Corticothalamic input derived from corticospinal neurons contributes to chronic neuropathic pain after spinal cord injury.

Neuropathic pain is a significant and persistent issue for individuals with spinal cord injuries (SCI), severely impacting their quality of life. While changes at the peripheral and spinal levels are known to contribute to SCI-related pain, whether and how supraspinal centers contribute to post SCI chronic neuropathic pain is poorly understood. Here, we first validated delayed development of chronic neuropathic pain in mice with moderate contusion SCI. To identify supraspinal regions involved in the pathology of neuropathic pain after SCI, we next performed an activity dependent genetic screening and identified multiple cortical and subcortical regions that were activated by innocuous tactile stimuli at a late stage following contusion SCI. Notably, chemogenetic inactivation of pain trapped neurons in the lateral thalamus alleviated neuropathic pain and reduced tactile stimuli evoked cortical overactivation. Retrograde tracing showed that contusion SCI led to enhanced corticothalamic axonal sprouting and over-activation of corticospinal neurons. Mechanistically, ablation or silencing of corticospinal neurons prevented the establishment or maintenance of chronic neuropathic pain following contusion SCI. These results highlighted a corticospinal-lateral thalamic feed-forward loop whose activation is required for the development and maintenance of chronic neuropathic pain after SCI. Our data thus shed lights into the central mechanisms underlying chronic neuropathic pain associated with SCI and the development of novel therapeutic avenues to treat refractory pain caused by traumatic brain or spinal cord injuries.

Regulation of neuronal plasticity associated with neuropsychiatric disorders by the orexinergic system.

Orexins are a family of neuropeptides secreted by neurons in the lateral hypothalamus (LH). These peptides act widespreadly across the body by interacting with specific orexin receptors on target cells, which comprise the orexinergic system. Emerging evidence has revealed that the orexinergic system is tightly associated with neuropsychiatric disorders; however, the underlying mechanisms require further exploration. Neuropsychiatric disorders have also been associated with neuroplasticity, while orexins have been shown to play regulatory roles in neuronal plasticity. As such, this review aims to summarize the recent progress of research investigating the roles of the orexinergic system in neuronal plasticity and associated neuropsychiatric disorders, including addiction, depression, and schizophrenia, which may provide novel insights into the mechanism of the orexinergic system in the pathogenesis of these neuropsychiatric disorders.

The role of m6A methylation in targeted therapy resistance in lung cancer.

Targeted therapies have greatly improved clinical outcomes for patients with lung cancer (LC), but acquired drug resistance and disease relapse inevitably occur. Increasingly, the role of epigenetic mechanisms in driving acquired drug resistance is appreciated. In particular, N6-methyladenosine (m6A), one of the most prevalent RNA modifications, has several roles regulating RNA stability, splicing, transcription, translation, and destruction. Numerous studies have demonstrated that m6A RNA methylation can modulate the growth and invasion of cancer cells as well as contribute to targeted therapy resistance in LC. In this study, we outline what is known regarding the function of m6A in the acquisition of targeted therapy resistance in LC.

Gut microbiota-derived fatty acid and sterol metabolites: biotransformation and immunomodulatory functions.

Commensal microorganisms in the human gut produce numerous metabolites by using small molecules derived from the host or diet as precursors. Host or dietary lipid molecules are involved in energy metabolism and maintaining the structural integrity of cell membranes. Notably, gut microbes can convert these lipids into bioactive signaling molecules through their biotransformation and synthesis pathways. These microbiota-derived lipid metabolites can affect host physiology by influencing the body's immune and metabolic processes. This review aims to summarize recent advances in the microbial transformation and host immunomodulatory functions of these lipid metabolites, with a special focus on fatty acids and steroids produced by our gut microbiota.

3,4,5-tri-O-caffeoylquinic acid attenuates influenza A virus induced inflammation through Toll-like receptor 3/7 activated signaling pathway.

BACKGROUND: 3,4,5-tri-O-caffeoylquinic acid (3,4,5-TCQA), a natural polyphenolic acid, has been shown to be effective against influenza A virus (IAV) infection. Although it was found to inhibit the neuraminidase of IAV, it may also perturb other cellular functions, as polyphenolic acids have shown antioxidant, anti-inflammatory and other activities. PURPOSE: This study aimed to investigate the effect of 3,4,5-TCQA at a cell level, which is critical for protecting host cell from IAV infection. STUDY DESIGN AND METHODS: We explored the effect of 3,4,5-TCQA on H292 cells infected or un-infected with Pr8 IAV. The major genes and related pathway were identified through RNA sequencing. The pathway was confirmed by qRT-PCR and western blot analysis. The anti-inflammatory activity was evaluated using nitric oxide measurement assay. RESULTS: We showed that 3,4,5-TCQA downregulated the immune response in H292 cells, and reduced the cytokine production in Pr8-infected cells, through Toll-like receptor (TLR) signaling pathway. In addition, 3,4,5-TCQA showed anti-inflammatory activity in LPS-activated RAW264.7 cells. CONCLUSION: Collectively, our results indicated that 3,4,5-TCQA suppressed inflammation caused by IAV infection through TLR3/7 signaling pathway. This provides a new insight into the antiviral mechanism of 3,4,5-TCQA.

Association between high uric acid and the risk of Parkinson's disease: A meta-analysis.

BACKGROUND: Uric acid, as an important antioxidant substance in human body, has attracted much attention in relation to the risk of Parkinson's disease (PD). However, the causal relationship between them is still controversial. We perform a meta-analysis to summarize the available evidence from cohort studies on the association between high uric acid and the risk of PD. METHODS: We searched the Cochrane Library, PubMed, Medline, and Embase to obtain the Odds Ratio (OR) of high uric acid and PD and pooled the data using RevMan software (v5.4; Cochrane library). RESULTS: A total of 18 studies involving more than 840,774 participants were included. Overall, we found a significant association (OR = 0.84; 95% CI: 0.77-0.91) between high uric acid and PD. Subgroup analysis was stratified by gender, indicating more statistically significant protective effects of serum urate in men (OR = 0.66; 95% CI: 0.54-0.81) than that of in women (OR = 0.86; 95% CI: 0.76-0.98). People under the age of 60 (OR = 0.53, 95% CI: 0.33-0.86) are more likely to benefit from high uric acid than people over age of 60 (OR = 0.73, 95% CI: 0.63-0.86). The resistance of high uric acid to PD in LRRK2 mutation carriers (OR = 0.22, 95% CI: 0.11-0.45) is stronger than that in non-manifesting LRRK2 mutation carriers (OR = 0.37, 95% CI: 0.16-0.85). In addition, a dose-response trend of serum urate to reduce PD risk was also observed (OR = 0.68; 95% CI: 0.48-0.93). CONCLUSION: Our study confirms a significant association between high uric acid and the risk of PD, especially in men under 60 years old, and a dose-response trend of uric acid to reduce PD risk was also observed. Furthermore, LRRK2 mutation carriers are more likely to benefit from high uric acid than non-manifesting LRRK2 mutation carriers.

Novel mRNA adjuvant ImmunER enhances prostate cancer tumor-associated antigen mRNA therapy via augmenting T cell activity.

Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8+T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.

PD-1 inhibitor combined with paclitaxel and cisplatin in the treatment of recurrent and metastatic hypopharyngeal/laryngeal squamous cell carcinoma: efficacy and survival outcomes.

Objective: This retrospective study analyzed the efficacy of PD-1 inhibitors combined with albumin-bound paclitaxel and cisplatin (TP regimen) in the treatment of recurrent and metastatic hypopharyngeal/laryngeal squamous cell carcinoma (RMHSCC/RMLSCC). Methods: Patients diagnosed and treated at the Sun Yat-sen University Cancer Center from August 1, 2020, to August 15, 2023, with histologically confirmed RMHSCC/RMLSCC were included. All patients received PD-1 inhibitors combined with albumin-bound paclitaxel (260mg/m2) and cisplatin (60mg/m2) for 3-4 cycles. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Results: A total of 50 patients with RMHSCC/RMLSCC who received TP+PD-1 inhibitor therapy were included, with an objective response rate (ORR) of 56.0% (28/50). The 1-year and 2-year OS rates were 80.2% (95% CI: 69.3%-92.9%) and 68.6% (95% CI: 52.6%-89.5%), respectively, while the 1-year and 2-year PFS rates were 44.7% (95% CI: 31.9%-62.5%) and 26.0% (95% CI: 12.6%-53.4%), respectively. Treatment-related adverse events mainly included rash, myelosuppression, gastrointestinal reactions, and hypothyroidism. Conclusion: In the treatment of RMHSCC/RMLSCC with TP + PD-1 inhibitors, survival rates of patients can be improved while ensuring the safety of the treatment regimen.

Comprehensive evaluation of drought tolerance of six Chinese chestnut varieties (clones) based on flavonoids and other physiological indexes.

Flavonoids are crucial secondary metabolites that possess the ability to mitigate UV damage and withstand both biotic and abiotic stresses. Therefore, it is of immense significance to investigate the flavonoid content as a pivotal indicator for a comprehensive assessment of chestnut's drought tolerance. This study aimed to determine the flavonoid content and drought tolerance-related physiological and biochemical indices of six chestnut varieties (clones) grafted trees-Qianxi 42 (QX42), Qinglong 45 (QL45), Yanshanzaofeng (YSZF), Yanzi (YZ), Yanqiu (YQ), and Yanlong (YL)-under natural drought stress. The results were used to comprehensively analyze the drought tolerance ability of these varieties. The study revealed that the ranking of drought tolerance indices in terms of their ability to reflect drought tolerance was as follows: superoxide (oxide) dismutase (SOD) activity, ascorbate peroxidase (APX) activity, flavone content, catalase (CAT) activity, proline (PRO) content, soluble sugar content, peroxidase (POD) activity, betaine content, flavonol content, hydrogen peroxide (H2O2) content, soluble protein content, superoxide ion (OFR) content, superoxide (ion OFR) production rate, malondialdehyde (MDA) content, chlorophyll content. Through principal component analysis, the contents of flavonoids and flavonols can be used as indicators for comprehensive evaluation of drought tolerance of chestnut. The comprehensive evaluation order of drought tolerance of grafted trees of 6 chestnut varieties (Clones) was: QL45 > QX42 > YQ > YZ > YSZF > YL.

Discovery and biological evaluation of biaryl acetamide derivatives as selective and in vivo active sphingosine kinase-2 inhibitors.

Sphingosine kinase 2 (SphK2) has emerged as a promising target for cancer therapy due to its critical role in tumor growth. However, the lack of potent and selective inhibitors has hindered its clinical application. Herein, we report the design and synthesis of a series of novel SphK2 inhibitors, culminating in the identification of compound 12q as a highly selective and potent inhibitor of SphK2. Molecular dynamics simulations suggest that the incorporation of larger substitution groups facilitates a more effective occupation of the binding site, thereby stabilizing the complex. Compared to the widely used inhibitor ABC294640, compound 12q exhibits superior anti-proliferative activity against various cancer cells, inducing G2 phase arrest and apoptosis in liver cancer cells HepG2. Notably, 12q inhibited migration and colony formation in HepG2 and altered intracellular sphingolipid content. Moreover, intraperitoneal administration of 12q in mice resulted in decreased levels of S1P. 12q provides a valuable tool compound for exploring the therapeutic potential of targeting SphK2 in cancer.

ONC206 targeting ClpP induces mitochondrial dysfunction and protective autophagy in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for approximately 90 % of all cases. ONC201, a member of the imipridone drug family, has shown promising therapeutic potential and a good safety profile in both malignant pediatric central nervous system tumors (diffuse midline glioma [DMG]) and hematologic malignancies. ONC206 is a more potent analog of ONC201. However, the ONC206 potential and mechanism of action in HCC remain to be elucidated. We found that ONC206 hindered HCC growth by suppressing cell proliferation and inducing apoptosis. Moreover, ONC206 induced cytoprotective autophagy, and blocking autophagy enhanced the proapoptotic effect of ONC206. Additionally, ONC206 induced mitochondrial swelling, reduced the mitochondrial membrane potential (MMP), and led to the accumulation of mitochondrial ROS in HCC cells, ultimately resulting in mitochondrial dysfunction. The HCC patient samples exhibited notably elevated levels of caseinolytic protease proteolytic subunit (ClpP), which serves as a mediator of ONC206-induced mitochondrial dysfunction and the activation of protective autophagy. knockdown of ClpP reversed the cytotoxic effects of ONC206 on HCC cells. In summary, our results provide the first insight into the mechanism by which ONC206 exerts its anti-HCC effects and induces protective autophagy in HCC cells through ClpP.

Combining the Elicitor Up-Regulated Production of Unusual Linear Diterpene-Derived Variants for an In-Depth Assessment of the Application Value and Risk of the Medicinal and Edible Basidiomycete Schizophyllum commune.

To better assess the practical value and avoid potential risks of the traditionally medicinal and edible basidiomycete Schizophyllum commune, which may arise from undescribed metabolites, a combination of elicitors was introduced for the first time to discover products from cryptic and low-expressed gene clusters under laboratory cultivation. Treating S. commune NJFU21 with the combination of five elicitors led to the upregulated production of a class of unusual linear diterpene-derived variants, including eleven new ones (1-11), along with three known ones (12-14). The structures and stereochemistry were determined by 1D and 2D NMR, HRESIMS, ECD, OR and VCD calculations. Notably, the elongation terminus of all the diterpenes was decorated by an unusual butenedioic acid moiety. Compound 1 was a rare monocyclic diterpene, while 2-6 possessed a tetrahydrofuran moiety. The truncated metabolites 4, 5 and 13 belong to the trinorditerpenes. All the diterpenes displayed approximately 70% scavenging of hydroxyl radicals at 50 µM and null cytotoxic activity at 10 µM. In addition, compound 1 exhibited potent antifungal activity against the plant pathogenic fungi Colletotrichum camelliae, with MIC values of 8 µg/mL. Our findings indicated that this class of diterpenes could provide valuable protectants for cosmetic ingredients and the lead compounds for agricultural fungicide development.

Lower HBV DNA level is associated with more severe liver fibrosis in HBeAg-positive chronic hepatitis B with normal alanine transaminase.

BACKGROUND: The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored the association between liver fibrosis and HBV DNA levels in HBeAg-positive CHB patients with normal alanine transaminase (ALT) with relatively high HBV DNA. METHODS: Six hundred and twenty-two HBeAg-positive CHB patients with normal ALT were included. Patients were divided into three categories: low (6 log10 IU/mL ≤ HBV DNA < 7 log10 IU/mL), moderate (7 log10 IU/mL ≤ HBV DNA < 8 log10 IU/mL), and high (HBV DNA ≥ 8 log10 IU/mL). APRI, FIB-4, transient elastography, or liver biopsy were used to assess liver fibrosis. RESULTS: The median age of patients was 33.0 years and 57.9% patients were male. 18.8%, 52.1%, and 29.1% of patients had low, moderate, and high HBV DNA levels, respectively. The APRI (0.33 vs. 0.26 vs. 0.26, P < 0.001), FIB-4 (1.03 vs. 0.71 vs. 0.68, P < 0.001), and LSM values (7.6 kPa vs. 5.6 kPa vs. 5.5 kPa, P = 0.086) were higher in low HBV DNA group than other two groups. Low HBV DNA group had higher proportions of significant fibrosis (24.8% vs. 9.9% vs. 3.3%, P < 0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P = 0.004) than moderate and high HBV DNA groups. Moderate (OR 3.095, P = 0.023) and low (OR 4.968, P = 0.003) HBV DNA were independent risk factors of significant fibrosis. CONCLUSION: Lower HBV DNA level was associated with more severe liver fibrosis in HBeAg-positive CHB patients with ALT.

Orexin B protects dopaminergic neurons from 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity associated with reduced extracellular signal-regulated kinase phosphorylation.

BACKGROUND: The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been reported to promote the growth of DA neurons. However, the roles of OXB in the degeneration of DA neurons still remained not fully clear. METHODS: An in vivo PD model was constructed by administrating 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Pole test was performed to investigate the motor function of mice and the number of DA neurons was detected by immunofluorescence (IF). A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+). OXB was added to the culture medium 2 h after MPP + treatment. Microscopic analysis was carried out to investigate the function of OXB in the cell model of PD 24 h after MPP + challenge. RNA-Seq analysis of the PD cell model was performed to explore the possible mechanisms. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase (ERK). RESULTS: OXB significantly decreased the DA neurons death caused by MPTP, alleviated MPP+-induced neurotoxicity in SH-SY5Y cells, and robustly enhanced the weight and motor ability of PD mice. Besides, RNA-Seq analysis demonstrated that the mitogen-activated protein kinase (MAPK) pathway was involved in the pathology of PD. Furthermore, MPP + led to increased levels of phosphorylation of ERK (p-ERK), OXB treatment significantly decreased the levels of p-ERK in MPP+-treated SH-SY5Y cells. CONCLUSIONS: This study demonstrated that OXB exerts a neuroprotective role associated with reduced ERK phosphorylation in the PD model. This suggests that OXB may have therapeutic potential for treatment of PD.

Interpretable multiphasic CT-based radiomic analysis for preoperatively differentiating benign and malignant solid renal tumors: a multicenter study.

BACKGROUND: To develop and compare machine learning models based on triphasic contrast-enhanced CT (CECT) for distinguishing between benign and malignant renal tumors. MATERIALS AND METHODS: In total, 427 patients were enrolled from two medical centers: Center 1 (serving as the training set) and Center 2 (serving as the external validation set). First, 1781 radiomic features were individually extracted from corticomedullary phase (CP), nephrographic phase (NP), and excretory phase (EP) CECT images, after which 10 features were selected by the minimum redundancy maximum relevance method. Second, random forest (RF) models were constructed from single-phase features (CP, NP, and EP) as well as from the combination of features from all three phases (TP). Third, the RF models were assessed in the training and external validation sets. Finally, the internal prediction mechanisms of the models were explained by the SHapley Additive exPlanations (SHAP) approach. RESULTS: A total of 266 patients with renal tumors from Center 1 and 161 patients from Center 2 were included. In the training set, the AUCs of the RF models constructed from the CP, NP, EP, and TP features were 0.886, 0.912, 0.930, and 0.944, respectively. In the external validation set, the models achieved AUCs of 0.860, 0.821, 0.921, and 0.908, respectively. The "original_shape_Flatness" feature played the most important role in the prediction outcome for the RF model based on EP features according to the SHAP method. CONCLUSIONS: The four RF models efficiently differentiated benign from malignant solid renal tumors, with the EP feature-based RF model displaying the best performance.

Combined image-guided radiofrequency and iodine-125 seeds implantation in the treatment of recurrent hepatocellular carcinoma after hepatectomy.

BACKGROUND: Currently, there is no consensus on the treatment of recurrent hepatocellular carcinoma (HCC) after hepatectomy. It is necessary to assess the efficacy and safety of radiofrequency ablation (RFA) combined with iodine-125 seeds implantation (RFA-125I) in the treatment of recurrent HCC. METHODS: This study retrospectively analyzed the clinical data of patients with postoperative recurrence of HCC receiving RFA-125I or RFA treatment from January 2013 to January 2023. Both RFA and 125I seeds implantation were performed under dual guidance of ultrasound and CT. Overall survival (OS), progression-free survival (PFS), recurrence, and complications were compared between the two groups. RESULTS: A total of 210 patients with recurrent HCC were enrolled in this study, including 125 patients in the RFA-125I group and 85 patients in the RFA group. The RFA-125I group showed a significantly better survival benefit than RFA group (median OS: 37 months vs. 16 months, P < 0.001; median PFS: 15 months vs. 10 months, P = 0.001). The uni- and multivariate analysis showed that RFA-125I was a protective factor for OS and PFS. There were no procedure-related deaths and no grade 3 or higher adverse events in both groups. CONCLUSIONS: RFA combined with 125I seeds implantation under dual guidance of ultrasound and CT is effective and safe for the treatment of HCC patients with recurrence after hepatectomy.

Low-Dose Naltrexone for Excoriation Disorder.

Excoriation (skin-picking) disorder (ED) is a condition characterized by the repeated compulsion to pick at the skin, causing physical trauma and psychiatric distress. Patients often desire to cease skin-picking behavior but are unable to do so. Multiple treatment modalities are effective for ED, including naltrexone. Previous reports of naltrexone for ED were at a high dose of 50 mg. The efficacy of low-dose naltrexone (LDN) at 4.5 mg in managing ED has not been reported. We present a case of a 51-year-old female with ED who was evaluated in the pain clinic for fibromyalgia management. Her medications included gabapentin 600 mg PO TID and a history of opioid prescription for diffuse pain. She was started on naltrexone 4.5 mg PO QD for the management of fibromyalgia. Three months later, the patient reported improvement in her skin-picking disorder, with a lessened compulsion to itch at her skin and improved healing of existing lesions. When the naltrexone was temporarily interrupted for an elective procedure, her lesions worsened. Her lesions improved after she resumed the medication. Thereby, this patient experienced a therapeutic benefit from naltrexone for her skin-picking disorder, as demonstrated by the temporal changes in her symptoms. To our knowledge, this is the first reported case of ED improving with LDN, as other cases utilized 50 mg. Though few clinical trials or systematic reviews recommend the use of naltrexone for EDs, our case supports trialing LDN in the appropriate context.

Nomograms for predicting prognostic value of combined neutrophil-to-lymphocyte ratio and SCC-Ag in locally advanced cervical cancer.

Background: Accumulating evidence supports the important role of inflammation in tumorigenesis and progression. Squamous cell carcinoma-associated antigen (SCC-Ag) is a tumor marker widely used to predict the prognosis of patients with cervical squamous cell carcinoma. This paper explored the predictive value of combined detection of neutrophil-to-lymphocyte ratio (NLR) to SCC-Ag for prognosis in patients with locally advanced cervical cancer (LACC). Methods: A retrospective analysis was conducted on 190 LACC patients who underwent concurrent chemoradiotherapy (CCRT) from January 2012 to December 2016. NLR and SCC-Ag were analyzed before treatment. Receiver operating characteristic (ROC) curve analysis was employed to determine the optimal cutoff point for NLR and SCC-Ag. Kaplan-Meier analysis and Cox regression analysis were performed to assess their prognostic values. Nomograms were established to predict progression-free survival (PFS) and overall survival (OS), and the Harrell's concordance index (C-index) was introduced to evaluate the accuracy of predictions. Results: The optimal cutoff values for SCC-Ag and NLR were 3.25 ng/mL and 2.52, respectively. Patients with SCC-Ag >3.25 ng/mL and NLR >2.52 were significantly associated with decreased PFS and OS. Multivariate analysis indicated that SCC-Ag and NLR were independent prognostic factors for PFS (P=0.022 and P=0.004, respectively) and OS (P=0.031 and P=0.001, respectively). The area under the curve of SCC-Ag, NLR and their combination to predict PFS and OS of LACC were 0.688, 0.623, 0.708 and 0.684, 0.658, 0.723, respectively. C-index of nomograms based on PFS and OS were 0.725 [95% confidence interval (CI): 0.653-0.797] and 0.731 (95% CI: 0.658-0.804), respectively. Conclusions: The combination of SCC-Ag and NLR could provide a better predictive prognosis than SCC-Ag or NLR alone, and nomograms based on PFS and OS can be recommended as practical models for evaluating the prognosis of LACC patients.

MiR-339-5p Inhibits Ferroptosis by Promoting Autophagic Degradation of FTH1 Through Targeting ATG7 in Liver Cancer Cells.

Background: Liver cancer has a high incidence and mortality rate worldwide, and there is an urgent need to identify new therapeutic strategies and predictive targets to improve the clinical outcomes of advanced liver cancer. Ferroptosis holds promise as a novel strategy for cancer therapy. Epigenetic dysregulation is a hallmark of cancer, and noncoding RNAs are tightly involved in cell fate determination. Therefore, we aimed to identify a novel ferroptosis regulator from aberrantly expressed microRNAs that may serve as a novel biomarker and therapeutic target for liver cancer. Methods: The expression signature and prognostic value of miR-339 was assessed using TCGA data set. The role of miR-339/ATG7/FTH1 axis in liver cancer cells were evaluated through growth curve, colony formation, 7-AAD staining. The role of miR-339 in regulation of ferroptosis was determined by immunofluorescence staining, flow cytometry, and Elisa kits. Results: Here, we showed that miR-339 is aberrantly overexpressed in patients with liver cancer. In addition, miR-339 inhibition dramatically suppresses liver cancer progression. Furthermore, miR-339 silencing drives cell death and inhibits liver cancer progression, indicating that miR-339 may serve as a novel ferroptosis suppressor. Mechanistically, we demonstrated that miR-339 targets ATG7 to facilitate the autophagic degradation of FTH1 and prevent ferroptosis in liver cancer cells. Conclusions: We provide important evidence that the miR-339 inhibition activates of the autophagy pathway to promote ferroptosis by degrading FTH1 in liver cancer cells. We found that miR-339 regulates the balance between ferroptosis and autophagy in liver cancer cells.

Clinical outcomes of treatment-naïve HBeAg-negative patients with chronic hepatitis B virus infection with low serum HBsAg and undetectable HBV DNA.

Serum hepatitis B surface antigen (HBsAg) level < 100 IU/ml and undetectable hepatitis B virus (HBV) DNA have been recently proposed as an alternate endpoint of "partial cure" in chronic hepatitis B (CHB). We investigated clinical outcomes of hepatitis B e antigen (HBeAg)-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA. Treatment-naïve HBeAg-negative CHB patients with undetectable HBV DNA and normal alanine aminotransferase were retrospectively included from three institutions. Patients were classified into the low HBsAg group (<100 IU/ml) and the high HBsAg group (≥100 IU/ml). Liver fibrosis was evaluated by noninvasive tests (NITs). A total of 1218 patients were included and the median age was 41.5 years. Patients with low HBsAg were older (45.0 vs. 40.0 years, P < 0.001) than those in the high HBsAg group, while the NIT parameters were comparable between groups. During a median follow-up of 25.7 months, patients with low HBsAg achieved a higher HBsAg clearance rate (13.0% vs. 0%, P < 0.001) and a lower rate of significant fibrosis development (2.2% vs. 7.0%, P = 0.049) compared to patients with high HBsAg. No patient developed HCC in either group. HBsAg level was negatively associated with HBsAg clearance (HR 0.213, P < 0.001) and patients with HBsAg < 100 IU/ml had a low risk of significant fibrosis development (HR 0.010, P = 0.002). The optimal cutoff value of HBsAg for predicting HBsAg clearance was 1.1 Log10 IU/ml. Treatment-naïve HBeAg-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA had favourable outcomes with a high rate of HBsAg clearance and a low risk of fibrosis progression.