BNIP3-mediated mitophagy boosts the competitive growth of Lenvatinib-resistant cells via energy metabolism reprogramming in HCC.

An increasing evidence supports that cell competition, a vital selection and quality control mechanism in multicellular organisms, is involved in tumorigenesis and development; however, the mechanistic contributions to the association between cell competition and tumor drug resistance remain ill-defined. In our study, based on a contructed lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obvious competitive growth dominance over sensitive cells through reprogramming energy metabolism. Mechanistically, the hyperactivation of BCL2 interacting protein3 (BNIP3) -mediated mitophagy in lenvatinib-resistant HCC cells promotes glycolytic flux via shifting energy production from mitochondrial oxidative phosphorylation to glycolysis, by regulating AMP-activated protein kinase (AMPK) -enolase 2 (ENO2) signaling, which perpetually maintaining lenvatinib-resistant HCC cells' competitive advantage over sensitive HCC cells. Of note, BNIP3 inhibition significantly sensitized the anti-tumor efficacy of lenvatinib in HCC. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism reprogramming; meanwhile, this work recognizes BNIP3 as a promising target to overcome HCC drug resistance.

Comparison of children and adults in deep brain stimulation for Tourette Syndrome: a large-scale multicenter study of 102 cases with long-term follow-up.

BACKGROUND: Deep brain stimulation (DBS) is a promising therapy for refractory Gilles de la Tourette syndrome (GTS). However, its long-term efficacy, safety, and recommended surgical age remain controversial, requiring evidence to compare different age categories. METHODS: This retrospective cohort study recruited 102 GTS patients who underwent DBS between October 2006 and April 2022 at two national centers. Patients were divided into two age categories: children (aged < 18 years; n = 34) and adults (aged ≥ 18 years; n = 68). The longitudinal outcomes as tic symptoms were assessed by the YGTSS, and the YBOCS, BDI, and GTS-QOL were evaluated for symptoms of obsessive-compulsive disorder (OCD), depression, and quality of life, respectively. RESULTS: Overall, these included patients who finished a median 60-month follow-up, with no significant difference between children and adults (p = 0.44). Overall, the YGTSS total score showed significant postoperative improvements and further improved with time (improved 45.2%, 51.6%, 55.5%, 55.6%, 57.8%, 61.4% after 6, 12, 24, 36, 48, and ≥ 60 months of follow-up compared to baseline, respectively) in all included patients (all p < 0.05). A significantly higher improvement was revealed in children than adults at ≥ 60 months of follow-up in the YGTSS scores (70.1% vs 55.9%, p = 0.043), and the time to achieve 60% improvement was significantly shorter in the children group (median 6 months vs 12 months, p = 0.013). At the last follow-up, the mean improvements were 45.4%, 48.9%, and 55.9% and 40.3%, 45.4%, and 47.9% in YBOCS, BDI, and GTS-QOL scores for children and adults, respectively, which all significantly improved compared to baseline (all p < 0.05) but without significant differences between these two groups (all p > 0.05), and the children group received significantly higher improvement in GTS-QOL scores than adults (55.9% vs. 47.9%, p = 0.049). CONCLUSIONS: DBS showed acceptable long-term efficacy and safety for both children and adults with GTS. Surgeries performed for patients younger than 18 years seemed to show acceptable long-term efficacy and safety and were not associated with increased risks of loss of benefit compared to patients older than 18 at the time of surgery. However, surgeries for children should also be performed cautiously to ensure their refractoriness and safety.

Repolarization of Immunosuppressive Macrophages by Targeting SLAMF7-Regulated CCL2 Signaling Sensitizes Hepatocellular Carcinoma to Immunotherapy.

Immune checkpoint inhibitors have limited efficacy in hepatocellular carcinoma (HCC). Macrophages are the most abundant immune cells in HCC, suggesting that a better understanding of the intrinsic processes by which tumor cells regulate macrophages could help identify strategies to improve response to immunotherapy. As signaling lymphocytic activation molecule (SLAM) family members regulate various immune functions, we investigated the role of specific SLAM receptors in the immunobiology of HCC. Comparison of the transcriptomic landscapes of immunotherapy-responsive and nonresponsive patients with advanced HCC identified SLAMF7 upregulation in immunotherapy-responsive HCC, and patients with HCC who responded to immunotherapy also displayed higher serum levels of SLAMF7. Loss of Slamf7 in liver-specific knockout mice led to increased hepatocarcinogenesis and metastasis, elevated immunosuppressive macrophage infiltration, and upregulated PD-1 expression in CD8+ T cells. HCC cell-intrinsic SLAMF7 suppressed MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization in vitro. Mechanistically, SLAMF7 associated with SH2 domain-containing adaptor protein B (SHB) through its cytoplasmic 304 tyrosine site to facilitate the recruitment of SHIP1 to SLAMF7 and inhibit the ubiquitination of TRAF6, thereby attenuating MAPK pathway activation and CCL2 transcription. Pharmacological antagonism of the CCL2/CCR2 axis potentiated the therapeutic effect of anti-PD-1 antibody in orthotopic HCC mouse models with low SLAMF7 expression. In conclusion, this study highlights SLAMF7 as a regulator of macrophage function and a potential predictive biomarker of immunotherapy response in HCC. Strategies targeting CCL2 signaling to induce macrophage repolarization in HCC with low SLAMF7 might enhance the efficacy of immunotherapy. SIGNIFICANCE: CCL2 upregulation caused by SLAMF7 deficiency in hepatocellular carcinoma cells induces immunosuppressive macrophage polarization and confers resistance to immune checkpoint blockade, providing potential biomarkers and targets to improve immunotherapy response in patients.

Localizing seizure onset zone by a cortico-cortical evoked potentials-based machine learning approach in focal epilepsy.

OBJECTIVE: We aimed to develop a new approach for identifying the localization of the seizure onset zone (SOZ) based on corticocortical evoked potentials (CCEPs) and to compare the connectivity patterns in patients with different clinical phenotypes. METHODS: Fifty patients who underwent stereoelectroencephalography and CCEP procedures were included. Logistic regression was used in the model, and six CCEP metrics were input as features: root mean square of the first peak (N1RMS) and second peak (N2RMS), peak latency, onset latency, width duration, and area. RESULTS: The area under the curve (AUC) for localizing the SOZ ranged from 0.88 to 0.93. The N1RMS values in the hippocampus sclerosis (HS) group were greater than that of the focal cortical dysplasia (FCD) IIa group (p < 0.001), independent of the distance between the recorded and stimulated sites. The sensitivity of localization was higher in the seizure-free group than in the non-seizure-free group (p = 0.036). CONCLUSIONS: This new method can be used to predict the SOZ localization in various focal epilepsy phenotypes. SIGNIFICANCE: This study proposed a machine-learning approach for localizing the SOZ. Moreover, we examined how clinical phenotypes impact large-scale abnormality of the epileptogenic networks.

Global research trends in cutaneous neurofibromas: A bibliometric analysis from 2003 to 2022.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a common inherited disorder characterized by cutaneous neurofibromas and other features. It is still a challenge in managing inoperable patients and the complex nature of the disease. Bibliometric analyses for cutaneous neurofibromas (cNF) could offer insights into impactful research and collaborations, guiding future efforts to improve patient care and outcomes. METHODS: We conducted a comprehensive literature search of the Web of Science Core Collection database for the period 2003-2022. Data processing and analysis were performed using bibliometric tools including VOSviewer, CiteSpace, and "Bibliometrix" package. Our analysis assessed the publication or collaboration of countries, institutions, authors, and journals, as well as the co-citation and burst of references and keywords. RESULTS: The analysis included 927 articles from 465 journals and 1402 institutions in 67 countries. Research on cNF has been increasing in recent years. The United States leads the field. Pierre Wolkenstein was the top author, while The University of Hamburg was the most productive institution. The American Journal of Medical Genetics Part A published the most articles in cNF. Co-citation analysis revealed major research topics and trends over time, showing growing interest in evaluating quality of life and genotype-phenotype correlation for cNF patients. Emerging topical MEK inhibitors show potential as a promising therapy. CONCLUSION: In conclusion, our bibliometric analysis of cNF research over the past two decades highlights the growing interest in this complex genetic disorder. Leading countries, authors, institutions, and journals have played significant roles in shaping the field. Notably, recent trends emphasize the importance of evaluating quality of life and genotype-phenotype correlations in cNF patients. Furthermore, the emergence of promising topical therapy marks an exciting development in the quest to improve patient care and outcomes for those affected by cNF, paving the way for future research and collaboration.

HSP90a promotes the resistance to oxaliplatin in HCC through regulating IDH1-induced cell competition.

Though burgeoning research manifests that cell competition, an essential selection and quality control mechanism for maintaining tissue or organ growth and homeostasis in multicellular organisms, is closely related to tumorigenesis and development, the mechanism of cell competition associated with tumor drug resistance remains elusive. In the study, we uncovered that oxaliplatin-resistant hepatocellular carcinoma (HCC) cells exhibit a pronounced competitive advantage against their sensitive counterparts, which is related to lipid takeover of resistant cells from sensitive cells. Of note, such lipid takeover is dependent on the existence of isocitrate dehydrogenase 1 (IDH1) in resistant HCC cells. Mechanistically, IDH1 activity is regulated by heat shock protein 90 alpha (HSP90α) through binding with each other, which orchestrates the expressions of lipid metabolic enzymes and lipid accumulation in resistant HCC cells. Our results suggest that HCC cell competition-driven chemoresistance can be regulated by HSP90α/IDH1-mediated lipid metabolism, which may serve as a promising target for overcoming drug resistance in HCC.

Histological features of chronic hepatitis B patients with normal alanine aminotransferase according to different criteria.

BACKGROUND: The upper limits of normal (ULNs) for alanine aminotransferase (ALT) are different among international guidelines for chronic hepatitis B (CHB). We aimed to investigate the proportion of significant histological disease in Asian patients with CHB with detectable hepatitis B virus (HBV) DNA under diverse ALT ULNs. METHODS: Consecutive patients with CHB and detectable HBV DNA who underwent liver biopsy were retrospectively included from four tertiary hospitals. Above grade 2 inflammation and stage 2 fibrosis were defined as significant inflammation and significant fibrosis, respectively. Significant histological disease was defined as above grade 2 inflammation or stage 2 fibrosis. RESULTS: Among the 414 patients with detectable HBV DNA and normal ALT, the proportion of those with significant histological disease was lower (59.7%) according to the ULN for ALT at 30/19 U/L (male/female), while the corresponding proportions were 66.7% and 62.3% according to the ULNs of 40 U/L and 35/25 U/L (male/female), respectively. In patients with detectable HBV DNA and normal ALT levels without significant fibrosis, the proportions of significant inflammation were comparable among different ULNs of ALT at 40 U/L (30.7%), 35/25 U/L (27.3%) and 30/19 U/L (25.0%). The proportion of significant histological disease was significantly lower in patients with normal ALT for 2 determinations at least 6 months apart compared to patients with normal ALT once. CONCLUSIONS: Although a more stringent ALT ULN may reduce the risk of the presence of significant histological disease in patients with detectable HBV DNA, the rates of significant histological disease remain high. Persistently normal ALT levels are more important for excluding patients with CHB with a high probability of significant histological disease.

Responses of the intestinal microbiota to exposure of okadaic acid in marine medaka Oryzias melastigma.

It is still limited that how the microalgal toxin okadaic acid (OA) affects the intestinal microbiota in marine fishes. In the present study, adult marine medaka Oryzias melastigma was exposed to the environmentally relevant concentration of OA (5 µg/L) for 10 days, and then recovered in fresh seawater for 10-days depuration. Analysis of taxonomic composition and diversity of the intestinal microbiota, as well as function prediction analysis and histology observation were carried out in this study. Functional prediction analysis indicated that OA potentially affected the development of colorectal cancer, protein and carbohydrate digestion and absorption functions, and development of neurodegenerative diseases like Parkinson's disease, which may be associated with changes in Proteobacteria and Firmicutes in marine medaka. Significant increases of C-reactive protein (CRP) and inducible nitric oxide synthase (iNOS) levels, as well as the changes of histology of intestinal tissue demonstrated that an intestinal inflammation was induced by OA exposure in marine medaka. This study showed that the environmental concentrations of OA could harm to the intestinal microbiota thus threatening the health of marine medaka, which hints that the chemical ecology of microalgal toxins should be paid attention to in future studies.

A synergistic regulation works in matrix stiffness-driven invadopodia formation in HCC.

Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells. However, whether and how increased matrix stiffness regulates the formation of invadopodia in HCC cells remain largely unknown. In the study, we developed different experimental systems in vitro and in vivo to explore the effects of matrix stiffness on the formation of invadopodia and its relevant molecular mechanism. Our results demonstrated that increased matrix stiffness remarkably augmented the migration and invasion abilities of HCC cells, upregulated the expressions of invadopodia-associated genes and enhanced the number of invadopodia. Two regulatory pathways contribute to matrix stiffness-driven invadopodia formation together in HCC cells, including direct triggering invadopodia formation through activating integrin ß1 or Piezo1/ FAK/Src/Arg/cortactin pathway, and indirect stimulating invadopodia formation through improving EGF production to activate EGFR/Src/Arg/cortactin pathway. Src was identified as the common hub molecule of two synergistic regulatory pathways. Simultaneously, activation of integrin ß1/RhoA/ROCK1/MLC2 and Piezo1/Ca2+/MLCK/MLC2 pathways mediate matrix stiffness-reinforced cell migration. This study uncovers a new mechanism by which mechanosensory pathway and biochemical signal pathway synergistically regulate the formation of invadopodia in HCC cells.

Shuyu capsule alleviates premenstrual depression via allopregnanolone metabolic pathway targeting GABA (A) receptors δ subunit in the hippocampus.

To reveal the exact changes of allopregnanolone-mediated γ-aminobutyric acid A receptor pathways and its specific therapeutic targets by Shuyu Capsule treating premenstrual depression, female Wistar rat models of premenstrual depression was established by Forced swimming test (FST). Behavioral tests, enzyme-linked immunosorbent assay (ELISA), interference knockdown adenovirus, and overexpressed vector adenovirus of GABAARδ, RT-qPCR, Western-Blot, and immunohistochemical detecting expressions were applied to identify the therapeutic targets. FST-based rat model indicated that Shuyu capsules alleviated typical premenstrual depression and may regulate alternations of 5α-reductase and 3α-steroid dehydrogenase, enhancing the metabolic pathway of progesterone to allopregnanolone, as well as targeting the GABAARδ subunit, thereby alleviating premenstrual depression of PMDD rat models.

Effect of different metastasis patterns on the prognosis of patients with stage III high-grade serous ovarian cancer.

To investigate the effect of different metastatic patterns of stage III high-grade serous ovarian cancer on the patient prognosis. The clinical data of 134 patients with Stage III, high-grade serous ovarian cancer diagnosed in The Affiliated Hospital of Qingdao University from January 2018 to April 2020 were retrospectively collected, and the patients were grouped according to metastasis mode. Patients with simple lymph node metastasis (SLNM) were included in the SLNM group, and patients with simple abdominal implantation alone and patients with abdominal metastasis combined with lymph node metastasis were all in the abdominal metastasis (AM) group. The prognosis of the two groups was analyzed. Of the 134 enrolled patients, complete datasets from 128 were successfully collected. There were 20 cases of SLNM (15.63%) and 108 cases of AM (84.37%). Initial CA125, initial HE4, and whether neoadjuvant chemotherapy was used were compared between the two groups (P < 0.05). According to the chemotherapy results, patients was divided into two groups: chemotherapy remission and uncontrolled, including 111 patients with chemotherapy remission and 17 patients with uncontrolled chemotherapy. According to the criteria of relapse after complete completion of chemotherapy and clinical remission, 91 cases relapsed, 20 cases did not relapse, of which 78 cases were platinum-sensitive, and 13 were platinum-resistant relapses. There were 4 recurrence cases in SLNM group (4.40%) and 87 recurrence cases (95.60%) in AM group (P < 0.05). The recurrence sites of 91 patients were analyzed, including 52 cases (57.14%) in the peritoneum, 11 cases (12.09%) in distant regions, 9 cases (9.89%) in lymph nodes, 19 cases (20.88%) in the peritoneum and lymph nodes. Significant differences were noted in the two groups' peritoneum, lymph node, and distance (P < 0.05). The two groups had significant differences in progression-free survival, overall survival, and 3-year survival (all P < 0.05). Initial HE4 levels, chemotherapy sensitivity, and SLNM are independent prognostic factors for Stage III high-grade serous ovarian cancer patients. Initial HE4 level < 233.7 pmol/l and chemotherapy sensitivity were protective factors, indicating a good prognosis. Patients in the SLNM group had lower initial CA125 and HE4 levels and higher survival rates. Initial HE4 levels and chemotherapy sensitivity are independent factors affecting prognosis in Stage III high-grade serous ovarian cancer patients.

Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignancy with limited treatment options and poor prognosis. Macrophages are enriched in the HCC microenvironment and have a significant impact on disease progression and therapy efficacy. We aim to identify critical macrophages subsets involved in HCC development. METHODS: Macrophage-specific marker genes were identified through single-cell RNA sequencing analyses. The clinical significance of macrophages with palmitoyl-protein thioesterase 1 (PPT1) positive was investigated in 169 patients with HCC from Zhongshan Hospital using immunohistochemistry and immunofluorescence. The immune microenvironment of HCC and the functional phenotype of PPT1+ macrophages were explored using cytometry by time-of-flight (CyTOF) and RNA sequencing. RESULTS: Single-cell RNA sequencing analyses revealed that PPT1 was predominantly expressed in macrophages in HCC. Intratumoral PPT1+ macrophages abundance was associated with inferior survival durations of patients and an independent risk factor of prognosis for HCC. High throughput analyses of immune infiltrates showed that PPT1+ macrophage-enriched HCCs were characterized by high infiltration of CD8+ T cells with increased programmed death-1 (PD-1) expression. PPT1+ macrophages exhibited higher galectin-9, CD172a, and CCR2 levels but lower CD80 and CCR7 levels than PPT1- macrophages. Pharmacological inhibition of PPT1 by DC661 suppressed mitogen-activated protein kinase (MAPK) pathway activity but activated nuclear factor kappa B (NF-κB) pathway in macrophages. In addition, DC661 enhanced the therapeutic efficacy of anti-PD-1 antibody in the HCC mouse model. CONCLUSIONS: PPT1 is mainly expressed in macrophages in HCC and promotes immunosuppressive transformation of macrophages and tumor microenvironment. PPT1+ macrophage infiltration is associated with poor prognosis of patients with HCC. Targeting PPT1 may potentiate the efficacy of immunotherapy for HCC.

Phosphatase regenerating liver 3 participates in Integrinß1/FAK-Src/MAPK signaling pathway and contributes to the regulation of malignant behaviors in hepatocellular carcinoma cells.

Background: Hepatocellular carcinoma (HCC) is the leading cause of mortality worldwide. Phosphatase regenerating liver 3 (PRL-3) was associated with cancer metastasis. However, the significance of PRL-3 in the prognosis of HCC remains elusive. The aim of this study was to elucidate the role of PRL-3 in HCC metastasis and its prognosis. Methods: The expressions of PRL-3 in cancer tissues isolated from 114 HCC patients, who underwent curative hepatectomy from May to November in 2008, were analyzed by immunohistochemistry, and its prognostic significance was evaluated. Thereafter, the migration, invasion, and metastatic alterations in MHCC97H cells with PRL-3 overexpression or knockdown were explored and compared with the tumor size and lung metastasis in orthotopic HCC model of nude mice derived from MHCC97H cells with PRL-3 overexpression or knockdown. The underlying mechanism involving PRL-3-mediated effect on HCC migration, invasion, and metastasis was further examined. Results: Univariate and multivariate analysis demonstrated PRL-3 overexpression was an independent prognostic factor for poor overall survival (OS) and progression-free survival (PFS) of the HCC patients. Increased PRL-3 expression in MHCC97H cells was in accordance with the enhanced metastasis potential. PRL-3 knockdown inhibited the migration, invasiveness, and clone forming ability in MHCC97H cells, whereas PRL-3 overexpression reverted the above behavior. The growth of xenograft tumor in the liver was suppressed, and the lung metastasis in nude mice was inhibited by PRL-3 downregulation. The knockdown of PRL-3 could downregulate the expressions of Integrinß1 and p-Src (Tyr416), p-Erk (Thr202/Tyr204) activation, and reduce MMP9 expression. Both MEK1/2 inhibitor (U0126) and Src inhibitor could repress PRL-3-induced invasiveness and migration in MHCC97H cells. Conclusions: PRL-3 was significantly overexpressed and an independent prognostic factor to predict the death of HCC patients. Mechanically, PRL-3 plays a critical role in HCC invasive and metastasis via Integrinß1/FAK-Src/RasMAPK signaling. Validation of PRL-3 as a clinical prediction marker in HCC warrants further research.

SSH1 promotes progression of intrahepatic cholangiocarcinoma via p38 MAPK-CXCL8 axis.

Protein tyrosine phosphatases (PTPs) are involved in malignant transformation and metastasis. According to one of our previous studies, Slingshot homolog 1 (SSH1), a member of PTPs, is significantly associated with the survival of intrahepatic cholangiocarcinoma (iCCA) patients. However, the underlying mechanisms of SSH1 in iCCA remain largely elusive. Here, the expression and clinical significance of SSH1 were assessed using the iCCA patient samples. The results showed that SSH1 was dramatically up-regulated in iCCA tissues and elevated SSH1 expression was associated with worse overall survival of iCCA patients. Overexpression of SSH1 accelerated the proliferation, migration, and invasion of iCCA cells, and also inhibited cell apoptosis. Furthermore, the downstream signaling pathway of SSH1 in iCCA was explored and it was revealed that the increased expression of SSH1 could activate the p38 mitogen-activated protein kinase (MAPK) pathway and enhance the expression of C-X-C motif chemokine ligand 8 (CXCL8). Notably, the high correlation of SSH1 with CXCL8 jointly indicated the poor prognosis in iCCA patients. Thus, our study suggests SSH1 as a potentially promising target for iCCA, which promoted iCCA progression through a potential p38 MAPK-CXCL8 axis.

Disruption of SLFN11 Deficiency-Induced CCL2 Signaling and Macrophage M2 Polarization Potentiates Anti-PD-1 Therapy Efficacy in Hepatocellular Carcinoma.

BACKGROUND & AIMS: The therapeutic effect of immune checkpoint inhibitors (ICIs) is poor in hepatocellular carcinoma (HCC) and varies greatly among individuals. Schlafen (SLFN) family members have important functions in immunity and oncology, but their roles in cancer immunobiology remain unclear. We aimed to investigate the role of the SLFN family in immune responses against HCC. METHODS: Transcriptome analysis was performed in human HCC tissues with or without response to ICIs. A humanized orthotopic HCC mouse model and a co-culture system were constructed, and cytometry by time-of-flight technology was used to explore the function and mechanism of SLFN11 in the immune context of HCC. RESULTS: SLFN11 was significantly up-regulated in tumors that responded to ICIs. Tumor-specific SLFN11 deficiency increased the infiltration of immunosuppressive macrophages and aggravated HCC progression. HCC cells with SLFN11 knockdown promoted macrophage migration and M2-like polarization in a C-C motif chemokine ligand 2-dependent manner, which in turn elevated their own PD-L1 expression by activating the nuclear factor-κB pathway. Mechanistically, SLFN11 suppressed the Notch pathway and C-C motif chemokine ligand 2 transcription by binding competitively with tripartite motif containing 21 to the RNA recognition motif 2 domain of RBM10, thereby inhibiting tripartite motif containing 21-mediated RBM10 degradation to stabilize RBM10 and promote NUMB exon 9 skipping. Pharmacologic antagonism of C-C motif chemokine receptor 2 potentiated the antitumor effect of anti-PD-1 in humanized mice bearing SLFN11 knockdown tumors. ICIs were more effective in patients with HCC with high serum SLFN11 levels. CONCLUSIONS: SLFN11 serves as a critical regulator of microenvironmental immune properties and an effective predictive biomarker of ICIs response in HCC. Blockade of C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 signaling sensitized SLFN11low HCC patients to ICI treatment.

Mechanism Study on Chinese Medicine in Treatment of Nodular Goiter.

Nodular goiter has become increasingly prevalent in recent years. Clinically, there has been a burgeoning interest in nodular goiter due to the risk of progression to thyroid cancer. This review aims to provide a comprehensive summary of the mechanisms underlying the therapeutic effect of Chinese medicine (CM) in nodular goiter. Articles were systematically retrieved from databases, including PubMed, Web of Science and China National Knowledge Infrastructure. New evidence showed that CM exhibited multi-pathway and multi-target characteristics in the treatment of nodular goiter, involving hypothalamus-pituitary-thyroid axis, oxidative stress, blood rheology, cell proliferation, apoptosis, and autophagy, especially inhibition of cell proliferation and promotion of cell apoptosis, involving multiple signal pathways and a variety of cytokines. This review provides a scientific basis for the therapeutic use of CM against nodular goiter. Nonetheless, future studies are warranted to identify more regulatory genes and pathways to provide new approaches for the treatment of nodular goiter.

HSF1 is involved in immunotherapeutic response through regulating APOJ/STAT3-mediated PD-L1 expression in hepatocellular carcinoma.

Hepatocellular cancer (HCC) is a serious illness with high prevalence and mortality throughout the whole world. For advanced HCC, immunotherapy is somewhat impactful and encouraging. Nevertheless, a substantial proportion of patients with advanced HCC are still unable to achieve a durable response, owing to heterogeneity from clonal variability and differential expression of the PD-1/PD-L1 axis. Recently, heat shock factor 1 (HSF1) is recognized as an important component of tumor immunotherapeutic response as well as related to PD-L1 expression in cancer. However, the mechanism of HSF1 regulating PD-L1 in cancer, especially in HCC, is still not fully clear. In this study, we observed the significantly positive correlation between HSF1 expression and PD-L1 expression in HCC samples; meanwhile combination expressions of HSF1 and PD-L1 served as the signature for predicting prognosis of patients with HCC. Mechanistically, HSF1 upregulated PD-L1 expression by inducing APOJ expression and activating STAT3 signaling pathway in HCC. In addition, we explored further the potential values of targeting the HSF1-APOJ-STAT3 axis against CD8+ T cells-mediated cancer cells cytotoxicity. These findings unveiled the important involvement of HSF1 in regulating PD-L1 expression in HCC as well as provided a novel invention component for improving the clinical response rate and efficacy of PD-1/PD-L1 blockade.

Intratumor microbiome features reveal antitumor potentials of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy with a high prevalence in China. This study aimed to characterize the ICC tissues' bacterial metagenomics signature and explore its antitumor potential for cancer. In this study, 16S rRNA sequencing was carried out on 99 tissues to characterize the features of intratumoral microbiota, followed by single-cell RNA sequencing (scRNA-seq) and multilevel validation. The presence of microbial DNA in tissues was determined using staining, fluorescence in situ hybridization (FISH), and transmission electron microscopy (TEM). A Gram-positive aerobic bacterium, identified as Staphylococcus capitis, was cultured from fresh tissues. Meanwhile, scRNA-seq showed that intratumoral bacteria could be present in multiple cell types. Using 16S rRNA sequencing, we identified a total of 2,320,287 high-quality reads corresponding to 4,594 OTU (operational taxonomic units) sequences. The most abundant bacterial orders include Burkholderiales, Pseudomonadales, Xanthomonadales, Bacillales and Clostridiales. Alpha and Beta diversity analysis revealed specific features in different tissues. In addition, the content of Paraburkholderia fungorum was significantly higher in the paracancerous tissues and negatively correlated with CA199 (Carbohydrate antigen199) levels. The results of in vitro and in vivo experiments suggest that P. fungorum possesses an antitumor activity against tumors. Metabolomics and transcriptomics showed that P. fungorum could inhibit tumor growth through alanine, aspartate and glutamate metabolism. We determined the characteristic profile of the intratumoral microbiota and the antitumor effect of P. fungorum in ICC.

Significant histological disease of patients with chronic hepatitis B virus infection in the grey zone.

BACKGROUND: Many patients with chronic hepatitis B (CHB) do not meet the definitions of the traditional natural phases and are classified as being in the grey zone (GZ). AIMS: To investigate liver histology, and to establish a management strategy for patients with CHB in the GZ. METHODS: This study included 1043 patients with CHB who underwent liver biopsy. Phases of natural history were determined according to the AASLD 2018 hepatitis B guidance. CHB patients in the GZ were divided into HBeAg-positive, normal ALT and HBV DNA ≤106  IU/ml (GZ-A); HBeAg-positive, elevated ALT and HBV DNA ≤2 × 104  IU/ml (GZ-B); HBeAg-negative, normal ALT and HBV DNA ≥2 × 103  IU/ml (GZ-C) and HBeAg-negative, elevated ALT and HBV DNA ≤2 × 103  IU/ml (GZ-D). Significant histological disease was defined as liver inflammation ≥G2 and/or liver fibrosis ≥S2. RESULTS: Two hundred and forty two (23.2%) patients were in the GZ. Approximately 72.7% had significant histological disease. HBeAg-positive GZ CHB patients had a higher proportion of significant histological disease than HBeAg-negative GZ patients (91.1% vs. 68.5%, p = 0.002). GZ-D (42.6%) was the dominant category, followed by GZ-C (38.8%), GZ-A (10.3%) and GZ-B (8.3%). The highest proportion of significant histological disease was observed patients in GZ-B (100.0%), followed by GZ-A (84.0%), GZ-D (69.9%) and GZ-C (67.0%). Prothrombin time (PT) was an independent risk factor of significant histological disease in the HBeAg-negative GZ. CONCLUSIONS: Over 70% of GZ CHB patients had significant histological disease. We recommend antiviral treatment for HBeAg-positive and HBeAg-negative GZ CHB patients with high PT.

Nucleotide sugar transporter SLC35A2 is involved in promoting hepatocellular carcinoma metastasis by regulating cellular glycosylation.

PURPOSE: Recently, aberrant glycosylation has been recognized to be relate to malignant behaviors of cancer and outcomes of patients with various cancers. SLC35A2 plays an indispensable role on glycosylation as a nucleotide sugar transporter. However, effects of SLC35A2 on malignant behaviors of cancer cells and alteration of cancer cells surface glycosylation profiles are still not fully understood, particularly in hepatocellular carcinoma (HCC). Hence, from a glycosylation perspective, we investigated the effects of SLC35A2 on metastatic behaviors of HCC cells. METHODS: SLC35A2 expression in clinical samples and HCC cells was examined by immunohistochemical staining or Western blot/quantitative PCR and was regulated by RNA interference or vectors-mediated transfection. Effects of SLC35A2 expression alteration on metastatic behaviors and membrane glycan profile of HCC cells were observed by using respectively invasion, migration, cell adhesion assay, in vivo lung metastatic nude mouse model and lectins microarray. Co-location among proteins in HCC cells was observed by fluorescence microscope and detected by an in vitro co-immunoprecipitation assay. RESULTS: SLC35A2 was upregulated in HCC tissues, and is associated with poor prognosis of HCC patients. SLC35A2 expression alteration significantly affected the invasion, adhesion, metastasis and membrane glycan profile and led to the dysregulated expressions or glycosylation of cell adhesion-related molecules in HCC cells. Mechanistically, the maintenance of SLC35A2 activity is critical for the recruitment of the key galactosyltransferase B4GalT1, which is responsible for complex glycoconjugate and lactose biosynthesis, to Golgi apparatus in HCC cells. CONCLUSION: SLC35A2 plays important roles in promoting HCC metastasis by regulating cellular glycosylation modification and inducing the cell adhesive ability of HCC cells.