Explore the vast range of titles available.

ObjectiveHepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy.DesignNeutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry.ResultsNeutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1+ dendritic cell activation and CD8+ T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8+ T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8+ T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs.ConclusionCXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC.

The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context. Here, we used several mouse models of spontaneous and inflammation-driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors. CXCR2-activating chemokines were part of the secretome of cultured primary benign intestinal adenomas (ApcMin/+) and highly expressed by all tumors in all models. CXCR2 deficiency profoundly suppressed inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation in a model of invasive intestinal adenocarcinoma (AhCreER;Apcfl/+;Ptenfl/fl mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in ApcMin/+ mice. Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment. Moreover, systemic Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced ApcMin/+ adenoma formation. CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation. Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer.

Oncogenic mutations in the K-ras gene occur in ≈50% of human colorectal cancers. However, the precise role that K-ras oncogenes play in tumor formation is still unclear. To address this issue, we have conditionally expressed an oncogenic$K-ras^{v12}$allele in the small intestine of adult mice either alone or in the context of Apc deficiency. We found that expression of$K-ras^{v12}$does not affect normal intestinal homeostasis or the immediate phenotypes associated with Apc deficiency. Mechanistically we failed to find activation of the Raf/MEK/ERK pathway, which may be a consequence of the up-regulation of a number of negative feedback loops. However,$K-ras^{v12}$expression accelerates intestinal tumorigenesis and confers invasive properties after Apc loss over the long term. In renal epithelium, expression of the oncogenic$K-ras^{V12}$allele in the absence of Apc induces the rapid development of renal carcinoma. These tumors, unlike those of intestinal origin, display activation of the Raf/MEK/ERK and Akt signaling pathways. Taken together, these data indicate that normal intestinal and kidney epithelium are resistant to malignant transformation by an endogenous K-ras oncogene. However, activation of$K-ras^{v12}$after Apc loss results in increased tumorigenesis with distinct kinetics. Whereas the effect of K-ras oncogenes in the intestine can been observed only after long latencies, they result in rapid carcinogenesis in the kidney epithelium. These data imply a window of opportunity for anti-K-ras therapies after tumor initiation in preventing tumor growth and invasion.

How the inflammatory response is initiated has been well defined but relatively little is known about how such responses are resolved. Here we show that the D6 chemokine receptor is involved in the post-inflammatory clearance of β-chemokines from cutaneous sites. After induction of inflammation by phorbol esters, wild-type mice showed a transient inflammatory response. However, in D6-deficient mice, an excess concentration of residual chemokines caused a notable inflammatory pathology with similarities to human psoriasis. These results suggest that D6 is involved in the resolution of the cutaneous inflammatory response.

Hepatocytes and cholangiocytes self-renew following liver injury. Following severe injury hepatocytes are increasingly senescent, but whether hepatic progenitor cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where the E3 ubiquitin ligase Mdm2 is inducibly deleted in more than 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution. HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro . These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease. Forbes and colleagues report on a population of hepatic progenitor cells that regenerate the adult liver in a mouse model where more than 98% of all hepatocytes are irreversibly damaged.

The mTORC1 complex has been implicated in tumorigenesis owing partially to its ability to increase protein translation; now, mTORC1 activity in the mouse intestine is shown not to be required for normal homeostasis but to be necessary for the triggering of tumorigenesis by APC mutations, suggesting that it could be a good target for the prevention of colorectal cancer in high-risk patients. How mTORC sustains tumour growth The mTORC1 complex, a protein kinase complex found in all eukaryotic cells, has been implicated in tumorigenesis because it is known to stimulate protein translation. The main effector pathway downstream of mTORC1 is thought to be 4EBP1, which promotes initiation of translation. William Faller et al . now show that in the mouse intestine, mTORC1 activity is not required for normal homeostasis, but is absolutely required for intestinal tumour formation triggered by APC tumour suppressor gene mutations. The authors identify increased translational elongation downstream of S6 kinase via the elongation factor eEF2 as a requirement for proliferation in APC-deficient but not normal cells. This suggests that translational elongation, rather than initiation, is limiting to cancer cell proliferation in vivo . These findings raise the possibility that targeting mTORC1 signalling may be beneficial in prevention of colorectal cancers in high-risk patients. Inactivation of APC is a strongly predisposing event in the development of colorectal cancer 1 , 2 , prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth 3 , 4 , 5 , and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6 , 7 ). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8 ), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc -deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1–S6K–eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.

In many situations, incentives exist to acquire knowledge and make correct political decisions. We conduct an experiment that contributes to a small but growing literature on incentives and political knowledge, testing the effect of certain and uncertain incentives on knowledge. Our experiment builds on the basic theoretical point that acquiring and using information is costly, and incentives for accurate answers will lead respondents to expend greater effort on the task and be more likely to answer knowledge questions correctly. We test the effect of certain and uncertain incentives and find that both increase effort and accuracy relative to the control condition of no incentives for accuracy. Holding constant the expected benefit of knowledge, we do not observe behavioral differences associated with the probability of earning an incentive for knowledge accuracy. These results suggest that measures of subject performance in knowledge tasks are contingent on the incentives they face. Therefore, to ensure the validity of experimental tasks and the related behavioral measures, we need to ensure a correspondence between the context we are trying to learn about and our experimental design.

To eliminate climate gas emissions from aluminum electrolysis, modifying a cryolite-based electrolyte partly replacing Na with K reduces liquidus, allowing a process temperature of 800°C. This enables the use of various metallic alloys for oxygen-evolving inert anode technology. This alternative process requires a higher energy efficiency to compensate for an increased reaction voltage, which highlights the importance of evaluating the kinetics and overpotential on oxygen-evolving anodes. This study evaluates anodic overpotentials using steady-state polarization on platinum and three Ni-Fe-Cu-based alloy compositions in a KF-NaF-AlF3-Al203(sat.) electrolyte at 800°C. The polarization curve on the platinum anode reveals two linear Tafel regions, while Ni-Fe-Cu anodes exhibit a single Tafel region. Notably, Ni-Fe-Cu anodes treated with high-temperature air oxidation to develop a preformed oxide layer exhibit better electrocatalytic activity than untreated anodes of corresponding composition. The kinetic equations, based on a theoretical model for the proposed mechanism of the oxygen evolution reaction, are derived and utilized to simulate overpotential and current, taking into account surface coverage. This model accurately predicts the two experimentally observed Tafel regions on the platinum anode, indicating a two-step charge transfer-controlled mechanism. We illustrate that multiple Tafel slopes can be attributed to the potential-dependent surface coverage of an adsorbate and can be correlated with the particular rate-determining step.

Previous research demonstrates that pandemics, including COVID-19, have disproportionate effects on communities of color, further exacerbating existing healthcare inequities. While increasing evidence points to the greater threat posed by COVID-19 to Latinx communities, less remains known about how identification as Latinx and migration status influence their perception of risk and harm. In this article, we use cross-sectional data from a large national probability sample to demonstrate a large positive association between ethnic identity and migration status and perceptions of harm from COVID-19 in the US. We find that individuals identifying as Hispanic/Latinx and first-generation immigrants report significantly greater risks of becoming infected by COVID-19 in the next three months, and dying from the virus if they do contract it. Further, subgroup analysis reveals that health risks are especially felt by individuals of Mexican descent, who represent the largest share of US Latinxs. Collectively, our results provide evidence about how the pandemic places increased stress on people from Latinx and immigrant communities relative to White non-Hispanic individuals in the US.

To eliminate climate gas emissions from aluminum electrolysis, modifying a cryolite-based electrolyte partly replacing Na with K reduces liquidus, allowing a process temperature of 800°C. This enables the use of various metallic alloys for oxygen-evolving inert anode technology. This alternative process requires a higher energy efficiency to compensate for an increased reaction voltage, which highlights the importance of evaluating the kinetics and overpotential on oxygen-evolving anodes. This study evaluates anodic overpotentials using steady-state polarization on platinum and three Ni-Fe-Cu-based alloy compositions in a KF-NaF-AlF 3 -Al 2 O 3 (sat.) electrolyte at 800°C. The polarization curve on the platinum anode reveals two linear Tafel regions, while Ni-Fe-Cu anodes exhibit a single Tafel region. Notably, Ni-Fe-Cu anodes treated with high-temperature air oxidation to develop a pre-formed oxide layer exhibit better electrocatalytic activity than untreated anodes of corresponding composition. The kinetic equations, based on a theoretical model for the proposed mechanism of the oxygen evolution reaction, are derived and utilized to simulate overpotential and current, taking into account surface coverage. This model accurately predicts the two experimentally observed Tafel regions on the platinum anode, indicating a two-step charge transfer-controlled mechanism. We illustrate that multiple Tafel slopes can be attributed to the potential-dependent surface coverage of an adsorbate and can be correlated with the particular rate-determining step.