that is reduced in fibrotic lungs, to promote capillary morphogenesis. These findings offer insights into aging-related lung endothelial cell dysfunction that may contribute to defective lung injury repair and persistent fibrosis.
Topics: Animals; Endothelial Cells; Aging; Bleomycin; Humans; Mice; Pulmonary Fibrosis; Lung; Lung Injury; Receptor, trkB; Mice, Inbred C57BL; Brain-Derived Neurotrophic Factor; YAP-Signaling Proteins; Male; Single-Cell Analysis; Adaptor Proteins, Signal Transducing; Female; Disease Models, Animal
PubMed: 38937456
DOI: 10.1038/s41467-024-49545-x -
The Kobe Journal of Medical Sciences Jun 2024Olfactory neuroblastoma (ONB) is an uncommon malignant tumor and is usually treated by a multidisciplinary approach includes surgery, radiotherapy, and chemotherapy. A...
Olfactory neuroblastoma (ONB) is an uncommon malignant tumor and is usually treated by a multidisciplinary approach includes surgery, radiotherapy, and chemotherapy. A 62 years-old male had a tumor in the nasal cavity and diagnosed as ONB with Kadish A stage. Anterior skull base surgery was performed as radical treatment. Since the surgical margin was negative, no postoperative radiotherapy was administered. 14 years after the surgery, bilateral otitis media with effusion (OME) was occurred, we found the recurrence tumor at bilateral retropharyngeal lymph node (RPLN) which surrounded the internal carotid arteries. Since these were unresectable, we planned chemoradiotherapy which was 70Gy of intensity modulated radiotherapy combined with two courses of carboplatin and etoposide. The tumor volume was reduced and bilateral OME were improved. He has been alive for 3 years after salvage treatment. Although ONB has a relatively good prognosis, it is known to often cause cervical lymph node metastasis. Grades III and IV of Hyams classification are considered high risk. This case, initial tumor was limited in the nasal cavity and its clinical classification was early stage, but Hyams classification was grade III. In reference to this case, considering that RPLN metastasis are difficult to radically resect at the salvage surgery, including this area in postoperative radiotherapy was considered an option.
Topics: Humans; Male; Esthesioneuroblastoma, Olfactory; Middle Aged; Lymphatic Metastasis; Nose Neoplasms; Nasal Cavity; Skull Base; Neoplasm Recurrence, Local; Chemoradiotherapy
PubMed: 38936878
DOI: 10.24546/0100489917 -
International Journal of Surgery Case... Jun 2024Obturator hernias are rare, occur mainly in slender people and predominantly in females. Underlying pathology of the obturator hernia is a weakening of the obturator...
INTRODUCTION
Obturator hernias are rare, occur mainly in slender people and predominantly in females. Underlying pathology of the obturator hernia is a weakening of the obturator membrane. The obturator hernia is situated between the pubic and ischial bones and is therefore clinically occult. Patients predominantly present with symptoms of bowel obstruction, but can also present with sensory disturbance, leg pain and hip pain. Due to the usually delayed diagnosis, the obturator hernia is associated with increased morbidity and mortality.
CASE PRESENTATION
A 71-year-old female patient with hip pain underwent a protracted diagnostic work-up and was referred to the surgical department by the treating orthopedic surgeon. An incarcerated obturator hernia with a fistula in the adductor ligament was finally diagnosed via CT. The operation included laparoscopic reduction, hernia repair, open small bowel segment resection, local surgical exploration, lavage and antibiotic treatment. The primary hernia repair was performed by direct suture due to the contamination, and a post-primary mesh repair was indicated. However, after complete recovery and no remaining symptoms, the patient refused this despite the indication for definitive laparoscopic hernia repair.
DISCUSSION
Hip pain can have multiple causes. Taking physical characteristics into account can lead to the correct diagnostic pathway. The CT scan revealed the fistula which led to the laparoscopic surgery. Due to the intestinal damage and contamination, the surgical steps were adapted.
CONCLUSION
Obturator hernias should be considered as a reason for atypical symptoms in slender, older patients. Adequate surgical management can be chosen after correct diagnosis.
PubMed: 38936138
DOI: 10.1016/j.ijscr.2024.109945 -
American Society of Clinical Oncology... Jun 2024The landscape of prostate cancer care has rapidly evolved. We have transitioned from the use of conventional imaging, radical surgeries, and single-agent androgen... (Review)
Review
The landscape of prostate cancer care has rapidly evolved. We have transitioned from the use of conventional imaging, radical surgeries, and single-agent androgen deprivation therapy to an era of advanced imaging, precision diagnostics, genomics, and targeted treatment options. Concurrently, the emergence of large language models (LLMs) has dramatically transformed the paradigm for artificial intelligence (AI). This convergence of advancements in prostate cancer management and AI provides a compelling rationale to comprehensively review the current state of AI applications in prostate cancer care. Here, we review the advancements in AI-driven applications across the continuum of the journey of a patient with prostate cancer from early interception to survivorship care. We subsequently discuss the role of AI in prostate cancer drug discovery, clinical trials, and clinical practice guidelines. In the localized disease setting, deep learning models demonstrated impressive performance in detecting and grading prostate cancer using imaging and pathology data. For biochemically recurrent diseases, machine learning approaches are being tested for improved risk stratification and treatment decisions. In advanced prostate cancer, deep learning can potentially improve prognostication and assist in clinical decision making. Furthermore, LLMs are poised to revolutionize information summarization and extraction, clinical trial design and operations, drug development, evidence synthesis, and clinical practice guidelines. Synergistic integration of multimodal data integration and human-AI integration are emerging as a key strategy to unlock the full potential of AI in prostate cancer care.
Topics: Humans; Male; Prostatic Neoplasms; Artificial Intelligence
PubMed: 38935882
DOI: 10.1200/EDBK_438516 -
PloS One 2024Chronic liver diseases are caused by hepatic viral infection, chemicals, and metabolic stress. The protein Grb2-associated binder 1 (Gab1) binds to various growth factor...
Chronic liver diseases are caused by hepatic viral infection, chemicals, and metabolic stress. The protein Grb2-associated binder 1 (Gab1) binds to various growth factor receptors, and triggers cell differentiation/survival signaling pathways. To identify signaling molecules involved in the progression of liver diseases, we performed reverse-phase protein microarray (RPMA)-based screening of hepatocytes isolated from humanized mice after acute HCV infection. Acute viral infection in humanized liver mice significantly decreased the level of hepatocyte p-Gab1. Moreover, hepatoma cells upon HCV infection decreased Gab1 mRNA at later times of infection (D3 to D5) and p-Gab1 level was inversely related to the production of TGF-β. In contrast, the level of p-Gab1 was increased in CCL4-induced fibrotic liver. Hepatoma cells showed elevation of p-Gab1, along with an increase in STAT3 and ERK activation, upon treatment with HGF (ligand of HGF receptor/c-Met) and CCL4. In Gab1 knockdown hepatoma cells, cell proliferative signaling activity was reduced but the level of activated caspase-3 was increased. These findings suggest that hepatocyte Gab1 expression may play a role in promoting liver fibrosis progression by triggering ERK activation and inhibiting apoptosis. It implies that the Gab1-mediated signaling pathway would be a promising therapeutic target to treat chronic liver diseases.
Topics: Animals; Hepatocytes; Liver Cirrhosis; Adaptor Proteins, Signal Transducing; Apoptosis; Signal Transduction; Cell Proliferation; Humans; Mice; Proto-Oncogene Proteins c-met; Hepatocyte Growth Factor; Cell Line, Tumor; Hepatitis C
PubMed: 38935609
DOI: 10.1371/journal.pone.0306345 -
PLoS Biology Jun 2024Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized...
Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized by normal auditory thresholds but reduced amplitude of sound-evoked auditory potentials. It has been proposed that synaptopathy and HHL result in poor performance in challenging hearing tasks despite a normal audiogram. However, this has only been tested in animals after exposure to noise or ototoxic drugs, which can cause deficits beyond synaptopathy. Furthermore, the impact of supernumerary synapses on auditory processing has not been evaluated. Here, we studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC supporting cells. As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds. We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels. These results indicate that IHC synaptopathy causes temporal processing deficits predicted in HHL. Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies.
Topics: Animals; Hair Cells, Auditory, Inner; Synapses; Neurotrophin 3; Mice; Auditory Threshold; Evoked Potentials, Auditory; Reflex, Startle; Auditory Perception; Spiral Ganglion; Female; Male; Hearing Loss, Hidden
PubMed: 38935589
DOI: 10.1371/journal.pbio.3002665