FGFR2 fusion/rearrangement is associated with favorable prognosis and immunoactivation in patients with intrahepatic cholangiocarcinoma.

Increasing evidence highlights that fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement shows important therapeutic value for patients with intrahepatic cholangiocarcinoma (ICC). This study aims to explore the association of FGFR2 status with the prognosis and immune cell infiltration profiles of patients with ICC. A total of 226 ICC tissue samples from patients who received surgery at the Department of Liver Surgery at Zhongshan Hospital, Fudan University, were collected retrospectively and assigned to a primary cohort (n = 152) and validation cohort (n = 74) group. Fluorescence in situ hybridization was performed to determine FGFR2 status. Multiplex immunofluorescence (mIF) staining and immunohistochemistry were performed to identify immune cells. Thirty-two (14.2%) ICC tissues presented with FGFR2 fusion/rearrangement. FGFR2 fusion/rearrangement was associated with low levels of carcinoembryonic antigen (CEA, P = .026) and gamma glutamyl transferase (γ-GGT, P = .003), low TNM (P = .012), CNLC (P = .008) staging as well as low tumor cell differentiation (P = .016). Multivariate COX regression analyses revealed that FGFR2 fusion/rearrangement was an independent protective factor for both overall survival (OS) and relapse-free survival in patients with ICC. Furthermore, correlation analysis revealed that an FGFR2 fusion/rearrangement was associated with low levels of Tregs and N2 neutrophils and high levels of N1 neutrophils infiltrating into tumors but not with CD8+ T-cell or macrophage tumor infiltration. FGFR2 fusion/rearrangement may exert a profound impact on the prognosis of ICC patients and reprogram the tumor microenvironment to be an immune-activated state. FGFR2 status may be used for ICC prognostic stratification and as an immunotherapeutic target in patients with ICC.

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.

Chemokine CCL21 determines immunotherapy response in hepatocellular carcinoma by affecting neutrophil polarization.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is poor and great heterogeneity among individuals. Chemokines are highly correlated with tumor immune response. Here, we aimed to identify an effective chemokine for predicting the efficacy of immunotherapy in HCC. METHODS: Chemokine C-C motif ligand 21 (CCL21) was screened by transcriptomic analysis in tumor tissues from HCC patients with different responses to ICIs. The least absolute shrinkage and selection operator (LASSO) regression analysis was conducted to construct a predictive nomogram. Neutrophils in vitro and HCC subcutaneous tumor model in vivo were applied to explore the role of CCL21 on the tumor microenvironment (TME) of HCC. RESULTS: Transcriptome analysis showed that CCL21 level was much higher in HCC patients with response to immunotherapy. The predictive nomogram was constructed and validated as a classifier. CCL21 could inhibit N2 neutrophil polarization by suppressing the activation of nuclear factor kappa B (NF-κB) pathway. In addition, CCL21 enhanced the therapeutic efficacy of ICIs. CONCLUSION: CCL21 may serve as a predictive biomarker for immunotherapy response in HCC patients. High levels of CCL21 in TME inhibit immunosuppressive polarization of neutrophils. CCL21 in combination with ICIs may offer a novel therapeutic strategy for HCC.

Genetic architecture of ecological divergence between Oryza rufipogon and Oryza nivara.

Ecological divergence due to habitat difference plays a prominent role in the formation of new species, but the genetic architecture during ecological speciation and the mechanism underlying phenotypic divergence remain less understood. Two wild ancestors of rice (Oryza rufipogon and Oryza nivara) are a progenitor-derivative species pair with ecological divergence and provide a unique system for studying ecological adaptation/speciation. Here, we constructed a high-resolution linkage map and conducted a quantitative trait locus (QTL) analysis of 19 phenotypic traits using an F2 population generated from a cross between the two Oryza species. We identified 113 QTLs associated with interspecific divergence of 16 quantitative traits, with effect sizes ranging from 1.61% to 34.1% in terms of the percentage of variation explained (PVE). The distribution of effect sizes of QTLs followed a negative exponential, suggesting that a few genes of large effect and many genes of small effect were responsible for the phenotypic divergence. We observed 18 clusters of QTLs (QTL hotspots) on 11 chromosomes, significantly more than that expected by chance, demonstrating the importance of coinheritance of loci/genes in ecological adaptation/speciation. Analysis of effect direction and v-test statistics revealed that interspecific differentiation of most traits was driven by divergent natural selection, supporting the argument that ecological adaptation/speciation would proceed rapidly under coordinated selection on multiple traits. Our findings provide new insights into the understanding of genetic architecture of ecological adaptation and speciation in plants and help effective manipulation of specific genes or gene cluster in rice breeding.

RNA m6A methylation regulators in liver cancer.

Liver cancer is one of the most common cancers in the world and a primary cause of cancer-related death. In recent years, despite the great development of diagnostic methods and targeted therapies for liver cancer, the incidence and mortality of liver cancer are still on the rise. As a universal post-transcriptional modification, N6-methyladenosine (m6A) modification accomplishes a dynamic and reversible m6A modification process, which is executed by three types of regulators, methyltransferases (called writers), demethylases (called erasers) and m6A-binding proteins (called readers). Many studies have shown that m6A RNA methylation has an important impact on RNA metabolism, whereas its regulation exception is bound up with the occurrence of human malignant tumors. Aberrant methylation of m6A RNA and the expression of related regulatory factors may be of the essence in the pathogenesis and progression of liver cancer, yet the precise molecular mechanism remains unclear. In this paper, we review the current research situations of m6A methylation in liver cancer. Among the rest, we detail the mechanism by which methyltransferases, demethylases and m6A binding proteins regulate the occurrence and development of liver cancer by modifying mRNA. As well as the potential effect of m6A regulators in hepatocarcinogenesis and progression. New ideas and approaches will be given to the prevention and treatment of liver cancer through the following relevant research results.

Development and performance of SIAT bPET: a high-resolution and high-sensitivity MR-compatible brain PET scanner using dual-ended readout detectors.

PURPOSE: Positron emission tomography/magnetic resonance imaging (PET/MRI) is a powerful tool for brain imaging, but the spatial resolution of the PET scanners currently used for brain imaging can be further improved to enhance the quantitative accuracy of brain PET imaging. The purpose of this study is to develop an MR-compatible brain PET scanner that can simultaneously achieve a uniform high spatial resolution and high sensitivity by using dual-ended readout depth encoding detectors. METHODS: The MR-compatible brain PET scanner, named SIAT bPET, consists of 224 dual-ended readout detectors. Each detector contains a 26 × 26 lutetium yttrium oxyorthosilicate (LYSO) crystal array of 1.4 × 1.4 × 20 mm3 crystal size read out by two 10 × 10 silicon photomultiplier (SiPM) arrays from both ends. The scanner has a detector ring diameter of 376.8 mm and an axial field of view (FOV) of 329 mm. The performance of the scanner including spatial resolution, sensitivity, count rate, scatter fraction, and image quality was measured. Imaging studies of phantoms and the brain of a volunteer were performed. The mutual interferences of the PET insert and the uMR790 3 T MRI scanner were measured, and simultaneous PET/MRI imaging of the brain of a volunteer was performed. RESULTS: A spatial resolution of better than 1.5 mm with an average of 1.2 mm within the whole FOV was obtained. A sensitivity of 11.0% was achieved at the center FOV for an energy window of 350-750 keV. Except for the dedicated RF coil, which caused a ~ 30% reduction of the sensitivity of the PET scanner, the MRI sequences running had a negligible effect on the performance of the PET scanner. The reduction of the SNR and homogeneity of the MRI images was less than 2% as the PET scanner was inserted to the MRI scanner and powered-on. High quality PET and MRI images of a human brain were obtained from simultaneous PET/MRI scans. CONCLUSION: The SIAT bPET scanner achieved a spatial resolution and sensitivity better than all MR-compatible brain PET scanners developed up to date. It can be used either as a standalone brain PET scanner or a PET insert placed inside a commercial whole-body MRI scanner to perform simultaneous PET/MRI imaging.

Vericiguat improves cardiac function and microcirculation of a male patient with Fabry disease: A case report.

Fabry disease (FD) is a rare X chromosome-linked disorder and can be easily misdiagnosed. Here, we report the case of a 69-year-old male patient with FD who developed heart failure and showed extremely high pulmonary artery pressure. His initial symptom was recurrent atrial fibrillation. The left and right atrial inner diameters were large, and the ventricular wall was thick. Gene analysis which showed GLA c.215T>C p.Met72Thr mutation and single photon emission computed tomography indicated the diagnosis of FD with coronary microvascular dysfunction. The patient was prescribed anti-heart failure drugs, including vericiguat. Following the treatment, his heart function and microvascular perfusion significantly improved, which might be due to the beneficial effects of vericiguat.

MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway.

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies.

Inflammasomes in human reproductive diseases.

Inflammasomes are multi-protein complexes localized within immune and non-immune cells that induce caspase activation, proinflammatory cytokine secretion, and ultimately pyroptosis-a type of cell death. Inflammasomes are involved in a variety of human diseases, especially acute or chronic inflammatory diseases. In this review, we focused on the strong correlation between the NLRP3 inflammasome and various reproductive diseases, including ovarian aging or premature ovarian insufficiency, PCOS, endometriosis, recurrent spontaneous abortion, preterm labor, pre-eclampsia, and male subfertility, as well as the multifaceted role of NLRP3 in the pathogenesis and treatment of these diseases. In addition, we provide an overview of the structure and amplification of inflammasomes. This comprehensive review demonstrates the vital role of NLRP3 inflammasome activation in human reproductive diseases together with the underlying mechanisms, offers new insights for mechanistic studies of reproduction, and provides promising possibilities for the development of drugs targeting the NLRP3 inflammasome for the treatment of reproductive disorders in the future.

Potential Value of FAPI PET/CT in the Detection and Treatment of Fibrosing Mediastinitis: Preclinical and Pilot Clinical Investigation.

Fibrosing mediastinitis (FM) is a rare proliferative disease within the mediastinum that leads to pulmonary hypertension, which has been regarded as a major cause of death. This study aims to evaluate the potential value of fibroblast activation protein inhibitor (FAPI)-PET/CT in the integration of diagnosis and treatment of FM through targeting FAPI in fibrosis rats and provide a theoretical basis for clinical management of FM patients. By performing a 18F-FAPI PET/CT scan, the presence of FAPI-avid in the fibrotic lesion was determined. Through a fibrosis rat model, 18F-FAPI-74 was used for lesion imaging and 177Lu-FAPI-46 was utilized to investigate the potential therapeutic effect on FM in vivo. In addition, biodistribution analysis and radiation dosimetry were carried out. With the 177Lu-FAPI-46 pharmacokinetic data of rats as the input, the estimated dose for female adults was computed, which can provide some useful information for the safe application of radiolabeled FAPI in the detection and treatment of FM in patients. Then, major findings on the use of FAPI PET/CT and SPECT/CT in FM were presented. 18F-FAPI-74 showed a high-level uptake in FM lesions of patients (SUVmax 7.94 ± 0.26), which was also observed in fibrosis rats (SUVmax 2.11 ± 0.23). Consistently, SPECT/CT imaging of fibrosis rats also revealed that 177Lu-FAPI-46-avid was active for up to 60 h in fibrotic lesions. In addition to this robust diagnostic performance, a possible therapeutic impact was evaluated as well. It turned out that no spontaneous healing of lesions was observed in the control group, whereas there was complete healing on day 9, day 11, and day 14 in the 30, 100, and 300 MBq groups, respectively. With a significant difference in the free of event rate in the Kaplan-Meier curve among four groups (P < 0.001), a dose of 300 MBq displayed the best therapeutic effect, and no obvious damage was observed in the kidney. Furthermore, organ-absorbed doses and an effective dose (0.4320 mSv/MBq) of 177Lu-FAPI-46 presumed for patients were assumed to give a preliminary indication of its safe use in clinical practice. In conclusion, 18F-FAPI-46 PET/CT can be a potentially valuable tool for the diagnosis of FM. Of note, 177Lu-FAPI-46 may be a novel and safe radiolabeled reagent for the integration of diagnosis and treatment of FM.

Surface Chain-Transfer Ring-Opening Metathesis Polymerization.

Ring-opening metathesis polymerization (ROMP) is a powerful method to graft various types of polymer chains to a given surface. While surface-initiated ROMP (SI-ROMP) serves as an efficient tool for surface modification and is therefore widely reported, the method requires grafting (1) the olefin substrate and (2) the metathesis catalyst to the surface prior to the polymerization with multiple synthetic and work up steps. To overcome this difficulty, we proposed the use of the chain-transfer reaction as an alternative method for surface modification. Terminal olefins are grafted to the surface without the need to graft the metathesis catalysts, and polymers with olefin backbones are polymerized and grafted simultaneously via both ROMP and chain transfer (cross-metathesis between olefins from backbones and surfaces). Compared to SI-ROMP, this surface-chain transfer ROMP (SC-ROMP) method avoids grafting the catalyst and growing polymer chains from the surface and could be achieved in a single step. Various types of surfaces like carbon nanotubes, carbon fibers, graphene nanosheets, and silica microspheres are used for demonstration. We envision that this work could bring a convenient and effective solution to surface modification via ROMP.

Ferroptosis: a new promising target for hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is the sixed most common malignant tumor in the world. The study for HCC is mired in the predicament confronted with the difficulty of early diagnosis and high drug resistance, the survival rate of patients with HCC being low. Ferroptosis, an iron-dependent cell death, has been discovered in recent years as a cell death means with tremendous potential to fight against cancer. The in-depth researches for iron metabolism, lipid peroxidation and dysregulation of antioxidant defense have brought about tangible progress in the firmament of ferroptosis with more and more results showing close connections between ferroptosis and HCC. The potential role of ferroptosis has been widely used in chemotherapy, immunotherapy, radiotherapy, and nanotherapy, with the development of various new drugs significantly improving the prognosis of patients. Based on the characteristics and mechanisms of ferroptosis, this article further focuses on the main signaling pathways and promising treatments of HCC, envisioning that existing problems in regard with ferroptosis and HCC could be grappled with in the foreseeable future.

Perioperative and oncologic outcomes of laparoscopic versus open liver resection for combined hepatocellular-cholangiocarcinoma: a propensity score matching analysis.

BACKGROUND: Laparoscopic liver resection (LLR) has now been established as a safe and minimally invasive technique that is deemed feasible for treating hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). However, the role of LLR in treating combined hepatocellular-cholangiocarcinoma (cHCC-CC) patients has been rarely reported. This study aimed to assess the efficacy of LLR when compared with open liver resection (OLR) procedure for patients with cHCC-CC. METHODS: A total of 229 cHCC-CC patients who underwent hepatic resection (34 LLR and 195 OLR patients) from January 2014 to December 2018 in Zhongshan Hospital, Fudan University were enrolled and underwent a 1:2 propensity score matching (PSM) analysis between the LLR and OLR groups to compare perioperative and oncologic outcomes. Overall survival (OS) and recurrence-free survival (RFS) parameters were assessed by the log-rank test and the sensitivity analysis. RESULTS: A total of 34 LLR and 68 OLR patients were included after PSM analysis. The LLR group displayed a shorter postoperative hospital stay (6.61 vs. 8.26 days; p value < 0.001) when compared with the OLR group. No significant differences were observed in the postoperative complications' incidence or a negative surgical margin rate between the two groups (p value = 0.409 and p value = 1.000, respectively). The aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory indicators in the LLR group were significantly lower than those in the OLR group on the first and third postoperative days. Additionally, OS and RFS were comparable in both the LLR and OLR groups (p value = 0.700 and p value = 0.780, respectively), and similar results were obtained by conducting a sensitivity analysis. CONCLUSION: LLR can impart less liver function damage, better inflammatory response attenuation contributing to a faster recovery, and parallel oncologic outcomes when compared with OLR. Therefore, LLR can be recommended as a safe and effective therapeutic modality for treating selected cHCC-CC patients, especially for those with small tumors in favorable location.

Printable Metal-Polymer Conductors for Local Drug Delivery.

Safe and effective local drug delivery is challenging due to complex physiological barriers that limit the entry of drugs. Here, we report the metal-polymer conductors (MPCs) for local drug delivery via iontophoresis or electroporation. The MPCs are stretchable, conductive, and biocompatible. The flexible MPCs of different geometries are used both on a dry, flat surface (skin) and a moist, curved surface (cornea) with conformability. Conformal integration with the tissues enables good mechanical/electrical properties and realizes application of electrical voltage to the target areas for local drug delivery. By iontophoresis and electroporation, the MPCs achieve efficient delivery of doxorubicin and siRNA, leading to tumor regression and inhibition of corneal neovascularization, respectively. Our work presents an efficient strategy to harness the power of the MPCs to broaden the scope of local drug delivery to dry and wet organs with different surface topography.

Novel Lanthanide Complexes Synthesized from 3-Dimethylamino Benzoic Acid and 5,5'-Dimethyl-2,2' Bipyridine Ligand: Crystal Structure, Thermodynamics, and Fluorescence Properties.

Two isostructural lanthanide complexes were synthesized by solvent evaporation with 3-dimethylaminobenzoic acid and 5,5'-dimethyl-2,2'-bipyridine as ligands. The general formula of the structure is a [Ln(3-N,N-DMBA)3(5,5'-DM-2,2'-bipy)]2·2(3-N,N-DMHBA), Ln = (Gd(1), Tb(2)), 3-N,N-DMBA = 3-Dimethylamino benzoate, 5,5'-DM-2,2'-bipy = 5,5'-dimethyl-2,2' bipyridine. Both complexes exhibited dimeric structures based on X-ray diffraction analysis. At the same time, infrared spectroscopy and Raman spectroscopy were used to measure the spectra of the complex. A thermogravimetric infrared spectroscopy experiment was performed to investigate the thermal stability and decomposition mechanism of the complexes. Measurements of the low-temperature heat capacity of the complexes were obtained within the temperature range of 1.9 to 300 K. The thermodynamic function was calculated by heat capacity fitting. In addition, the fluorescence spectra of complex 2 were studied and the fluorescence lifetime values were determined, and the energy transfer mechanism of complex 2 was elucidated.

The spatial distribution of immune cell subpopulations in hepatocellular carcinoma.

Infiltrating immune cells in the tumor microenvironment (TME) influence tumor progression and patient prognosis, making them attractive therapeutic targets for immunotherapy research. A deeper understanding of immune cell distributions in the TME in hepatocellular carcinoma (HCC) is needed to identify interactions among different immune cell types that might impact the effectiveness of potential immunotherapies. We performed multiplex immunohistochemistry using a tissue microarray of samples from 302 patients with HCC to elucidate the spatial distributions of immune cell subpopulations (CD3+ , CD4+ , CD8+ , CD66b+ , and CD68+ ) in HCC and normal liver tissues. We analyzed the associations between different immune subpopulations using Pearson's correlation. G(r) functions, K(r) functions and Euclidean distance were applied to characterize the bivariate distribution patterns among the immune cell types. Cox regression and Kaplan-Meier analysis were used to evaluate the associations between tumor infiltration by different immune cells and patient outcomes after curative surgery. We also analyzed the relationship between the spatial distribution of different immune cell subpopulations with HCC patient prognosis. We found that the immune cell spatial distribution in the HCC TME is heterogeneous. Our study provides a theoretical basis for HCC immunotherapy.

PARG inhibition limits HCC progression and potentiates the efficacy of immune checkpoint therapy.

BACKGROUND & AIMS: Although the treatment of hepatocellular carcinoma (HCC) has been revolutionized by the advent of effective systemic therapies, the prognosis of patients with HCC remains dismal. Herein, we examined the pathophysiological role of PARG and assessed the utility of targeting dePARylation for HCC therapy. METHODS: The oncogenic function of PARG was evaluated in 2 orthotopic xenograft models and a Pargflox/flox mice model. The therapeutic efficacy of PARG inhibitors in combination with an anti-PD-1 antibody were assessed in murine orthotopic models. Microarray analysis was used to evaluate the pathological relevance of the PARG/DDB1/c-Myc/MMR axis. RESULTS: High PARG expression was strongly associated with poor HCC prognosis. Hepatocyte-specific PARG deletion significantly impaired liver tumorigenesis. PARG promoted HCC growth and metastasis through DDB1-dependent modulation of c-Myc. Specifically, PARG dePARylated DDB1 and consequently promoted DDB1 autoubiquitination, thus stabilizing the c-Myc protein in HCC cells. PARG downregulation attenuated c-Myc-induced MMR expression and PARG deficiency was correlated with a favorable prognosis in patients with HCC treated with anti-PD-1-based immunotherapy. In addition, PARG inhibitors could act in synergy with anti-PD-1 antibodies in orthotopic mouse models. CONCLUSIONS: PARG can act as an oncogene in HCC by modulating PARG/DDB1/c-Myc signaling and could be used as a biomarker to identify patients with HCC who may benefit from anti-PD-1 treatment. Our findings suggest that co-inhibition of PARG and PD-1 is an effective novel combination strategy for patients with HCC. LAY SUMMARY: The increase in deaths due to hepatocellular carcinoma (HCC) is a growing concern, with the mechanisms responsible for HCC development still incompletely understood. Herein, we identify a novel mechanism by which the protein PARG contributes to HCC development. Inhibition of PARG increased the efficacy of anti-PD-1 therapy (a type of immunotherapy) in HCC. These findings support the future clinical development of PARG inhibitors, potentially in combination with anti-PD-1 inhibitors.

Phosphorylation of OsABA2 at Ser197 by OsMPK1 regulates abscisic acid biosynthesis in rice.

The mitogen-activated protein kinase OsMPK1 is involved in abscisic acid (ABA) biosynthesis in rice (Oryza sativa L.). However, the underlying molecular mechanisms of OsMPK1 in regulating ABA biosynthesis are poorly understood. Here, by using yeast two-hybrid assay and firefly luciferase complementary imaging assay, we show that OsMPK1 physically interact with a short-chain dehydrogenase protein OsABA2. However, OsMPK5, a homolog of OsMPK1, does not interact with OsABA2. Further, OsMPK1 can phosphorylate OsABA2S197 in vitro. Phosphorylation at the position of OsABA2S197 does not affect its subcellular localization, but enhances the stability of OsABA2 protein. We also found that OsABA2 has feedback regulation on OsMPK1 kinase activity. Further research reveals that OsMPK1 and OsABA2 coordinately regulate the biosynthesis of ABA, and phosphorylation of OsABA2 at Ser197 by OsMPK1 plays a crucial role in regulating the biosynthesis of ABA. Finally, genetic analysis showed that OsABA2 can enhance the sensitivity of rice to ABA and the tolerance of rice to drought and salt stress.

Trend in the incidence of hepatitis A in mainland China from 2004 to 2017: a joinpoint regression analysis.

BACKGROUND: China has experienced a continuous decreasing trend in the incidence of hepatitis A in recent years. Temporal trend analyses are helpful in exploring the reasons for the changing trend. Thus, this study aims to analyse the incidence trend of viral hepatitis A by region and age group in mainland China from 2004 to 2017 to evaluate the effectiveness of prevention and control measures. METHODS: Data on hepatitis A and population information were collected and analysed with a joinpoint regression model. Annual percentage changes (APCs) and average annual percentage changes (AAPCs) were estimated for the whole country and for each region and age group. RESULTS: From 2004 to 2017, the seasonality and periodicity of hepatitis A case numbers were obvious before 2008 but gradually diminished from 2008 to 2011 and disappeared from 2012-2017. The national incidence of hepatitis A (AAPC = - 12.1%) and the incidence rates for regions and age groups showed decreasing trends, with differences in the joinpoints and segments. Regarding regions, the hepatitis A incidence in the western region was always the highest among all regions, while a nonsignificant rebound was observed in the northeastern region from 2011 to 2017 (APC = 14.2%). Regarding age groups, the hepatitis A incidence showed the fastest decrease among children (AAPC = - 15.3%) and the slowest decrease among elderly individuals (AAPC = - 6.6%). Among all segments, the hepatitis A incidence among children had the largest APC value in 2007-2017, at - 20.4%. CONCLUSION: The national annual incidence of hepatitis A continually declined from 2004 to 2017 and the gaps in hepatitis A incidence rates across different regions and age groups were greatly narrowed. Comprehensive hepatitis A prevention and control strategies, including the use of routine vaccination during childhood in mainland China, especially the implementation of the national Expanded Program on Immunization (EPI) in 2008, resulted in substantial progress from 2004 to 2017. However, gaps remain. Regular monitoring and analysis of hepatitis A epidemic data and prompt adjustment of hepatitis A prevention and control strategies focusing on children, elderly individuals and those living in certain regions are recommended.

Ribonuclease 7-driven activation of ROS1 is a potential therapeutic target in hepatocellular carcinoma.

BACKGROUND & AIMS: There are currently limited therapeutic options for hepatocellular carcinoma (HCC), particularly when it is diagnosed at advanced stages. Herein, we examined the pathophysiological role of ROS1 and assessed the utility of ROS1-targeted therapy for the treatment of HCC. METHODS: Recombinant ribonucleases (RNases) were purified, and the ligand-receptor relationship between RNase7 and ROS1 was validated in HCC cell lines by Duolink, immunofluorescence, and immunoprecipitation assays. Potential interacting residues between ROS1 and RNase7 were predicted using a protein-protein docking approach. The oncogenic function of RNase7 was analyzed by cell proliferation, migration and invasion assays, and a xenograft mouse model. The efficacy of anti-ROS1 inhibitor treatment was evaluated in patient-derived xenograft (PDX) and orthotopic models. Two independent patient cohorts were analyzed to evaluate the pathological relevance of RNase7/ROS1. RESULTS: RNase7 associated with ROS1's N3-P2 domain and promoted ROS1-mediated oncogenic transformation. Patients with HCC exhibited elevated plasma RNase7 levels compared with healthy individuals. High ROS1 and RNase7 expression were strongly associated with poor prognosis in patients with HCC. In both HCC PDX and orthotopic mouse models, ROS1 inhibitor treatment markedly suppressed RNase7-induced tumorigenesis, leading to decreased plasma RNase7 levels and tumor shrinkage in mice. CONCLUSIONS: RNase7 serves as a high-affinity ligand for ROS1. Plasma RNase7 could be used as a biomarker to identify patients with HCC who may benefit from anti-ROS1 treatment. LAY SUMMARY: Receptor tyrosine kinases are known to be involved in tumorigenesis and have been targeted therapeutically for a number of cancers, including hepatocellular carcinoma. ROS1 is the only such receptor with kinase activity whose ligand has not been identified. Herein, we show that RNase7 acts as a ligand to activate ROS1 signaling. This has important pathophysiological and therapeutic implications. Anti-ROS1 inhibitors could be used to treatment patients with hepatocellular carcinoma and high RNase7 levels.