Intelligent Sensing of Thermal Error of CNC Machine Tool Spindle Based on Multi-Source Information Fusion.

Aiming at the shortcomings of single-sensor sensing information characterization ability, which is easily interfered with by external environmental factors, a method of intelligent perception is proposed in this paper. This method integrates multi-source and multi-level information, including spindle temperature field, spindle thermal deformation, operating parameters, and motor current. Firstly, the internal and external thermal-error-related signals of the spindle system are collected by sensors, and the feature parameters are extracted; then, the radial basis function (RBF) neural network is utilized to realize the preliminary integration of the feature parameters because of the advantages of the RBF neural network, which offers strong multi-dimensional solid nonlinear mapping ability and generalization ability. Thermal-error decision values are then generated by a weighted fusion of different pieces of evidence by considering uncertain information from multiple sources. The spindle thermal-error sensing experiment was based on the spindle system of the VMC850 (Yunnan Machine Tool Group Co., LTD, Yunnan, China) vertical machining center of the Yunnan Machine Tool Factory. Experiments were designed for thermal-error sensing of the spindle under constant speed (2000 r/min and 4000 r/min), standard variable speed, and stepped variable speed conditions. The experiment's results show that the prediction accuracy of the intelligent-sensing model with multi-source information fusion can reach 98.1%, 99.3%, 98.6%, and 98.8% under the above working conditions, respectively. The intelligent-perception model proposed in this paper has higher accuracy and lower residual error than the traditional BP neural network perception and wavelet neural network models. The research in this paper provides a theoretical basis for the operation, maintenance management, and performance optimization of machine tool spindle systems.

Case report of penile squamous cell carcinoma continuous treatment with BRCA2 mutation.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a highly aggressive malignancy with a poor prognosis. BRCA1/2 mutations are associated with impaired DNA double-strand break repair and are among the common mutations in penile cancer, potentially paving the way for poly ADP-ribose polymerase inhibitor therapy. CASE PRESENTATION: We report a 65-year-old male with PSCC who progressed to thigh metastasis at 10 months after partial penectomy. Next-generation sequencing showed that the penis primary lesion and metastatic thigh lesion harboured a BRCA2 mutation. Chemotherapy plus immunotherapy was used for treatment, and the thigh metastasis was found to involve no tumour. Progression-free survival (PFS) lasted for 8 months until the appearance of lung metastasis. Afterwards, the patient benefited from second-line therapy of olaparib with pembrolizumab and anlotinib, and his disease was stable for 9 months. The same BRCA2 was identified in the lung biopsy. Given the tumour mutation burden (TMB, 13.97 mutation/Mb), the patient received third-line therapy with nivolumab plus ipilimumab, but PFS only lasted for 3 months, with the appearance of right frontal brain metastasis. Then, the patient was treated with radiation sequential fluzoparib therapy as fourth-line treatment, and the treatment efficacy was evaluated as PR. Currently, this patient is still alive. CONCLUSIONS: This is the first report of penile cancer with BRCA2 mutation, receiving a combination treatment with olaparib and experiencing a benefit for 9 months. This case underscores the pivotal role of BRCA2 in influencing treatment response in PSCC, providing valuable insights into the application of targeted therapies in managing recurrent PSCC with BRCA2 alterations. This elucidation establishes a crucial foundation for further research and clinical considerations in similar cases.

The correlation between clinical outcomes and genomic analysis with high risk factors for the progression of osteosarcoma.

Osteosarcoma (OS) is a rare but aggressive malignancy. Despite previous reports, molecular characterization of this disease is not well understood, and little is known regarding OS in Chinese patients. Herein, we analyzed the genomic signatures of 73 Chinese OS cases. TP53, NCOR1, LRP1B, ATRX, RB1, and TFE3 were the most frequently mutated gene in our OS cohort. In addition, the genomic analysis of Western OS patients was performed. Notably, there were remarkable disparities in mutational landscape, base substitution pattern, and tumor mutational burden between the Chinese and Western OS cohorts. Specific molecular mechanisms, including DNA damage repair (DDR) gene mutations, copy number variation (CNV) presence, aneuploidy, and intratumoral heterogeneity, were associated with disease progression. Additionally, 30.1% of OS patients carried clinically actionable alterations, which were mainly enriched in PI3K, MAPK, DDR, and RTK signaling pathways. A specific molecular subtype incorporating DDR alterations and CNVs was significantly correlated with distant metastasis-free survival and event-free survival, and this correlation was observed in all subgroups with different characteristics. These findings comprehensively elucidated the genomic profile and revealed novel prognostic factors in OS, which would contribute to understanding this disease and promoting precision medicine of this population.

The mutational pattern of homologous recombination repair genes in urothelial carcinoma and its correlation with immunotherapeutic response.

BACKGROUND: The mutational pattern of homologous recombination repair (HRR)-associated gene alterations in Chinese urothelial carcinoma (UC) necessitates comprehensive sequencing efforts, and the clinical implications of HRR gene mutations in UC remain to be elucidated. MATERIALS AND METHODS: We delineated the mutational landscape of 343 Chinese UC patients from West China Hospital and 822 patients from The Cancer Genome Atlas (TCGA) using next-generation sequencing (NGS). Data from 182 metastatic UC patients from MSK-IMPACT cohort were used to assess the association between HRR mutations and immunotherapy efficacy. Comprehensive transcriptomic analysis was performed to explore the impact of HRR mutations on tumor immune microenvironment. RESULTS: Among Chinese UC patients, 34% harbored HRR gene mutations, with BRCA2, ATM, BRCA1, CDK12, and RAD51C being the most prevalently mutated genes. Mutational signatures contributing to UC differed between patients with and without HRR mutations. Signature 22 for exposure to aristolochic acid was only observed in Chinese UC patients. The presence of HRR mutations was correlated with higher tumor mutational burden, neoantigen burden, and PD-L1 expression. Importantly, patients with HRR mutations exhibited significantly improved prognosis following immunotherapy compared to those without HRR mutations. CONCLUSIONS: Our findings provide valuable insights into the genomic landscape of Chinese UC patients and underscore the molecular rationale for utilizing immunotherapy in UC patients with HRR mutations.

Case Report: A novel TP53 mutation in a patient with quadruple wild-type gastrointestinal stromal tumor.

In this report, we present a case study of a 64-year-old female who was diagnosed with gastrointestinal stromal tumors (GISTs) and subsequently developed liver metastases despite undergoing radical resection. Next-generation sequencing (NGS) assays indicated that the tumor lacked KIT/PDGFRA/SDH/RAS-P (RAS pathways, RAS-P) mutations, thereby classifying this patient as quadruple WT GIST (qGIST). Treatment with imatinib was initiated, and after 2.5 months, recurrence of the tumor and multiple metastases around the surgical site were observed. Consequently, the patient was switched to sunitinib treatment and responded well. Although she responded well to sunitinib, the patient died of tumor dissemination within 4 months. This case study highlights the potential efficacy of imatinib and the VEGFR-TKI sunitinib in treating qGIST patients harboring a TP53 missense mutation.

Effects of hypoxia on the gill morphological structure, apoptosis and hypoxia-related gene expression in blunt snout bream (Megalobrama amblycephala).

The blunt snout bream (Megalobrama amblycephala) is a typical hypoxia-sensitive fish, and hypoxia stress leads to reduced vitality and yield during aquaculture. To explore the specific adaptation mechanism under hypoxia, the blunt snout bream was treated with hypoxia (DO = 2.0 ± 0.1 mg/L) for 24 h, followed by 3 h of recovery. Our results depicted that the gill filament structure of blunt snout bream changed after hypoxia. During hypoxia for 24 h, the gill filament structure was altered, including a more than 80% expansion of the lamellar respiratory surface area and a proportionate apoptosis decrease in interlamellar cell mass (ILCM) volume. Thus, the water-blood diffusion distance was shortened to less than 46%. During hypoxia for 24 h, the activity of ROS in gill tissue increased significantly (p < 0.05), while the mitochondrial membrane potential decreased significantly (p < 0.05). During hypoxia, mRNA expression level of anti-apoptotic gene Bcl-2 in the gills of blunt snout bream decreased significantly (p < 0.05), while the expression of pro-apoptotic gene Bax mRNA increased significantly (p < 0.05). Thus, the ratio of Bax/Bcl-2 mRNA increased in the gills of blunt snout bream to promote the activity of Caspase-3. Together, our results indicated hypoxia-induced apoptosis in the gills of blunt snout bream through the mitochondrial pathway. In addition, a decreased expression of Phd1 and an increased expression of Hif-1α in gills under hypoxia stress indicates that blunt snout bream may cope with hypoxia-induced apoptosis by enhancing the HIF pathway. These results provide new insights into fish's adaptation strategies and mechanisms of hypoxia.

Numerical simulation and exergy analysis of a single-stage GM cryocooler.

Improving the efficiency of the GM cryocoolers is of great importance for energy saving and CO2 emission reduction due to the large amount of cryocoolers installed in the emerging fields of semiconductor manufacture and High Temperature Superconductors (HTS) cooling. Previous studies mainly focused on the losses analysis and optimization on the part of cold head, but the details of losses distribution in the parts of compressor and rotary valve were seldom carried out. In this paper, a numerical model of a single stage GM cryocooler including compressor, rotary valve and expander is built, and the feasibility of the model is verified by the experimental results. The losses characteristics of the whole cryocooler are studied based on the exergy analysis method with the help of the numerical model. The results indicate that the main losses are occurred in compressor and rotary valve, the value of exergy loss in compressor decrease with the cooling temperature, and accounts for more than 60% at all cooling temperature. The loss in rotary valve accounts for about 20% of the input electric power, and it does not significantly vary at different cooling temperatures. Pressure drop dominates the loss in the compressor and rotary valve. The insufficient heat exchange between the working gas and regenerative material is the main loss in regenerator, and the losses in regenerator increase significantly with the decrease of cooling temperature when the compressor and rotary valve are fixed. This study provides useful guides for the optimization of GM-type cryocoolers.

Successive onset of Vogt-Koyanagi-Harada syndrome in father and son.

BACKGROUND: Vogt‒Koyanagi‒Harada (VKH) disease is a multifactorial systemic autoimmune disorder against melanocytes that is characterized by panuveitis. Familial occurrence of VKH disease is rare. Here, we report two cases of a father and his son with characteristic manifestations of VKH disease. CASE PRESENTATION: A 53-year-old male with typical clinical symptoms of VKH disease was referred to Tangshan Eye Hospital. Examination showed the presence of ciliochoroidal effusion and exudative retinal detachment in both eyes. The patient was given intravenous methylprednisolone 120 mg for 2 days and intravenous methylprednisolone 80 mg for 1 day followed by 48 mg (1 mg/kg/day) oral methylprednisolone daily, accompanied by oral azathioprine 50 mg daily. Cycloplegic agent (0.5% tropicamide three times daily [TID]) was added. The patient was free of symptoms and recurrence within more than 1-year-follow-up period, the best corrected visual acuity (BVCA) was increased and maintained in both eyes with complete resolution of subretinal fluid. One year and nine months later, case 2 (his son) also presented with the typical clinical symptoms of VKH disease at 29 years of age. The son also recovered from VKH disease after routine and standard treatment. CONCLUSIONS: To the best of our knowledge, this is the first VKH disease case report of a father-son relationship. Although genetic factors have been demonstrated to be involved in the pathogenesis of VKH disease, the different inheritance modes of VKH patients need to be further explored and studied.

The dual role of the CD95 and CD95L signaling pathway in glioblastoma.

Binding of CD95, a cell surface death receptor, to its homologous ligand CD95L, transduces a cascade of downstream signals leading to apoptosis crucial for immune homeostasis and immune surveillance. Although CD95 and CD95L binding classically induces programmed cell death, most tumor cells show resistance to CD95L-induced apoptosis. In some cancers, such as glioblastoma, CD95-CD95L binding can exhibit paradoxical functions that promote tumor growth by inducing inflammation, regulating immune cell homeostasis, and/or promoting cell survival, proliferation, migration, and maintenance of the stemness of cancer cells. In this review, potential mechanisms such as the expression of apoptotic inhibitor proteins, decreased activity of downstream elements, production of nonapoptotic soluble CD95L, and non-apoptotic signals that replace apoptotic signals in cancer cells are summarized. CD95L is also expressed by other types of cells, such as endothelial cells, polymorphonuclear myeloid-derived suppressor cells, cancer-associated fibroblasts, and tumor-associated microglia, and macrophages, which are educated by the tumor microenvironment and can induce apoptosis of tumor-infiltrating lymphocytes, which recognize and kill cancer cells. The dual role of the CD95-CD95L system makes targeted therapy strategies against CD95 or CD95L in glioblastoma difficult and controversial. In this review, we also discuss the current status and perspective of clinical trials on glioblastoma based on the CD95-CD95L signaling pathway.

LncRNA 1700020I14Rik promotes AKR1B10 expression and activates Erk pathway to induce hepatocyte damage in alcoholic hepatitis.

Alcoholic hepatitis (AH), a kind of alcoholic liver disease, shows poor prognosis. Long noncoding RNAs (lncRNAs) exert critical role in liver diseases. Here, we intended to investigate the possible molecular mechanism that 1700020I14Rik-based regulation of microRNA (miR)-137/Aldo-keto reductase family 1 member B10 (AKR1B10) affecting the inflammatory response and hepatocyte damage in AH. AH-related genes and the down-stream regulatory pathway were screnned by bioinformatics. Mouse normal hepatocyte cell line AML12 was selected to construct an ethanol-induced hepatocyte injury model for in vitro mechanistic validation, while we also established an AH mouse model using the ethanol with gradually increased concentration of 2-4% (v/v) for in vivo study. Specific role of 1700020I14Rik/miR-137/AKR1B10 in AML12 cell viability, proliferation and apoptotic capacity as well as inflammation and liver damage in mice were analyzed following ectopic and depletion approaches. We found elevated AKR1B10 and 1700020I14Rik but reduced miR-137 in AH. 1700020I14Rik was able to elevated miR-137-mediated AKR1B10. In vitro cell experiments and in vivo animal experiments validated that 1700020I14Rik reduced ethanol-induced hepatocyte damage and inflammation in AH mice through regulation of miR-137-mediated AKR1B10/Erk axis. The current study underlied that 1700020I14Rik could activate AKR1B10/Erk signaling through inhibition of miR-137, thereby promoting the hepatocyte damage in AH mice.

Effectiveness of Trastuzumab Combined With Capecitabine Treatment in a Patient With Hilar Cholangiocarcinoma Complicated by Liver Metastases With an ERBB2-Activating Mutation: A Case Report.

The identification of ERBB2 (HER2) alteration in some solid tumors has become critically important due to the actionable events predictive of response to anti-HER2 therapy. However, the efficacy of ERBB2 mutated hilar cholangiocarcinoma (hCCA) against ERBB2 is rarely reported. Here we report a 76-year-old female diagnosed with hCCA complicated by liver metastases after radical resection. The next-generation sequencing assay showed that the tumor had an ERBB2 mutation. Then, the patient was treated with trastuzumab plus capecitabine. After 2 months of treatment, she had a partial response. Until now, the patient is still alive. This study has shown the potential of trastuzumab combined with capecitabine as an effective treatment for hilar cholangiocarcinoma complicated by liver metastases harboring ERBB2 alterations.

A meta-analysis of peer-assisted learning on examination performance in clinical knowledge and skills education.

BACKGROUND: Peer-assisted learning is a method of active learning that is gaining traction throughout higher education. In the medical curriculum, peer-assisted learning has been the subject of independent studies collecting various types of data. However, an overall analysis of those studies providing objective measurements of the influence of peer-assisted learning could be particularly useful for teachers and students alike in a knowledge-heavy curriculum such as medicine. In this study we set out to analyse the efficacy of peer-assisted learning on medical students' learning of clinical knowledge and skills that is assessed through some objective examination, and thereby define whether such approaches have a reproducible benefit for inclusion in the medical curriculum. METHODS: Databases including Pubmed, Embase and Science Direct were searched for relevant studies containing randomized controlled trials (RCTs) of peer-assisted learning published before July 29th ,2020. A meta-analysis was performed by using RevMan 5.3 software. RESULTS: Thirteen studies involving 2,003 medical students were analyzed for clinical knowledge and skills gains that included some objective measurement of learning. The results of this meta-analysis indicated that considering all these studies together, peer-assisted learning leads to improvements in clinical knowledge and skills learning for medical students compared with traditional teacher-led passive learning. One study was found likely to be a source of significant heterogeneity, and when this was removed from the meta-analysis, the pooled effect was no longer statistically significant. CONCLUSIONS: Peer-assisted learning can be an effective method of learning applied to medical student education. Active learning through peer-assisted learning should be seen as complementary to teacher-led approaches. Two of the individual studies on peer-assisted learning show a statistically significant benefit on examination performance compared to the other studies considered, that either show negligible benefits or at worst no detriment in learning. This highlights the need for more high-quality and focused randomized control trials to identify those critical parameters that lead to improved student learning using such approaches.

Metabolite Profiling and Transcriptome Analysis Revealed the Conserved Transcriptional Regulation Mechanism of Caffeine Biosynthesis in Tea and Coffee Plants.

Caffeine is a characteristic bioactive compound in tea and coffee plants, which is synthesized and accumulated extensively in leaves and seeds. However, little is known about the regulatory mechanism of caffeine synthesis in plants. This study compared the caffeine metabolite between tea and coffee plants. We found that tea leaves contained significantly higher caffeine than coffee leaves, which is perhaps due to more members of N-methyltransferase (NMT) genes as well as higher expression levels in tea plants. Substantial numbers of transcription factors were predicted to be involved in caffeine biosynthesis regulation, combining weighted gene co-expression network analysis and the cis-element of NMT promoter analysis in tea and coffee plants. Furthermore, analysis of the transcription factors from the caffeine-related modules suggested that the regulatory mechanism of caffeine biosynthesis was probably partly conservative in tea and coffee plants. This study provides an essential resource for the regulatory mechanism of caffeine biosynthesis in plants.

CsMYB1 integrates the regulation of trichome development and catechins biosynthesis in tea plant domestication.

Tea trichomes synthesize numerous specialized metabolites to protect plants from environmental stresses and contribute to tea flavours, but little is known about the regulation of trichome development. Here, we showed that CsMYB1 is involved in the regulation of trichome formation and galloylated cis-catechins biosynthesis in tea plants. The variations in CsMYB1 expression levels are closely correlated with trichome indexes and galloylated cis-catechins contents in tea plant populations. Genome resequencing showed that CsMYB1 may be selected in modern tea cultivars, since a 192-bp insertion in CsMYB1 promoter was found exclusively in modern tea cultivars but not in the glabrous wild tea Camellia taliensis. Several enhancers in the 192-bp insertion increased CsMYB1 transcription in modern tea cultivars that coincided with their higher galloylated cis-catechins contents and trichome indexes. Biochemical analyses and transgenic data showed that CsMYB1 interacted with CsGL3 and CsWD40 and formed a MYB-bHLH-WD40 (MBW) transcriptional complex to activate the trichome regulator genes CsGL2 and CsCPC, and the galloylated cis-catechins biosynthesis genes anthocyanidin reductase and serine carboxypeptidase-like 1A. CsMYB1 integratively regulated trichome formation and galloylated cis-catechins biosynthesis. Results suggest that CsMYB1, trichome and galloylated cis-catechins are coincidently selected during tea domestication by harsh environments for improved adaption and by breeders for better tea flavours.

Association of tumor mutational burden with genomic alterations in Chinese urothelial carcinoma.

The tumor mutational burden (TMB) calculated by whole-exome sequencing (WES) is a promising biomarker for the response to immune checkpoint inhibition (ICIs) in solid tumors. However, WES is not feasible in the routine clinical setting. In addition, the characteristics of the TMB in Chinese urothelial carcinoma (UC) are unclear. The aim of this study was to demonstrate the reliability of an Acornmed 808 panel and analyze the characteristics of the TMB in Chinese UC. An Acornmed 808 panel was designed and virtually validated using UC data from the cancer genome atlas (TCGA). Comprehensive analysis of sequencing and clinical data was performed to explore the characteristics of the TMB for 143 Chinese UC patients. Compared to the TMB calculated with random 808-, 500-, and 250-gene panels, the TMB calculated with the Acornmed 808 panel was closer to that calculated by WES. There were marked disparities in the mutational landscape and TMB between Chinese and TCGA UC data. The TMB was negatively associated with copy number variation (CNV). In contrast, the TMB was positive correlation with numbers of mutated DDR genes. Exposure to aristolochic acid signature was observed only in the TMB-high groups. The Acornmed 808 panel is a clinically practical method to assess the TMB. The TMB was associated with the DDR gene status and CNV counts and might be a biomarker for further stratification of UC patients. The study suggested that patients with high TMB may have a unique carcinogenic mechanism.

Germline Mutation Landscape and Associated Clinical Characteristics in Chinese Patients With Renal Cell Carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a disease of genomic alterations, of which the complete panorama helps in facilitating molecular-guided therapy. Germline mutation profiles and associated somatic and clinical characteristics remains unexplored in Chinese RCC patients. METHODS: We retrospectively profiled the germline and somatic mutations of 322 unselected RCC patients using a panel consisting of 808 cancer-related genes. We categorized patients into three groups based on germline mutation status and compared the somatic mutation spectrum among different groups. RESULTS: Approximately one out of ten (9.9%) RCC patients were identified to carry pathogenic/likely pathogenic (P/LP) germline variants (PGVs), of which 3.7% were variants in syndromic RCC-associated genes and 6.2% were other cancer-predisposition genes. The most common PGV was found in VHL (2.2%), followed by FH, TSC2, ATM, BRCA1, NBN, and BLM (0.6% each). Young patients (≤46 years) were more likely to harbor PGVs. Variants in syndromic RCC-associated genes were predominant identified in young patients, while variants in other cancer-predisposition genes were found in patients >46 years more frequently. Furthermore, 39.3% (11/28) of patients carrying PGVs were detected to have somatic "second hit" events. Germline and somatic sequencing, including microsatellite instability (MSI) status analysis, provided potentially actionable therapeutic targets in 17.1% of patients in the whole cohort. CONCLUSIONS: Our results revealed that approximately 10% of RCC patients carried clinically significant germline mutations. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing in RCC population.

MiRNA-29a serves as a promising diagnostic biomarker in children with temporal lobe epilepsy and regulates seizure-induced cell death and inflammation in hippocampal neurons.

Temporal lobe epilepsy (TLE) in children is one of the most common refractory epilepsies. MicroRNAs (miRNAs) show abnormal expression in neurological disorders. The objective of this study was to determine changes in expression and the role of miR-29a in children with TLE. Sixty-five TLE patients and 70 normal controls were recruited. The levels of miR-29a were quantified using qRT-PCR. An in vitro TLE cell model was established using primary hippocampal cells cultured in magnesium-free medium. Cell viability, cell apoptosis and inflammatory cytokine concentrations were evaluated. The luciferase reporter assay was applied to confirm the target gene, HMGB1. A low level of MiR-29a expression was observed in the serum of children with TLE, which demonstrated a negative association with the concentration of serum TNF-α, IL-6, and IFN-γ. The level of MiR-29a demonstrated high specificity and sensitivity in children with TLE. A low level of expression of miR-29a was also detected in the TLE cell model. MiR-29a over-expression reversed the decreased cell viability induced by TLE, and alleviated cell apoptosis. Release of TNF-α, IL-6, and IFN-γ induced by TLE was also inhibited by miR-29a over-expression. HMGB1, which was downregulated in the serum of TLE patients, was shown to be a target gene of miR-29a, and negatively correlated with miR-29a level. The downregulation of serum miR-29a may serve as a non-invasive diagnostic biomarker for children with TLE. MiR-29a may be involved in the pathogenesis of TLE through regulation of neuronal apoptosis and neuroinflammation via targeting HMGB1.

Whole-exome sequencing in osteosarcoma with distinct prognosis reveals disparate genetic heterogeneity.

The genomic profiles of osteosarcoma (OS) patients have been extensively investigated; however, the genetic prognostic biomarkers still remain unclear. In the present study, we analyzed the mutational profiles of pre-treatment primary tumor samples from 33 OS patients using whole exome sequencing (WES). These 33 OS patients were divided into two groups according to clinical outcomes: a good prognosis group involving 21 patients with tumor free survival, and a poor prognosis group involving the remaining12 patients who had lung metastases at initial diagnosis. Overall we found that the MAPK signaling pathway may play an important role in determining a good prognosis, while the PI3K-Akt signaling pathway may be an important factor leading to a poor prognosis. Significant differences were observed in the number of somatic copy number alterations, including del (3p), amp (4q), del (7p) and amp (8q), between the two groups. Moreover, significant differences were observed in mutation sites and frequencies between these two groups. The good prognosis group exhibited a significantly higher mutation frequency in somatic JAK-STAT and germline base excision repair pathways than the poor prognosis group. Furthermore, significant difference was also observed in the frequency of potentially actionable alterations between the two groups, suggesting that patients with a poor prognosis potentially have access to a larger number of treatment options. These findings highlight the importance of evaluating genomic disparities in OS, and provide a novel insight into the potential prognostic biomarkers.

Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder.

BACKGROUND: Different genomic characterization in urothelial carcinoma (UC) by site of origin may imply contrasting therapeutic opportunities and pathogenetic mechanisms. The aim of this study was to investigate whether differences between upper tract UC (UTUC) and UC of the bladder (UCB) result from intrinsic biological diversity. MATERIALS AND METHODS: We prospectively sequenced 118 tumors and matched blood DNA from Chinese patients with UC using next-generation sequencing techniques, including 45 UTUC and 73 UCB. Two hundred twenty-six patients with UTUC and 350 patients with UCB for The Cancer Genome Atlas were acquired from the cbioportal. RESULTS: There were marked disparities in the mutational landscape for UC according to race and site of origin. Signature 22 for exposure to aristolochic acid was only observed in the UTUC cohort. Conversely, signature 6 for defective DNA mismatch repair only existed in the UCB cohort. Compared with UCB, UTUC had higher clonal and subclonal mutation numbers. TP53, PIK3CA, and FGFR3 mutations may be the driver genes for UTUC, whereas for UCB, the driver gene may be BRCA1. Patients with UTUC had lower PD-L1 than those with UCB. There was no significant difference in the number of DDR mutations, copy number variation counts, and tumor mutational burden between UTUC and UCB. CONCLUSION: UTUC and UCB exhibit significant differences in the prevalence of genomic landscape and carcinogenesis. Consequently, molecular subtypes differ according to location, and these results may imply the site-specific management of patients with urothelial carcinoma. Mutational signature may be used as a screening tool to assist clinical differential diagnosis between UTUC and UCB. IMPLICATIONS FOR PRACTICE: This study's findings lay the foundation for a deeper understanding of distinct molecular mechanisms and similar treatment opportunities between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) and had important implications for the site-specific management of patients with urothelial carcinoma. A comprehensive understanding of the biology of UTUC and UCB is needed to identify new drug targets in order to improve clinical outcomes.