Establishment of a Rapid Detection Method for Cadmium Ions via a Specific Cadmium Chelator N-(2-Acetamido)-Iminodiacetic Acid Screened by a Novel Biological Method.

Heavy metal ions such as cadmium, mercury, lead, and arsenic in the soil cannot be degraded naturally and are absorbed by crops, leading to accumulation in agricultural products, which poses a serious threat to human health. Therefore, establishing a rapid and efficient method for detecting heavy metal ions in agricultural products is of great significance to ensuring the health and safety. In this study, a novel optimized spectrometric method was developed for the rapid and specific colorimetric detection of cadmium ions based on N-(2-Acetamido)-iminodiacetic acid (ADA) and Victoria blue B (VBB) as the chromogenic unit. The safety evaluation of ADA showed extremely low biological toxicity in cultured cells and live animals. The standard curve is y = 0.0212x + 0.1723, R2 = 0.9978, and LOD = 0.08 µM (0.018 mg/kg). The liner concentrations detection range of cadmium is 0.1-10 µM. An inexpensive paper strip detection method was developed with a detection limit of 0.2 µM to the naked eye and a detection time of less than 1 min. The method was successfully used to assess the cadmium content of rice, soybean, milk, grape, peach, and cabbage, and the results correlated well with those determined by inductively coupled plasma-mass spectrometry (ICP-MS). Thus, our study demonstrated a novel rapid, safe, and economical method for onsite, real-time detection of cadmium ions in agricultural products.

Synthesis and Biological Evaluation of Novel Piperidine-3-Carboxamide Derivatives as Anti-Osteoporosis Agents Targeting Cathepsin K.

A series of novel piperidamide-3-carboxamide derivatives were synthesized and evaluated for their inhibitory activities against cathepsin K. Among these derivatives, compound H-9 exhibited the most potent inhibition, with an IC50 value of 0.08 µM. Molecular docking studies revealed that H-9 formed several hydrogen bonds and hydrophobic interactions with key active-site residues of cathepsin K. In vitro, H-9 demonstrated anti-bone resorption effects that were comparable to those of MIV-711, a cathepsin K inhibitor currently in phase 2a clinical trials for the treatment of bone metabolic disease. Western blot analysis confirmed that H-9 effectively downregulated cathepsin K expression in RANKL-reduced RAW264.7 cells. Moreover, in vivo experiments showed that H-9 increased the bone mineral density of OVX-induced osteoporosis mice. These results suggest that H-9 is a potent anti-bone resorption agent targeting cathepsin K and warrants further investigation for its potential anti-osteoporosis values.

Structural damage and organelle destruction: Mechanisms of pseudolaric acid B against S. parasitica.

This study aimed to investigate the potential of Chinese herbs in treating aquatic diseases. More particularly, the antibacterial properties and mechanisms of Chinese herbs and their monomers against Saprolegnia parasitica were investigated. In vitro antibacterial testing revealed that Cortex pseudolaricis exhibited significant antibacterial activity, with a minimum inhibitory concentration (MIC) of 0.98 mg/mL. The primary monomer responsible for this antibacterial effect was identified as pseudolaric acid B (PAB), with an MIC of 0.03 mg/mL. SEM and TEM analyses demonstrated that treatment with PAB resulted in structural damage to the cell wall and cell membrane of hyphae, leading to lysis of the cell wall and membrane of spores, organelle destruction, and vacuole formation within the cells. Analysis of the transcriptome and metabolome revealed that PAB disrupts amino acid, lipid, and nucleic acid metabolism in S. parasitica. This disruption impacts the biosynthesis and metabolism of various amino acids, including arginine, proline, glycine, serine, cysteine, methionine, glutamate, lysine, histidine, phenylalanine, tyrosine, and tryptophan. PAB also results in increased energy consumption and hindered energy generation in S. parasitica, as well as interference with the synthesis of membrane components such as DAG and phytosphingosine. Furthermore, PAB disrupts RNA, DNA, and ATP production in S. parasitica. Consequently, protein synthesis, energy supply, immune function and barrier structure in S. parasitica are weakened, and potentially leading to death. This study identifies potential antibacterial agents for environmentally friendly solutions for controlling fish saprolegniasis.

Lathyrane and ent-isopimarane diterpenoids from Euphorbia wallichii and target prediction of active ingredient.

Fourteen undescribed diterpenoids, including eleven lathyrane diterpenoids wallathyanes A-K (1-11) and three ent-isopimarane diterpenoids wallisopiranes A-C (12-14), together with fourteen known analogues 15-28, were obtained from the whole plant of Euphorbia wallichii. Their chemical structures were elucidated by spectroscopic data analysis, experimental electronic circular dichroism measurements, and X-ray crystallography. Bioactivity screening indicated that compound 2 exhibited an inhibitory effect on NO generation in LPS-stimulated RAW264.7 macrophage cells with an IC50 value of 4.76 ± 1.08 µM. The network pharmacology and molecular docking studies also revealed that compound 2 can bind with the potential targets GRB, AKT1, MAPK1, MAPK14, HSP90AA1, PIK3R1, PIK3CB, PRKACA, SRC, CASP3, RXRA, PTPNA11, ZAP70, and PRKC of inflammation.

Preparation of antioxidant peptides from yak skin gelatin and their protective effect on myocardial ischemia reperfusion injury.

We herein report a study on the antioxidant peptides that show potential in alleviating myocardial ischemia reperfusion injury (MI/RI). Yak skin gelatin fraction Ac (YSG-Ac), obtained through ultrafiltration and gel filtration with Sephadex G-15, exhibits a favorable nutrient composition, high foaming capacity and stability, and resistance against gastrointestinal digestion. LC-MS/MS analysis reveals that YSG-Ac contains 26 peptide segments with sequence lengths of 8 to 12 amino acids. Online screening suggests that the antioxidant capacity of YSG-Ac is mainly attributed to the presence of hydrophobic and antioxidant amino acids. In vitro, our results demonstrate the MI/RI protective effects of YSG-Ac by effectively repairing H2O2-induced oxidative damage in H9c2 cells, which is achieved by inhibiting malondialdehyde (MDA) levels, and increasing glutathione peroxidase (GSH-pX) and superoxide dismutase (SOD) activity. In vivo, our results further confirm the effectiveness of YSG-Ac in narrowing the area of myocardial infarction, decreasing MDA levels, increasing SOD activity, and reducing the content of lactate dehydrogenase (LDH) in a mouse MI/RI model. Molecular docking analysis indicates that PGADGQPGAK with xanthine dehydrogenase (XDH) and GAAGPTGPIGS with tumor necrosis factor-alpha (TNF-α) exhibit strong bonding capability, and other related targets also show certain binding ability toward YSG-Ac. This suggests that YSG-Ac can regulate MI/RI through multiple targets and pathways. Overall, our findings highlight the potential of YSG-Ac as a functional food ingredient with antioxidant and MI/RI protective characteristics.

A Single-Arm Phase II Clinical Trial of Fulvestrant Combined with Neoadjuvant Chemotherapy of ER+/HER2- Locally Advanced Breast Cancer: Integrated Analysis of 18F-FES PET-CT and Metabolites with Treatment Response.

Purpose: This Phase II trial was objected to evaluate the efficacy and safety of adding fulvestrant to NCT in patients with ER+/HER2- locally advanced breast cancer (LABC). Additionally, the study aimed to investigate the association of 18F-FES PET-CT and metabolites with efficacy. Materials and Methods: Fulvestrant and EC-T regimen were given to ER+/HER2- LABC patients before surgery. At baseline, patients received 18F-FES PET-CT scan, and plasma samples were taken for LC-MS analysis. The primary endpoint was ORR. Secondary endpoints included tpCR and safety. Results: Among the 36 patients enrolled, the ORR was 86.1%, the tpCR rate was 8.3%. The incidence of grade ≥3 TEAEs was 22%. The decrease in ER value in sensitive patients was larger than that in non-sensitive patients, as was Ki-67 (p<0.05). The SUVmax, SUVmean, TL-ER of 18F-FES PET-CT in sensitive patients were significantly higher than those in non-sensitive patients (p<0.05). Moreover, these parameters were significantly correlated with MP grade and the change in ER expression before and after treatment (p<0.05). Thirteen differential expressed metabolites were identified, which were markedly enriched in 19 metabolic pathways. Conclusion: This regimen demonstrated acceptable toxicity and encouraging antitumor efficacy. 18F-FES PET-CT might serve as a tool to predict the effectiveness of this therapy. Altered metabolites or metabolic pathways might be associated with treatment response.

Involvement of the Laboratory Department in MDT Discussion for the Diagnosis of Unexplained Leukocytosis.

BACKGROUND: This paper reports the diagnostic process of a case involving an 86-year-old male patient who was admitted with cough, sputum, and fever, accompanied by persistent leukocytosis. METHODS: Through a multidisciplinary team (MDT) discussion, the laboratory department identified elevated ferritin levels, prompting clinical consideration of potential malignancy. RESULTS: Further investigations confirmed the diagnosis of thyroid cancer with multiple lung metastases. CONCLUSIONS: This case highlights the potential value of ferritin in tumor diagnosis, offering new insights into the etiology of abnormal leukocyte elevation. Additionally, the active involvement of the laboratory department in MDT discussions proves to be crucial for diagnosing challenging cases.

A Comparative Study of the Stability, Transport, and Structure-Activity Relationship of Round Scad Derived Peptides with Antineuroinflammatory Ability.

Our previous study identified round scad neuroprotective peptides with different characteristics. However, the intrinsic relationship between their structure and bioactivity, as well as their bioavailability, remains unclear. The aim of this study is to elucidate the bioavailability of these peptides and their structure-activity relationship against neuroinflammation. Results showed that the SR and WCP peptides were resistant to gastrointestinal digestion. Additionally, peptides SR, WCP, and WCPF could transport Caco-2 monolayers as intact peptides. The permeability coefficients (Papp) of SR, WCP, and WCPF in Caco-2 monolayer were (1.53 ± 0.01) × 10-5, (2.12 ± 0.01) × 10-5, and (8.86 ± 0.03) × 10-7 cm/s, respectively. Peptides SR, WCP, and WCPF, as promising inhibitors of JAK2 and STAT3, could attenuate the levels of pro-inflammatory cytokines and regulate the NFκB and JAK2/STAT3 signaling pathway in LPS-treated BV-2 cells. WCPF exerted the highest anti-inflammatory activity. Moreover, bioinformatics, molecular docking, and quantum chemistry studies indicated that the bioactivity of SR was attributed to Arg, whereas those of WCP and WCPF were attributed to Trp. This study supports the application of round-scad peptides and deepens the understanding of the structure-activity relationship of neuroprotective peptides.

Associations of Pap test utilisation with comorbidity and functional impairment among middle-aged non-Hispanic black women in the USA: a cross-sectional analysis of the 2018 BRFSS data.

OBJECTIVES: Limited evidence exists on the association of Pap test utilisation with comorbidity and functional impairment among middle-aged non-Hispanic black (NHB) women in the USA. We aimed to assess whether middle-aged NHB women with a higher burden of comorbidity and functional impairment have a lower rate of Pap test utilisation. DESIGN: Nationwide cross-sectional survey in the USA. SETTING: 2018 Behavioral Risk Factor Surveillance System. PARTICIPANTS: 6359 middle-aged NHB women. EXPOSURES AND OUTCOME: The primary exposures were comorbidity and functional impairment. The outcome of interest was whether a woman reported having a Pap test in the last 3 years. DATA ANALYSIS: We fit unadjusted and multivariable logistic regression models to calculate ORs and 95% CI for comorbidity and functional impairment. Sensitivity analysis was restricted to women without a history of hysterectomy or cancer. We added interaction terms between exposures and age, as well as lifestyle indicators. RESULTS: Of the 6359 women, 4141 (65.1%) had comorbidity and 2429 (38.2%) had functional impairment. Middle-aged NHB women with comorbidity (≥2 vs 0, aOR=0.72, 95% CI=0.61 to 0.85, p trend<0.01) or functional impairment (≥2 vs 0, aOR=0.69, 95% CI=0.57 to 0.83, p trend<0.01) had a lower rate of Pap test utilisation compared with healthier counterparts, regardless of histories of hysterectomy and prior cancer. The analyses for age and lifestyle indicators subgroup difference indicated no statistically significant effect (p interaction>0.05). However, the magnitude of these associations was stronger among women with adverse lifestyle factors (eg, comorbidity ≥2 v.s. 0, aOR=0.53, 95% CI=0.40, to 0.71; functional impairment ≥2 v.s. 0, aOR=0.35, 95% CI=0.16, to 0.72 among binge drinkers). CONCLUSION: Comorbidity or functional impairment could be a potential barrier to Pap test utilisation among middle-aged NHB women in the USA. Our study highlights the importance of implementing targeted intervention programmes and prioritised health resource allocation to promote Pap test utilisation. Cohort studies with clear temporality and indicators reflecting disease severity will be essential for further understanding this association.

4EBP1-mediated SLC7A11 protein synthesis restrains ferroptosis triggered by MEK inhibitors in advanced ovarian cancer.

Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here, we show that ferroptosis negative regulation signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High-throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor-resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/eIF4E binding protein 1 (4EBP1) signaling promoted solute carrier family 7 member 11 (SLC7A11) protein synthesis, leading to ferroptosis inhibition in MEK inhibitor-resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR/4EBP1 axis to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.

Spectrum and characteristics of germline PALB2 pathogenic variants in 1556 early-onset breast cancer patients in China.

PURPOSE: Limited data are available regarding the partner and localizer of BRCA2 (PALB2) in Chinese patients with early breast cancer. This study aimed to assess the spectrum and characteristics of germline PALB2 pathogenic variants in this population. METHODS: Peripheral blood samples were collected from 1556 patients diagnosed with BRCA1/2-negative early-onset breast cancer. All coding regions and exon‒intron boundaries of the PALB2 genes were screened through next-generation sequencing. RESULTS: The prevalence of PALB2 pathogenic variants was approximately 0.77% in the cohort. Eleven PALB2 pathogenic variants were identified in twelve participants, including five frameshift mutations and six nonsense mutations. All other variants were detected once, except for PALB2 c.1056_1057del (detected twice). Two PALB2 carriers (2/12, 16.7%) have documented family history of breast cancer and/or ovarian cancer. Patients with a positive family history exhibited a threefold higher possibility of being identified as PALB2 carriers than those without a family history (2% vs. 0.69%), although the difference was not statistically significant (p = 0.178). Compared to non-carriers, PALB2 carriers has a tendency to appear in younger age (≤ 30 years) (25% vs 14.4%), human epidermal growth factor receptor-2 (HER2)-negative status (83.3% vs. 70.2%), and diagnosed with invasive micropapillary carcinoma (16.7% vs 3.1%). CONCLUSION: The prevalence of the germline PALB2 pathogenic variants was approximately 0.77% in Chinese patients with BRCA1/2-negative early-onset breast cancer. Our findings is crucial for understanding population-specific genetic risks and offering insights that can enhance genetic counseling and genetic testing strategies in this population.

CDK4/6 inhibition augments anti-tumor efficacy of XPO1 inhibitor selinexor in natural killer/T-cell lymphoma.

XPO1 is an attractive and promising therapeutic target frequently overexpressed in multiple hematological malignancies. The clinical use of XPO1 inhibitors in natural killer/T-cell lymphoma (NKTL) is not well documented. Here, we demonstrated that XPO1 overexpression is an indicator of poor prognosis in patients with NKTL. The compassionate use of the XPO1 inhibitor selinexor in combination with chemotherapy showed favorable clinical outcomes in three refractory/relapsed (R/R) NKTL patients. Selinexor induced complete tumor regression and prolonged survival in sensitive xenografts but not in resistant xenografts. Transcriptomic profiling analysis indicated that sensitivity to selinexor was correlated with deregulation of the cell cycle machinery, as selinexor significantly suppressed the expression of cell cycle-related genes. CDK4/6 inhibitors were identified as sensitizers that reversed selinexor resistance. Mechanistically, targeting CDK4/6 could enhance the anti-tumor efficacy of selinexor via the suppression of CDK4/6-pRb-E2F-c-Myc pathway in resistant cells, while selinexor alone could dramatically block this pathway in sensitive cells. Overall, our study provids a preclinical proof-of-concept for the use of selinexor alone or in combination with CDK4/6 inhibitors as a novel therapeutic strategy for patients with R/R NKTL.

A proximity ligation hybridization triggered structure-switching based signal amplification strategy for sensitive and accurate exosome detection.

Exosomes have significant functions in intercellular communication, as well as in tumor migration and invasion. Nevertheless, the precise identification of exosomes poses a significant obstacle due to their low abundance in biofluids and potential disruption caused by free protein molecules, such as CD63 protein. In this study, we have developed a signal amplification method for precise detection of exosomes using a proximity ligation hybridization triggered structure-switching approach. The method involves the dual-recognition of exosomes by two probes: an aptamer probe that recognizes the exosomal surface protein CD63 (L1 probe), and a cholesterol probe that targets the biolipid layer of the exosomes (L2 probe). Based on the dual-recognition of exosomes, we have successfully developed an accurate and sensitive approach that integrates the proximity ligation hybridization technique with a structure-switching based signal cycle. This approach allows for the simultaneous analysis of two biomarkers, enabling both quantification and tracing of exosomes without the need for enzymes. Eventually, the proposed method exhibits a wide detection range of 5 orders of magnitude and a low limit of detection of 36 particles per µL, making it suitable for a wide range of applications in the fields of biological science, biomedical engineering, and personalized medicine.

Triblock polyadenine-based electrochemical aptasensor for ultra-sensitive detection of carcinoembryonic antigen via exonuclease III-assisted target recycling and hybridization chain reaction.

Carcinoembryonic antigen (CEA), a key colon biomarker, demands a precise detection method for cancer diagnosis and prognosis. This study introduces a novel electrochemical aptasensor using a triblock polyadenine probe for ultra-sensitive detection of CEA. The method leverages Exonuclease III (Exo III)-assisted target recycling and hybridization chain reaction. The triblock polyadenine probe self-assembles on the bare gold electrode through the strong affinity between adenine and gold electrode, blocking CEA diffusion and providing a large immobilization surface. CEA binding to hairpin probe 1 (HP1), followed by the hybridization between HP1 and hairpin probe 2 (HP2), triggers DNA cleavage by Exo III, amplifying the signal via a hybridization chain reaction and producing numerous dsDNA walkers that generates a dramatic electrochemical impedance signal. Under optimized conditions, the aptasensor achieved two ultra-low detection limits: 0.39 ag∙mL-1 within the concentration range of 5 ag∙mL-1 to 5 × 106 ag∙mL-1, and 1.5 ag∙mL-1 within the concentration range of 5 × 106 ag∙mL-1 to 1 × 1010 ag∙mL-1. Its performance in human serum samples meets the practical standards, offering a promising new tool for ultrasensitive tumor marker detection, potentially revolutionizing early cancer diagnosis.

TFAP2A downregulation mediates tumor-suppressive effect of miR-8072 in triple-negative breast cancer via inhibiting SNAI1 transcription.

BACKGROUND: Triple-negative breast cancer (TNBC) represents a highly aggressive subset of breast malignancies characterized by its challenging clinical management and unfavorable prognosis. While TFAP2A, a member of the AP-2 transcription factor family, has been implicated in maintaining the basal phenotype of breast cancer, its precise regulatory role in TNBC remains undefined. METHODS: In vitro assessments of TNBC cell growth and migratory potential were conducted using MTS, colony formation, and EdU assays. Quantitative PCR was employed to analyze mRNA expression levels, while Western blot was utilized to evaluate protein expression and phosphorylation status of AKT and ERK. The post-transcriptional regulation of TFAP2A by miR-8072 and the transcriptional activation of SNAI1 by TFAP2A were investigated through luciferase reporter assays. A xenograft mouse model was employed to assess the in vivo growth capacity of TNBC cells. RESULTS: Selective silencing of TFAP2A significantly impeded the proliferation and migration of TNBC cells, with elevated TFAP2A expression observed in breast cancer tissues. Notably, TNBC patients exhibiting heightened TFAP2A levels experienced abbreviated overall survival. Mechanistically, TFAP2A was identified as a transcriptional activator of SNAI1, a crucial regulator of epithelial-mesenchymal transition (EMT) and cellular proliferation, thereby augmenting the oncogenic properties of TFAP2A in TNBC. Moreover, miR-8072 was unveiled as a negative regulator of TFAP2A, exerting potent inhibitory effects on TNBC cell growth and migration. Importantly, the tumor-suppressive actions mediated by the miR-8072/TFAP2A axis were intricately associated with the attenuation of AKT/ERK signaling cascades and the blockade of EMT processes. CONCLUSIONS: Our findings unravel the role and underlying molecular mechanism of TFAP2A in driving tumorigenesis of TNBC. Targeting the TFAP2A/SNAI1 pathway and utilizing miR-8072 as a suppressor represent promising therapeutic strategies for treating TNBC.

Signaling pathways in liver cancer: pathogenesis and targeted therapy.

Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.

Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression.

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.

Development and validation of LCMM prediction algorithms to estimate recovery pattern of postoperative AKI in type A aortic dissection: a retrospective study.

Background: Postoperative acute kidney injury (PO-AKI) is a prevalent complication among patients with acute type A aortic dissection (aTAAD) for which unrecognized trajectories of renal function recovery, and their heterogeneity, may underpin poor success in identifying effective therapies. Methods: This was a retrospective, single-center cohort study in a regional Great Vessel Center including patients undergoing aortic dissection surgery. Estimated glomerular filtration rate (eGFR) recovery trajectories of PO-AKI were defined through the unsupervised latent class mixture modeling (LCMM), with an assessment of patient and procedural characteristics, complications, and early-term survival. Internal validation was performed by resampling. Results: A total of 1,295 aTAAD patients underwent surgery and 645 (49.8%) developed PO-AKI. Among the PO-AKI cohort, the LCMM identified two distinct eGFR trajectories: early recovery (ER-AKI, 51.8% of patients) and late or no recovery (LNR-AKI, 48.2% of patients). Binary logistic regression identified five critical determinants regarding poor renal recovery, including chronic kidney disease (CKD) history, renal hypoperfusion, circulation arrest time, intraoperative urine, and myoglobin. LNR-AKI was associated with increased mortality, continuous renal replacement therapies, mechanical ventilation, ICU stay, and hospital stay. The assessment of the predictive model was good, with an area under the curve (AUC) of 0.73 (95% CI: 0.69-0.76), sensitivity of 61.74%, and specificity of 75.15%. The internal validation derived a consistent average AUC of 0.73. The nomogram was constructed for clinicians' convenience. Conclusion: Our study explored the PO-AKI recovery patterns among surgical aTAAD patients and identified critical determinants that help to predict individuals at risk of poor recovery of renal function.

miR­576­3p/M­phase phosphoprotein 8 axis regulates the malignant progression of hepatocellular carcinoma cells via the PI3K/Akt signaling pathway.

Hepatocellular carcinoma (HCC) is a fatal digestive system cancer with unclear pathogenesis. M-phase phosphoprotein 8 (MPP8) has been shown to play a vital role in several cancer types, such as non-small cell lung cancer, gastric cancer and melanoma; however, there have been no studies into its role in HCC. The present study aimed to evaluate the role of MPP8 in regulating malignant phenotypes of liver cancer cells, and to further investigate the underlying mechanism. Bioinformatics analysis was performed to analyze related data from a public database, and to predict the potential microRNAs (miRNAs) that might target MPP8 mRNA; reverse transcription-quantitative PCR was used to measure the levels of mRNA and miRNA; western blotting was employed to detect protein levels; Cell Counting Kit-8 (CCK-8) and plate colony formation assays, wound healing assay and Transwell invasion assay were performed to evaluate the ability of cell proliferation, migration and invasion, respectively; dual-luciferase reporter gene assay was performed to identify the target association. The results showed that MPP8 was a risk factor for the survival of patients with HCC, and was up-regulated in HCC tissue samples and cell lines; MPP8 knockdown inhibited the proliferation, migration and invasion of liver cancer cells; MPP8 knockdown suppressed the PI3K/Akt pathway, and activation of this pathway reversed the inhibited liver cancer cell phenotypes by down-regulating MPP8; miR-576-3p, which was low in liver cancer cells, negatively regulated MPP8 expression by directly targeting its mRNA; up-regulating MPP8 expression reversed the inhibited signaling pathway and malignant phenotypes of liver cancer cells by miR-576-3p overexpression. In conclusion, the miR-576-3p/MPP8 axis regulates the proliferation, migration, and invasion of liver cancer cells through the PI3K/Akt signaling pathway. These findings lead novel insights into HCC progression, and propose MPP8 as a potential therapeutic target for HCC.

Gene features of tumor-specific T cells relevant to immunotherapy, targeted therapy and chemotherapy in lung cancer.

1 Background: In lung cancer, the use of small-molecule inhibitors, chemotherapy and immunotherapy has led to unprecedented survival benefits in selected patients. Considering most patients will experience a relapse within a short period of time due to single drug resistance, combination therapy is also particularly important to improve patient prognosis. Therefore, more robust biomarkers to predict responses to immunotherapy, targeted therapy, chemotherapy and rationally drug combination therapies may be helpful in clinical treatment choices. 2 Methods: We defined tumor-specific T cells (TSTs) and their features (TSTGs) by single-cell RNA sequencing. We applied LASSO regression to filter out the most survival-relevant TSTGs to form the Tumor-specific T cell score (TSTS). Immunological characteristics, enriched pathways, and mutation were evaluated in high- and low TSTS groups. 3 Results: We identified six clusters of T cells as TSTs in lung cancer, and four most robust genes from 9 feature genes expressed only on tumor-specific T cells were screened to construct a tumor-specific T cells score (TSTS). TSTS was positively correlated with immune infiltration and angiogenesis and negatively correlated with malignant cell proliferation. Moreover, potential vascular-immune crosstalk in lung cancer provides the theoretical basis for combined anti-angiogenic and immunotherapy. Noticeable, patients in high TSTS had better response to ICB and targeted therapy and patients in the low TSTS group often benefit from chemotherapy. 4 Conclusion: The proposed TSTS is a promising indicator to predict immunotherapy, targeted therapy and chemotherapy responses in lung cancer patients for helping clinical treatment choices.