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Biochar greatly influences the soil bacterial community and nutrient transformations, while our knowledge of the responses of fungal lifestyles to biochar is still in its infancy. Here, we used experimental pre-treatments (acetone extraction) of nutrient-rich biochars to identify which major biochar properties influence fungi the most: the easily mineralizable C, fused aromatic backbone, or the inorganic nutrients of biochars. Our objective was to investigate how different biochar fractions (easily mineralizable C, fused aromatic C, nutrients) structure the fungal taxonomic and functional communities. The easily mineralizable C of biochars induced greater short-term changes in fungal community composition compared to the fused aromatic C. The easily mineralizable C significantly decreased the relative abundance of Basidiomycota by avg. 10.6%, while it had no effects on Ascomycota and Zygomycota. Co-occurrence network indicated that saprophytic fungi were self-assembled in the easily mineralizable C-sufficient environment, whereas they were the connectors to interact with other groups when lower amounts of energy in form of mineralizable C were present. Thus, the easily mineralizable C in biochar as a microbial C source probably promoted saprotroph growth, caused them to self-assemble and to enhance their competitive capacity, leading to overall diversity decrease and relative decline of fungal pathogens. The inorganic nutrients had no effects on fungal diversity and saprotroph abundance, while they decreased the relative abundance of Zygomycota. Our study highlighted the important roles of both mineralizable C and inorganic nutrients in modification of the fungal community, and demonstrated that biochar probably favors the growth of saprotrophs over soil-borne fungal pathogens.

Background and Aims: The chemical carcinogen diethylnitrosamine (DEN) is often used to induce HCC in mice. Curiously, several labs have reported that the removal of oncoproteins from hepatocytes exacerbated DEN-induced HCC, with mechanisms unknown. This study aimed at deciphering molecular mechanisms underlying the tumor suppressive effect of oncoproteins., Approach and Results: We generated mutant mouse lines with hepatocyte-specific deletions of Met, Ptpn11/Shp2, Ikkβ, or Ctnnb1/β-catenin and assessed DEN-induced tumorigenesis in the wild-type and mutant mice. To systematically examine genetic and molecular signaling alterations, we performed whole exome and RNA-sequencing on liver samples collected at the pre-cancer and established cancer stages. Although the mutational profiles of DEN-induced tumors were barely different in wild-type and mutant mice, oncoprotein ablation increased DEN-induced mutational burdens, especially in Shp2-deficient tumors. RNA-sequencing revealed multiple changes in signaling pathways, in particular, upregulated epithelial-mesenchymal transition, cell migration, and tumor metastasis, as well as downregulated small molecule metabolism that was affected by oncoprotein ablation. We identified key molecules and pathways that are associated with hepatic innate immunity and implicated in liver tumorigenesis. In addition, we unveiled markedly changed expression of a few miRNAs in the human HCC database., Conclusions: The aggravation of DEN-induced HCC progression seen on oncoprotein ablation could be caused by common and distinct genomic and signaling alterations. This study reveals a new level of complexity in hepatocarcinogenesis and elucidates molecular mechanisms underlying tumor evolution and recurrence., (Copyright © 2024 American Association for the Study of Liver Diseases.)

The Ras/Erk and NF-κB pathways play critical roles in cell proliferation and are known to drive oncogenesis when overactivated. Herein we report a gatekeeper function of the two pathways by working in synergy to suppress liver tumorigenesis. Hepatocyte-specific deletion of both Shp2/Ptpn11 and Ikkβ in mice, which promote Ras/Erk and NF-κB signaling, respectively, exacerbated chemical carcinogenesis and even triggered spontaneous development of hepatocellular carcinoma (HCC). We show that the unanticipated severe tumor phenotype was contributed collectively by severe cholestasis, metabolic changes, upregulated cell-cycle progression, and disruption of circadian rhythm in mutant hepatocytes. Remarkably, human HCCs with dysregulated circadian gene expression displayed downregulation of Ras/Erk and NF-κB signaling and poor prognosis. Together, these data indicate that at the ground state, the two central pathways, previously known as oncogenic, cooperate to sustain tumor-suppressive physiologic homeostasis and to prevent hepatic damage. Disruption of this intricate signaling network is carcinogenic in the liver., Implications: We demonstrate here that basal levels of the Ras/MAPK and NF-κB pathways, while promoting tumorigenesis if overactivated, are required to maintain physiologic homeostasis and regulate circadian rhythm in the liver, which are antitumorigenic., (©2021 American Association for Cancer Research.)

The mechanisms of Myc-driven liver tumorigenesis are inadequately understood. Herein we show that Myc-driven hepatocellular carcinoma (HCC) is dramatically aggravated in mice with hepatocyte-specific Ptpn11/Shp2 deletion. However, Myc-induced tumors develop selectively from the rare Shp2-positive hepatocytes in Shp2-deficent liver, and Myc-driven oncogenesis depends on an intact Ras-Erk signaling promoted by Shp2 to sustain Myc stability. Despite a stringent requirement of Shp2 cell autonomously, Shp2 deletion induces an immunosuppressive environment, resulting in defective clearance of tumor-initiating cells and aggressive tumor progression. The basal Wnt/β-catenin signaling is upregulated in Shp2-deficient liver, which is further augmented by Myc transfection. Ablating Ctnnb1 suppresses Myc-induced HCC in Shp2-deficient livers, revealing an essential role of β-catenin. Consistently, Myc overexpression and CTNNB1 mutations are frequently co-detected in HCC patients with poor prognosis. These data elucidate complex mechanisms of liver tumorigenesis driven by cell-intrinsic oncogenic signaling in cooperation with a tumor-promoting microenvironment generated by disrupting the specific oncogenic pathway., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is a most deadly malignant disease worldwide, with no effective mechanism-based therapy available. Therefore, following the "miracle" outcomes seen in a few patients at the advanced stages of melanoma or lung cancer, the immune checkpoint inhibitors (ICIs) immediately entered clinical trials for advanced HCC patients without pre-clinical studies. Emerging data of clinical studies showed manageable toxicity and safety but limited therapeutic benefit to HCC patients, suggesting low response rate. Thus, one urgent issue is how to convert the liver tumors from cold to hot and responsive, which may rely on in-depth mechanistic studies in animal models and large scale data analysis in human patients. One ongoing approach is to design combinatorial treatment of different ICIs with other reagents and modalities. Indeed, a phase 3 clinical trial showed that combination of atezolizumab and bevacizumab achieved better overall and progression-free survival rates than sorafenib in unresectable HCC. This review highlights the value of animal models and the power of combining pre-clinical and clinical studies in efforts to improve HCC immunotherapy., (© 2020 by the American Association for the Study of Liver Diseases.)

The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH) and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation and elevated ROS and inflammation in the hepatic microenvironment. Inhibiting cJun partially suppressed NASH-driven liver tumorigenesis without improving NASH. SHP2 and PTEN deficiencies were detected in liver cancer patients with poor prognosis. These data depict a mechanism of hepato-oncogenesis and suggest a potential therapeutic strategy., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

This study underpins quantitative relationships that account for the combined effects that starting biomass and peak pyrolysis temperature have on physico-chemical properties of biochar. Meta-data was assembled from published data of diverse biochar samples (n=102) to (i) obtain networks of intercorrelated properties and (ii) derive models that predict biochar properties. Assembled correlation networks provide a qualitative overview of the combinations of biochar properties likely to occur in a sample. Generalized Linear Models are constructed to account for situations of varying complexity, including: dependence of biochar properties on single or multiple predictor variables, where dependence on multiple variables can have additive and/or interactive effects; non-linear relation between the response and predictors; and non-Gaussian data distributions. The web-tool Biochar Engineering implements the derived models to maximize their utility and distribution. Provided examples illustrate the practical use of the networks, models and web-tool to engineer biochars with prescribed properties desirable for hypothetical scenarios., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Some patients with chronic pain who are intolerant of or refractory to treatment with systemic analgesics may benefit from intrathecal therapy. Ziconotide is the first nonopioid analgesic approved by the United States Food and Drug Administration for intrathecal administration. Several randomized, double-blind, placebo-controlled clinical trials have demonstrated the efficacy and safety of ziconotide. However, the maximum recommended dosing and titration schedule provided in the prescribing information may be too aggressive for some patients, and experience has demonstrated that ziconotide is better tolerated with slower titration to a lower maximum dose. Efficacy can be assessed by an evaluation of changes in pain, functionality, and quality of life. Cognitive adverse events may be subtle; therefore, it is important that health care professionals not only monitor patients for signs and symptoms of cognitive adverse events, but also teach family members how to do the same. Careful patient assessment and monitoring can help optimize the potential benefit from treatment with ziconotide., (Copyright © 2013 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.)