Implementation of antibody-drug conjugates in HER2-positive solid cancers: Recent advances and future directions.

In recent decades, there has been a surge in the approval of monoclonal antibodies for treating a wide range of hematological and solid malignancies. These antibodies exhibit exceptional precision in targeting the surface antigens of tumors, heralding a groundbreaking approach to cancer therapy. Nevertheless, monoclonal antibodies alone do not show sufficient lethality against cancerous cells compared to chemotherapy. Consequently, a new class of anti-tumor medications, known as antibody-drug conjugates (ADCs), has been developed to bridge the divide between monoclonal antibodies and cytotoxic drugs, enhancing their therapeutic potential. ADCs are chemically synthesized by binding tumor-targeting monoclonal antibodies with cytotoxic payloads through linkers that are susceptible to cleavage by intracellular proteases. They combined the accurate targeting of monoclonal antibodies with the potent efficacy of cytotoxic chemotherapy drugs while circumventing systemic toxicity and boasting superior lethality over standalone targeted drugs. The human epidermal growth factor receptor (HER) family, which encompasses HER1 (also known as EGFR), HER2, HER3, and HER4, plays a key role in regulating cellular proliferation, survival, differentiation, and migration. HER2 overexpression in various tumors is one of the most frequently targeted antigens for ADC therapy in HER2-positive cancers. HER2-directed ADCs have emerged as highly promising treatment modalities for patients with HER2-positive cancers. This review focuses on three approved anti-HER2 ADCs (T-DM1, DS-8201a, and RC48) and reviews ongoing clinical trials and failed trials based on anti-HER2 ADCs. Finally, we address the notable challenges linked to ADC development and underscore potential future avenues for tackling these hurdles.

A chromosome-level genome assembly of the forestry pest Coronaproctus castanopsis.

As an important forestry pest, Coronaproctus castanopsis (Monophlebidae) has caused serious damage to the globally valuable Gutianshan ecosystem, China. In this study, we assembled the first chromosome-level genome of the female specimen of C. castanopsis by merging BGI reads, HiFi long reads and Hi-C data. The assembled genome size is 700.81 Mb, with a scaffold N50 size of 273.84 Mb and a contig N50 size of 12.37 Mb. Hi-C scaffolding assigned 98.32% (689.03 Mb) of C. Castanopsis genome to three chromosomes. The BUSCO analysis (n = 1,367) showed a completeness of 91.2%, comprising 89.2% of single-copy BUSCOs and 2.0% of multicopy BUSCOs. The mapping ratio of BGI, second-generation RNA, third-generation RNA and HiFi reads are 97.84%, 96.15%, 97.96%, and 99.33%, respectively. We also identified 64.97% (455.3 Mb) repetitive elements, 1,373 non-coding RNAs and 10,542 protein-coding genes. This study assembled a high-quality genome of C. castanopsis, which accumulated valuable molecular data for scale insects.

Exploring the mechanism of LncRNA CASC15 affecting hepatocellular carcinoma through miRNA.

This study aimed to determine the potential mechanisms through which long noncoding (Lnc) RNA cancer susceptibility candidate 15 (CASC15) affects hepatocellular carcinoma (HCC). We retrieved HCC RNA-seq and clinical information from the UCSC Xena database. The differential expression (DE) of CASC15 was detected. Overall survival was analyzed using Kaplan-Meier (K-M) curves. Molecular function and signaling pathways affected by CASC15 were determined using Gene Set Enrichment Analysis. Associations between CASC15 and the HCC microenvironment were investigated using immuno-infiltration assays. A differential CASC15-miRNA-mRNA network and HCC-specific CASC15-miRNA-mRNA ceRNA network were constructed. The overexpression of CASC15 in HCC tissues was associated with histological grade, clinical stage, pathological T stage, poor survival, more complex immune cell components, and 12 immune checkpoints. We identified 27 DE miRNAs and 270 DE mRNAs in the differential CASC15-miRNA-mRNA network, and 10 key genes that were enriched in 12 cancer-related signaling pathways. Extraction of the HCC-specific CASC15-miRNA-mRNA network revealed that IGF1R, MET, and KRAS were associated with HCC progression and occurrence. Our bioinformatic findings confirmed that CASC15 is a promising prognostic biomarker for HCC, and elevated levels in HCC are associated with the tumor microenvironment. We also constructed a disease-specific CASC15-miRNA-mRNA regulatory ceRNA network that provides a new perspective for the precise indexing of patients with elevated levels of CASC15.

Hydrogen sulfide protects cardiomyocytes from doxorubicin-induced ferroptosis through the SLC7A11/GSH/GPx4 pathway by Keap1 S-sulfhydration and Nrf2 activation.

Recent studies have demonstrated that ferroptosis, a novel form of nonapoptotic regulated cell death plays an important role in doxorubicin (DOX)-induced cardiotoxicity (DoIC). Hydrogen sulfide (H2S) is emerging as the third important gaseous mediator in cardiovascular system. However, whether H2S has an effect on DOX-induced ferroptosis remains unknown. Here, we found that DOX not only triggered cardiomyocyte ferroptosis but also significantly inhibited the synthesis of endogenous H2S in the murine model of chronic DoIC. Application of NaHS, an H2S donor obviously activated the SLC7A11/GSH/GPx4 antioxidant pathway and thus alleviated DOX-induced ferroptosis and cardiac injury in mice. In contrast, cardiac-specific knockout of cystathionine γ-lyase gene (Cse) in mice (Csef/f/Cre+) to abolish the cardiac synthesis of endogenous H2S evidently exacerbated DOX-induced ferroptosis and cardiac dysfunction. A further suppression of SLC7A11/GSH/GPx4 pathway was obtained in Csef/f/Cre+ mice with DoIC, as compared to Csef/f/Cre- mice with DoIC. The aggravation caused by cardiac-specific Cse deficiency was remarkably rescued by exogenous supplementation of NaHS. Moreover, in DOX-stimulated H9c2 cardiomyocytes, pretreatment with NaHS dose-dependently enhanced the activity of SLC7A11/GSH/GPx4 pathway and subsequently mitigated ferroptosis and mitochondrial impairment. On the contrary, transfection with Cse siRNA in DOX-stimulated H9c2 cardiomyocytes markedly inhibited SLC7A11/GSH/GPx4 pathway, thus leading to aggravated ferroptosis and more damage to mitochondrial structure and function. In addition, the protective effect of NaHS on DOX-induced ferroptosis was closely related to the S-sulfhydrated Keap1, which in turn promoted nuclear translocation of Nrf2 and the transcription of SLC7A11 and GPx4. In conclusion, our findings suggest that H2S may exert protective effect on DoIC by inhibiting DOX-induced ferroptosis via Keap1/Nrf2-dependent SLC7A11/GSH/GPx4 antioxidant pathway.

Deciphering the metabolic heterogeneity of hematopoietic stem cells with single-cell resolution.

Metabolic status is crucial for stem cell functions; however, the metabolic heterogeneity of endogenous stem cells has never been directly assessed. Here, we develop a platform for high-throughput single-cell metabolomics (hi-scMet) of hematopoietic stem cells (HSCs). By combining flow cytometric isolation and nanoparticle-enhanced laser desorption/ionization mass spectrometry, we routinely detected >100 features from single cells. We mapped the single-cell metabolomes of all hematopoietic cell populations and HSC subpopulations with different division times, detecting 33 features whose levels exhibited trending changes during HSC proliferation. We found progressive activation of the oxidative pentose phosphate pathway (OxiPPP) from dormant to active HSCs. Genetic or pharmacological interference with OxiPPP increased reactive oxygen species level in HSCs, reducing HSC self-renewal upon oxidative stress. Together, our work uncovers the metabolic dynamics during HSC proliferation, reveals a role of OxiPPP for HSC activation, and illustrates the utility of hi-scMet in dissecting metabolic heterogeneity of immunophenotypically defined cell populations.

Designed Nanomaterials-Assisted Proteomics and Metabolomics Analysis for In Vitro Diagnosis.

In vitro diagnosis (IVD) is pivotal in modern medicine, enabling early disease detection and treatment optimization. Omics technologies, particularly proteomics and metabolomics, offer profound insights into IVD. Despite its significance, omics analyses for IVD face challenges, including low analyte concentrations and the complexity of biological environments. In addition, the direct omics analysis by mass spectrometry (MS) is often hampered by issues like large sample volume requirements and poor ionization efficiency. Through manipulating their size, surface charge, and functionalization, as well as the nanoparticle-fluid incubation conditions, nanomaterials have emerged as a promising solution to extract biomolecules and enhance the desorption/ionization efficiency in MS detection. This review delves into the last five years of nanomaterial applications in omics, focusing on their role in the enrichment, separation, and ionization analysis of proteins and metabolites for IVD. It aims to provide a comprehensive update on nanomaterial design and application in omics, highlighting their potential to revolutionize IVD.

High dietary intake of unsaturated fatty acids is associated with improved insulin resistance - a cross-sectional study based on the NHANES database.

BACKGROUND: A moderate intake of unsaturated fatty acids (UFA) is associated positively with improved insulin resistance. The aim of this study was to investigate the relationship between the dietary intake of unsaturated fatty acids/total fats (UFA/TF) and insulin resistance. METHODS: 15,560 participants were selected from the National Health and Nutrition Examination Survey (NHANES) database enrolled between March 2017 and 2020, and excluded those under 20 years of age, pregnant, or with missing data for key research items. Finally, 7,630 participants were included in the study. R software was used for data analysis that included: (1) general descriptive statistics; (2) comparison of differences in baseline information of three UFA/TF groups, namely low, medium, and high ratios; (3) calculation of the correlation between the UFA/TF ratio and markers of insulin resistance: triglyceride-glucose index (TyG) and homeostatic model assessment for insulin resistance (HOMA-IR); (4) stratification of the study subjects into two groups, with or without insulin resistance, using a cut-off value of HOMA-IR ≥ 2, followed by logistic regression analysis to examine the relationship between UFA/TF and insulin resistance status in the two groups; and (5) further stratification of the subjects according to age, gender, body mass index (BMI), race, total energy intake, total protein, total carbohydrate, total sugars, total dietary fiber, total fat, alcohol consumption, diabetes, hypercholesterolemia to analyze the impact of UFA/TF on insulin resistance status in different subgroups. RESULTS: (1) A high UFA/TF level was associated with a low TyG index and HOMA-IR [ß (vs. TyG index) = -0.559, 95% CI: (-0.821~-0.297), P < 0.001; ß (vs. HOMA-IR) = -0.742, 95% CI: (-1.083~-0.402), P < 0.001]. This negative relationship became more pronounced when UFA/TF exceeded 57.9% (i.e., the higher group). (2) Logistic regression analysis showed that a higher UFA/TF level was associated with a lower risk of developing insulin resistance [Q3 vs. Q1: 0.838 (95%CI: 0.709 ~ 0.991); P for trend = 0.038]. After adjusting for covariates such as gender, age, and BMI, this protective effect remained significant (P value < 0.05). (3) Analysis also showed that increased UFA/TF intake reduced the risk of developing insulin resistance (OR = 0.266, 95% CI: (0.075 ~ 0.946), P = 0.041). Subgroup analysis showed that although elevated UFA/TF intake showed no statistically significant difference in its effect in most subgroups, the large study population in this study provides valuable insights on potential changes. Increased UFA/TF intake may confer relatively greater benefits within specific subgroups, particularly among the elderly [Q3 age group, OR = 0.114, 95%CI: (0.012 ~ 1.078), P = 0.058], females [OR = 0.234, 95%CI: (0.041 ~ 1.333), P = 0.102], those with a BMI ≤ 25 kg/m²[OR = 0.191, 95%CI: (0.016 ~ 2.344), P = 0.196], and individuals without hypercholesterolemia [OR = 0.207, 95%CI: (0.042 ~ 1.013), P = 0.0519]. The impact of high UFA/TF levels within subgroups based on the presence or absence of coronary heart disease and stroke displayed contrasting trends. In those without coronary heart disease, there was a significant protective effect against insulin resistance [OR = 0.254, 95% CI: (0.07 ~ 0.929), P = 0.0384], while in the stroke subgroup, a significantly protective effect against insulin resistance was observed [OR = 0.002, 95%CI: (0 ~ 0.695), P = 0.0376]. CONCLUSION: A high dietary intake of UFA relative to total fat consumption could be a protective factor against the risk of developing insulin resistance.

CDK13 promotes lipid deposition and prostate cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA.

Cyclin-dependent kinases (CDKs) regulate cell cycle progression and the transcription of a number of genes, including lipid metabolism-related genes, and aberrant lipid metabolism is involved in prostate carcinogenesis. Previous studies have shown that CDK13 expression is upregulated and fatty acid synthesis is increased in prostate cancer (PCa). However, the molecular mechanisms linking CDK13 upregulation and aberrant lipid metabolism in PCa cells remain largely unknown. Here, we showed that upregulation of CDK13 in PCa cells increases the fatty acyl chains and lipid classes, leading to lipid deposition in the cells, which is positively correlated with the expression of acetyl-CoA carboxylase (ACC1), the first rate-limiting enzyme in fatty acid synthesis. Gain- and loss-of-function studies showed that ACC1 mediates CDK13-induced lipid accumulation and PCa progression by enhancing lipid synthesis. Mechanistically, CDK13 interacts with RNA-methyltransferase NSUN5 to promote its phosphorylation at Ser327. In turn, phosphorylated NSUN5 catalyzes the m5C modification of ACC1 mRNA, and then the m5C-modified ACC1 mRNA binds to ALYREF to enhance its stability and nuclear export, thereby contributing to an increase in ACC1 expression and lipid deposition in PCa cells. Overall, our results disclose a novel function of CDK13 in regulating the ACC1 expression and identify a previously unrecognized CDK13/NSUN5/ACC1 pathway that mediates fatty acid synthesis and lipid accumulation in PCa cells, and targeting this newly identified pathway may be a novel therapeutic option for the treatment of PCa.

Using an aromatic amide as nucleating agent to enhance the crystallization and dimensional stability of poly(3-hydroxybutyrate-co-3-hydroxyhexanate).

Biosynthesized poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) has emerged as a promising biodegradable polymer with a great potential to compete with traditional petroleum-based plastics, however, the poor crystallization ability makes it challenge to transform into high-performance products via common melt-processing methods. Herein, we demonstrate that N,N'-dicyclohexyl-2,6-naphthalenedicarboxamide (TMB) can serve as an efficient nucleating agent to significantly enhance the crystallization and resulting storage stability of PHBHHx. The results indicate that PHBHHx with small amounts of TMB (0.3-0.5 wt%) can crystallize completely even under a rapid cooling rate of 100 °C/min and the isothermal crystallization time is greatly reduced. As a result, the crystallinity of the injection-molded PHBHHx products is increased from 24.5 % to 39.5 %, without secondary crystallization after being stored at room temperature for 6 h. The products exhibit superior dimensional stability and the post-shrinkage can be decreased to as low as 0.1 %. Our work offers a feasible method to develop high-performance PHBHHx materials with remarkably enhanced crystallization ability.

Neuroprotective effects of Longxue Tongluo Capsule on ischemic stroke rats revealed by LC-MS/MS-based metabolomics approach.

Objective: The present study aimed to evaluate the therapeutic effect and explore the underlying mechanisms of Longxue Tongluo Capsule (LTC) on ischemic stroke rats. Methods: Twenty-six rats were randomly divided into four groups, including sham group, sham + LTC group, MCAO group, and MCAO + LTC group. Ischemic stroke rats were simulated by middle cerebral artery occlusion (MCAO), and LTC treatment group were orally administrated with 300 mg/kg of LTC once daily for seven consecutive days. LTC therapy was validated in terms of neurobehavioral abnormality evaluation, cerebral infarct area, and histological assessments. The plasma metabolome comparisons amongst different groups were conducted by UHPLC-Q Exactive MS in combination with subsequent multivariate statistical analysis, aiming to finding the molecules in respond to the surgery or LTC treatment. Results: Intragastric administration of LTC significantly decreased not only the neurobehavioral abnormality scores but also the cerebral infarct area of MCAO rats. The interstitial edema, atrophy, and pyknosis of glial and neuronal cells occurred in the infarcted area, core area, and marginal area of cerebral cortex were improved after LTC treatment. A total of 13 potential biomarkers were observed, and Youden index of 11 biomarkers such as LysoPC, SM, and PE were more than 0.7, which were involved in neuroprotective process. The correlation and pathway analysis showed that LTC was beneficial to ischemic stroke rats via regulating glycerophospholipid and sphingolipid metabolism, together with nicotinate and nicotinamide metabolism. Heatmap and ternary analysis indicated the synergistic effect of carbohydrates and lipids may be induced by flavonoid intake from LTC. Conclusion: The present study could provide evidence that metabolomics, as systematic approach, revealed its capacity to evaluate the holistic efficacy of TCM, and investigate the molecular mechanism underlying the clinical treatment of LTC on ischemic stroke.

Novel agents and clinical trials in castration-resistant prostate cancer: latest updates from 2023 ASCO-GU Cancers Symposium.

Numerous novel and effective therapeutic agents and clinical trials addressing castration-resistant prostate cancer (CRPC) were reported during the 2023 American Society of Clinical Oncology-Genitourinary (ASCO-GU) Cancers Symposium. Notably, radionuclide drug conjugates (RDC), specifically 177Lu/111In-J591 and 225Ac-J591, exhibited enhanced therapeutic efficacy in treating patients with CRPC. Furthermore, promising treatment approaches for CRPC included dual anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) blockade in rare tumors (DART)-Lorigerlimab, prostate stem cell antigen (PSCA)-directed chimeric antigen receptor (CAR)-T cell immunotherapy-BPX-601, and protein kinase inhibitor (AKTi)-CAPltello-280. We have summarized the latest CRPC treatment strategies presented at the 2023 ASCO-GU Cancers Symposium, along with recent advances in CRPC clinical trials.

Hollow multishelled heterostructures with enhanced performance for laser desorption/ionization mass spectrometry based metabolic diagnosis.

High-performance metabolic diagnosis-based laser desorption/ionization mass spectrometry (LDI-MS) improves the precision diagnosis of diseases and subsequent treatment. Inorganic matrices are promising for the detection of metabolites by LDI-MS, while the structure and component impacts of the matrices on the LDI process are still under investigation. Here, we designed a multiple-shelled ZnMn2O4/(Co, Mn)(Co, Mn)2O4 (ZMO/CMO) as the matrix from calcined MOF-on-MOF for detecting metabolites in LDI-MS and clarified the synergistic impacts of multiple-shells and the heterostructure on LDI efficiency. The ZMO/CMO heterostructure allowed 3-5 fold signal enhancement compared with ZMO and CMO with the same morphology. Furthermore, the ZMO/CMO heterostructure with a triple-shelled hollow structure displayed a 3-fold signal enhancement compared to its nanoparticle counterpart. Taken together, the triple-shelled hollow ZMO/CMO exhibits 102-fold signal enhancement compared to the commercial matrix products (e.g., DHB and DHAP), allowing for sensitive metabolic profiling in bio-detection. We directly extracted metabolic patterns by the optimized triple-shelled hollow ZMO/CMO particle-assisted LDI-MS within 1 s using 100 nL of serum and used machine learning as the readout to distinguish hepatocellular carcinoma from healthy controls with the area under the curve value of 0.984. Our approach guides us in matrix design for LDI-MS metabolic analysis and drives the development of a nanomaterial-based LDI-MS platform toward precision diagnosis.

Prognostic significance of LRRC1 in hepatocellular carcinoma and construction of relevant prognostic model.

This study aimed to elucidate the prognostic value of the leucine rich repeat containing 1 (LRRC1) gene in hepatocellular carcinoma (HCC) and to determine the effects of high and low LRRC1 expression on mutation and immune cell infiltration. We downloaded HCC mRNA-seq expression and clinical data from University of California Santa Cruz Xena. The expression of LRRC1 was compared between HCC tumor and normal samples. Tumor samples were divided according to high and low LRRC1 expression. Differentially expressed genes between the 2 groups were identified, and function, mutation, and immune cell infiltration were analyzed. Genes associated with immune cells were identified using weighted gene co-expression network analysis, and transcription factors of these genes were predicted. Moreover, a prognostic model was developed and its performance was evaluated. The expression of LRRC1 was upregulated in HCC tissues, and this indicated a poor prognosis for patients with HCC. Differentially expressed genes between high and low LRRC1 expression were significantly enriched in pathways associated with cancer, amino acid metabolism, carbohydrate metabolism, and the immune system. We identified 15 differentially infiltrated immune cells between tumors with high and low LRRC1 expression and 14 of them correlated with LRRC1 gene expression. Weighted gene co-expression network analysis identified 83 immune cell-related genes, 27 of which had prognostic value. Cyclic AMP-response element binding protein regulated annexin A5, matrix metallopeptidase 9, and LRRC1 in the transcription factor regulatory network. Finally, a prognostic model composed of 7 genes were generated, which could accurately predict the prognosis of HCC patients. The LRRC1 gene might serve as a potential immune-associated prognostic biomarker for HCC.

Spectrophotometric- and LC/MS-Based Lipidomics Analyses Revealed Changes in Lipid Profiles of Pike Eel (Muraenesox cinereus) Treated with Stable Chlorine Dioxides and Vacuum-Packed during Chilled Storage.

Spectrophotometric- and liquid chromatography/mass spectrometry (LC/MS)-based lipidomics analyses were performed to explore the changes of lipid profiles in pike eel (Muraenesox cinereus) under stable chlorine dioxides (ClO2) and vacuum-packed treatment during chilled storage. The peroxide value (PV) and malondialdehyde (MDA) content in ClO2 treated and vacuum-packaged (VP) samples were significantly reduced compared to simple-packaged (SP) samples during whole chilled storage. The LC/MS-based lipidomics analyses identified 2182 lipid species in the pike eel muscle classified into 39 subclasses, including 712 triglycerides (TGs), 310 phosphatidylcholines (PCs), 153 phosphatidylethanolamines (PEs), and 147 diglycerides (DGs), among others. Further, in comparison with fresh pike eel (FE) muscle, 354 and 164 higher and 420 and 193 lower abundant levels of differentially abundant lipids (DALs) were identified in SP samples and VP samples, respectively. Compared with the VP batch, 396 higher and 404 lower abundant levels of DALs were identified in the SP batch. Among these, PCs, PEs, TGs, and DGs were more easily oxidized/hydrolyzed, which could be used as biomarkers to distinguish FE, SP, and VP samples. This research provides a reference for controlling lipid oxidation in fatty fish.

Novel ADCs and combination therapy in urothelial carcinoma: latest updates from the 2023 ASCO-GU Cancers Symposium.

Antibody-drug conjugates (ADCs) combine the cytotoxicity of small-molecule drugs with antibody targeting. Due to their precise and powerful effect, they have become a new hotspot and an important trend in the research and development of anti-tumor antibody drugs. Every year, exciting new developments and innovations in the treatment of urological tumors are introduced at the American Society of Clinical Oncology-Genitourinary (ASCO-GU) Cancers Symposium. In this article, we summarize some of the most impressive advances in new clinical trials and clinical data on ADCs in the 2023 ASCO-GU Cancers Symposium for the treatment of urothelial carcinoma.

A novel prognostic model based on immunogenic cell death-related genes for improved risk stratification in hepatocellular carcinoma patients.

PURPOSE: Hepatocellular carcinoma (HCC) is a prevalent primary malignant tumor with increasing incidence and mortality rates in recent years. The treatment options for advanced HCC are very limited. Immunogenic cell death (ICD) plays an important role in cancer, in particular immunotherapy. However, the specific ICD genes and their prognostic values in HCC remain to be investigated. METHODS: The TCGA-LIHC datasets were obtained from TCGA database, LIRI-JP datasets were obtained from ICGC database, and immunogenic cell death (ICD) genes datasets were obtained from previous literature. WGCNA analysis identifies ICD-related genes. Functional analysis was used to investigate the biological characteristics of ICD-related genes. Univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to select prognostic ICD-related genes and construct a prognostic risk score. Prognostic independence of ICD risk scores was determined by univariate and multivariate Cox regression analyses. A nomogram was then constructed and the diagnostic value was assessed using decision curve analysis. Immune infiltration analysis and drug sensitivity analysis were used to investigate immune cell enrichment and drug response in HCC patients classified as low or high risk based on their risk score. RESULTS: Most of the ICD genes were differentially expressed in normal and HCC patients, and some ICD genes were differentially expressed in different clinical groups. A total of 185 ICD-related genes were identified by WGCNA. Prognostic ICD-related genes were selected using a univariate Cox analysis. A model comprising nine prognosis ICD-related gene biomarkers was developed. Patients was divided into high-risk and low-risk groups, and patients in high-risk groups had poorer outcomes. Meanwhile, the reliability of the model was verified by external independent data. The Independent prognostic value of the risk score in HCC was investigated by univariate and multivariate Cox analyses. Diagnostic nomogram was constructed to predict prognosis. Through immune infiltration analysis, we found that some innate and adaptive immune cells were significantly different between low- and high-risk groups. CONCLUSION: We developed and validated a novel prognostic predictive classification system for HCC based on nine ICD-related genes. In addition, immune-related predictions and model could help predict the outcomes of HCC and could provide a reference for clinical practice.

Ruxolitinib Treatment During Myelofibrosis Leads to Cutaneous Mycobacterium marinum Infection: A Case Report.

Mycobacterium marinum is an atypical bacterium, and skin infections caused by it are relatively rare, usually occurring in workers engaged in seafood processing and housewives who clean and prepare fish for consumption. The infection often occurs after the skin is punctured by fish scales, spines, etc. The JAK/STAT signaling pathway is closely related to the human immune response to infections. Therefore, JAK inhibitors may induce and exacerbate various infections in clinical practice. This article reports a case of mycobacterium marinum skin infection in the left upper limb of a female patient with chronic idiopathic myelofibrosis during treatment with ruxolitinib. The patient denied being punctured or scratched by fish scales or spines. Clinical manifestations included multiple infiltrative erythemas and subcutaneous nodules in the thumb and forearm. Histopathological examination showed infiltration of mixed acute and chronic inflammatory cells in the subcutaneous tissue. The diagnosis was ultimately confirmed by NGS sequencing. The patient was cured after taking moxifloxacin and clarithromycin for 10 months. Infection is a common adverse reaction of JAK inhibitors, but no literature has reported on mycobacterium marinum skin infections occurring during JAK inhibitor treatment, which is relatively rare. As the clinical application of JAK inhibitors becomes more widespread, the skin infections they cause may present in various forms and require the attention of clinicians.

Risk factors and a predictive nomogram for hemodynamic instability during adrenalectomy for large pheochromocytomas and paragangliomas: A retrospective cohort study.

OBJECTIVE: This study aimed to investigate risk factors for intraoperative hemodynamic instability (HDI) and construct a clinical model for predicting intraoperative HDI for large pheochromocytomas and paragangliomas (PPGLs) patients. METHODS: A single-center retrospective study of the clinicopathological data of patients undergoing surgery for PPGLs larger than 5 cm in diameter was conducted. A total of 215 eligible patients were enrolled in the study. Three advanced statistical methods were used to select independent risk factors in the training cohort for constructing a nomogram for predicting intraoperative HDI. The predictive performance of the model was assessed by area under the curve (AUC), positive predictive value (PPV), negative predictive value (NPV), and calibration. Decision curve analysis (DCA) and clinical impact curves (CIC) were used to assess predictive accuracy and clinical utility. The performance of the nomogram of was further internally validated. RESULTS: Comorbid diabetes mellitus, anemia, hypoproteinemia, 24-h urine vanillylmandelic acid and intraoperative blood transfusion (P < 0.05) were identified as independent risk factors for constructing the nomogram. In the training cohort, the AUC, PPV and NPV of the nomogram were 0.846, 91.6% and 69.2%. In the validation cohort, the AUC, PPV and NPV were 0.842, 91.8% and 63.3%. These showed good predictive power of the model. The calibration curves demonstrated an optimal consistency between the nomogram-predicted and the actual observed survival probability. DCA and CIC examination showed superior clinical relevance. CONCLUSIONS: The nomogram can objectively and accurately predict intraoperative HDI in patients with large PPGLs, which can help in individualized pre-treatment decision-making.

Liquid biopsy in urothelial carcinoma: Detection techniques and clinical applications.

The types of urothelial carcinoma (UC) include urothelial bladder cancer and upper tract urothelial carcinoma. Current diagnostic techniques cannot meet the needs of patients. Liquid biopsy is an accurate method of determining the molecular profile of UC and is a cutting-edge and popular technique that is expected to complement existing detection techniques and benefit patients with UC. Circulating tumor cells, cell-free DNA, cell-free RNA, extracellular vesicles, proteins, and metabolites can be found in the blood, urine, or other bodily fluids and are examined during liquid biopsies. This article focuses on the components of liquid biopsies and their clinical applications in UC. Liquid biopsies have tremendous potential in multiple aspects of precision oncology, from early diagnosis and treatment monitoring to predicting prognoses. They may therefore play an important role in the management of UC and precision medicine.

Knocking down NSUN5 inhibits the development of clear cell renal cell carcinoma by inhibiting the p53 pathway.

Clear cell renal cell carcinoma (ccRCC) is the most common solid renal tumor. NSUN5, a gene encoding cytosine-5 RNA methyltransferase, has rarely been reported associated with cancer. A bioinformatics analysis revealed that NSUN5 was overexpressed in ccRCC. Gene Ontology and gene set variation analyses showed that NSUN5 was associated with tumor immunity in ccRCC. The effect of immunosuppressive treatment was superior in the low-risk group compared to the high-risk group, and higher stromal score in the high-risk group relative to the low-risk group. A drug sensitivity analysis revealed that the high-risk group was more sensitive to 5-fluorouracil, mitomycin C, methotrexate, and 17-AAG, whereas the low-risk group was more sensitive to crizotinib, sorafenib, foretinib, and ivozanib. NSUN5 knockout decreased ccRCC cell proliferation. The migration speed and number of invasive cells further decreased. The percentage of apoptotic cells increased. In NSUN5-knockout cells, the levels of BAX, caspase-8, caspase-9, and p53 increased significantly, whereas those of Bcl2, CCND1, CCND3, and MMP9 decreased significantly. NSUN5 is highly expressed in ccRCC and inhibits cancer cell invasion, proliferation, and migration while promoting apoptosis by activating the p53 signaling pathway. This study provides insights into the mechanisms of action of NSUN5 in urological tumors and may contribute to improving ccRCC treatment options.