Zhencang Zheng

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor with a high fatality rate, making it imperative to explore novel therapeutic approaches. This study aimed to assess the effectiveness and underlying mechanism of nutrient restriction in potentiating Sorafenib-induced cell death. Cell viability was measured using MTT assays. Mitochondrial membrane potential (MMP) was assessed by the JC-1 probes. The levels of Reactive oxygen species (ROS) were determined using a DCFH-DA probe. Lipid peroxidation was quantified using the C11-BODIPY probe and a malondialdehyde (MDA) kit. Intercellular Fe²⁺ was assessed using the FerroOrange probe. Western blot, HE staining, and immunohistochemistry (IHC) techniques were utilized to analyze the impact of combination therapy on NRF2, HO-1, and GPX4 proteins. Nude mice xenograft models were established to evaluate the inhibitory effects of the combination therapy in vivo. Nutrient restriction/Intermittent fasting enhanced Sorafenib-induced cell death both in vivo and in vitro by elevating ROS and MDA levels, promoting excessive lipid peroxidation, and increasing intercellular Fe²⁺ accumulation. Notably, key ferroptosis-associated proteins, including NRF2, GPX4, and HO-1, were significantly down-regulated by combination treatment, while glutathione (GSH) supplementation reversed this downregulation. The combination of nutrient restriction and Sorafenib significantly enhanced anti-tumor efficacy both in vivo and in vitro. Mechanistically, nutrient restriction potentiated Sorafenib-induced ferroptosis via the NRF2/HO-1/GPX4 pathway in HCC cells.

Sepsis and coronavirus disease 2019 (COVID-19) are life-threatening clinical syndromes with high mortality rate. This study aimed to investigate pancreatic stone protein (PSP) role as potential biomarker for sepsis/COVID-19 prognostication. Herein, based on the novel amplified luminescent proximity homogeneous assay (AlphaLISA), the PSP plasma concentrations were determined, and the PSP diagnostic and prognostic values were characterized in a total of 285 patients with inflammatory disorders and 15 healthy volunteers. We found that plasma PSP protein was significantly overexpressed in patients with sepsis covid-positive (Sepsis^+ve, n = 105) compared to non-sepsis covid-negative (Non-Sepsis^-ve, n = 60), non-sepsis covid-positive (Non-Sepsis^+ve, n = 75), sepsis covid-negative (Sepsis^-ve, n = 45), and normal controls (NC, n = 15). PSP showed good prediction ability of Sepsis^+ve short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8368 and 0.8070 at 28 and 90 days, respectively. Significant correlations were seen between plasma PSP and SOFA score, urea, immune mediators and inflammatory cytokines. Risk stratification analysis indicated higher mortality risk for Sepsis^+ve with plasma PSP level exceeding the optimal cut-off value (≥ 119 ng/mL). PSP might be sepsis/COVID-19 disease biomarker, and could provide clinicians with a potential target for improving diagnostic and therapeutic strategies.

Fructose-1, 6-bisphosphatase (FBP1) is a tumor suppressor and frequently deficient in various cancers, including clear cell renal cell carcinoma (ccRCC). VHL inactivation mutations are usually observed in ccRCC, which can lead to abnormal activation of the HIF signaling pathway. FBP1 could enter the nucleus and restrain HIF function in a non-enzymatic manner. However, its regulatory mechanism in ccRCC tumorigenesis remains poorly understood. Here, we report that nuclear FBP1 is degraded through the ubiquitin-proteasome pathway, and CUL4B acts as Cullin-RING E3 ubiquitin ligase (CRL) to promote the degradation of FBP1 in nucleus, while the neddylation inhibitor MLN4924 could inactivate CUL4B E3 ligase, block proteasomal degradation of FBP1 and suppress HIF target gene expression, including GLUT1, LDHA, PDK1 and VEGF, leading to decreased glucose uptake and lactate and NADPH production, thereby repressing tumor growth of ccRCC. Furthermore, MLN4924 sensitizes ccRCC to γ-glutamylcysteine synthetase inhibitor Buthionine sulfoximine (BSO) treatment in vivo. Collectively, these findings proposed that MLN4924 could inhibit the tumor growth of VHL deficiency-driven ccRCC by stabilizing FBP1, providing new target and strategy for clinic treatment of ccRCC.

MiRNA-208a is a molecular marker for the early stage of acute myocardial infarction (AMI), with satisfactory specificity and a relatively short time window, making it highly suitable for the early diagnosis of AMI. In this study, a CuNCs-cDNA-MoS₂ fluorescent probe is designed and a Förster resonance energy transfer (FRET) enzyme-free fluorescent biosensor is established for “on-off-on” detection of miRNA-208a. The results showed that the detection limit for miRNA-208a was 900 pM, with a linear range of 1 to 10 nM. Interestingly, after the addition of RNase inhibitor, the detection time and limit for serum miRNA-208a were reduced to 5 min and 380 pM, respectively. It also has a wide linear range (1-20 nM), with a recovery of 98.13 to 101.20%. Compared to traditional methods, this strategy is simple, rapid, efficient, and cost-effective. In summary, the FRET-based fluorescent sensor provides a high-performance method for detecting miRNA-208a. Graphical Abstract

Survival and prognosis of patients with acute myocardial infarction (AMI) are highly dependent on rapid and accurate diagnosis of myocardial damage. Troponin T is the primary diagnostic biomarker and is widely used in clinical practice. Amplified luminescent proximity homogeneous assay (AlphaLISA) may provide a solution to rapidly detect a small amount of analyte through molecular interactions between special luminescent donor beads and acceptor bead. Here, a double-antibody sandwich assay was introduced into AlphaLISA for rapid detection for early diagnosis of AMI and disease staging evaluation. The performance of the assay was evaluated. The study found that the cTnT assay has a linear range of 48.66 to 20,000 ng/L with a limit of detection of 48.66 ng/L. In addition, the assay showed no cross-reactivity with other classic biomarkers of myocardial infarction and was highly reproducible with intra- and inter-batch coefficients of variation of less than 10%, notably, only 3 min was taken, which is particularly suitable for clinical diagnosis. These results suggest that our method can be conveniently applied in the clinic to determine the severity of the patient’s condition.

Objectives: Lung adenocarcinoma (LUAD) is a prevalent form of non-small cell lung cancer with high morbidity and mortality rates. Identifying molecular markers and therapeutic targets is crucial for improving LUAD diagnosis and treatment. Pituitary tumor-transforming gene (PTTG) family members, PTTG1, PTTG2, and PTTG3P, have been linked to several malignancies; however, it is unclear how these genes relate to LUAD. The current retrospective study investigates the diagnostic, prognostic, and therapeutic importance of PTTG genes in LUAD. Methods: We used detailed in silico and in vitro experiments involving cell lines for experimental design. Results: Using RT-qPCR, we documented that PTTG1, PTTG2, and PTTG3P are significantly up-regulated in LUAD cell lines compared to controls, with PTTG2 showing the highest diagnostic potential (AUC = 1.0). Promoter methylation analysis revealed hypomethylation in LUAD samples, particularly for PTTG3P, further supporting its diagnostic relevance. Immunohistochemical staining confirmed overexpression of PTTG1 and PTTG2 proteins in LUAD tissue samples. The mutational analysis highlighted PTTG2 as the most frequently mutated gene within the PTTG family in LUAD samples, with mutations primarily being missense types. Survival analysis demonstrated that high expression of PTTG genes is associated with poorer overall survival, indicating their prognostic value. Gene enrichment analysis suggested that PTTG genes are involved in critical cancer-related pathways and cellular processes. Functional assays following siRNA-mediated knockdown of PTTG genes in A549 cells showed a significant reduction in cell proliferation. Lastly, drug sensitivity analysis revealed strong correlations between PTTG1/PTTG3P expression and resistance to various anticancer drugs. Conclusion: The findings of the current study highlight the potential of PTTG genes as diagnostic biomarkers, prognostic indicators, and therapeutic targets in LUAD.

Background. The incidence of polymicrobial bloodstream infections is increasing, the clinical characteristics of polymicrobial Acinetobacter baumannii bloodstream infections (AB-BSI) are unclear, and there are no reports of polymicrobial AB-BSI in mainland China. Therefore, our objective was to identify the clinical characteristics, risk factors, and outcomes of polymicrobial AB-BSI versus monomicrobial AB-BSI. Methods. A retrospective survey of all patients with AB-BSI from January 1, 2015, to December 31, 2019, and their clinical data were collected and analyzed by reviewing electronic medical records. All data were compared and analyzed between groups of monomicrobial and polymicrobial AB-BSI. Risk factors for polymicrobial AB-BSI were assessed using multivariable logistic regression analysis. Results. A total of 204 patients were included, of which 39 (19.1%) were patients with polymicrobial AB-BSI. The main sources of the pathogenicity of polymicrobial Acinetobacter baumannii bloodstream infections were skin and soft tissue (38.5% vs. 16.4%, ). Resistance to piperacillin/tazobactam as an independent factor for polymicrobial AB-BSI was found in multivariate analysis. Patients with polymicrobial AB-BSI had longer hospital stays compared to those with monomicrobial AB-BSI. However, there was no significant difference in mortality between the two groups. Conclusions. Polymicrobial AB-BSI accounted for a significant proportion among all AB-BSI, and it did not influence mortality but was related to slightly longer total hospital stays. Multidrug resistance was associated with the development of polymicrobial AB-BSI but does not directly lead to polymicrobial AB-BSI, whereas resistance to piperacillin/tazobactam was highly correlated with polymicrobial AB-BSI. Therefore, while treating A. baumannii bloodstream infections, clinicians cannot ignore the multidrug-resistant A. baumannii, especially piperacillin/tazobactam-resistant A. baumannii, which may predispose to the development of polymicrobial AB-BSI.