Functional polarization of tumour-associated macrophages by tumour-derived lactic acid.

Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their 'client cells': namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth. However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1α (HIF1α). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth.

Effect of a Home Health and Safety Intervention on Emergency Department Use in the Frail Elderly: A Prospective Observational Study.

INTRODUCTION: Geriatric patients are often frail and may lose independence through a variety of mechanisms including cognitive decline, reduced mobility, and falls. Our goal was to measure the effect of a multidisciplinary home health program that assessed frailty and safety and then coordinated ongoing delivery of community resources on short-term, all-cause emergency department (ED) utilization across three study arms that attempted to stratify frailty by fall risk. METHODS: Subjects became eligible for this prospective observational study via one of three pathways: 1) by visiting the ED after a fall (2,757 patients); 2) by self-identifying as at risk for falling (2,787); or 3) by calling 9-1-1 for a "lift assist" after falling and being unable to get up (121). The intervention consisted of sequential home visits by a research paramedic who used standardized assessments of frailty and risk of falling (including providing home safety guidance), and a home health nurse who aligned resources to address the conditions found. Outcomes of interest were all-cause ED utilization at 30, 60, and 90 days post-intervention compared with subjects who enrolled via the same study pathway but declined the study intervention (controls). RESULTS: Subjects in the fall-related ED visit arm were significantly less likely to have one or more subsequent ED encounters post-intervention than controls at 30 days (18.2% vs 29.2%, P<0.001); 60 days (27.5% vs 39.8%, P<0.001); and 90 days (34.6% vs 46.2%, P<0.001). In contrast, participants in the self-referral arm had no difference in ED encounters post-intervention compared to controls at 30, 60, or 90 days (P=0.30, 0.84, and 0.23, respectively). The size of the 9-1-1 call arm limited statistical power for analysis. CONCLUSION: A history of a fall requiring ED evaluation appeared to be a useful marker of frailty. Subjects recruited through this pathway experienced less all-cause ED utilization over subsequent months after a coordinated community intervention than without it. The participants who only self-identified as at risk for falling had lower rates of subsequent ED utilization than those recruited in the ED after a fall and did not significantly benefit from the intervention.

Ethical Considerations in Therapeutic Clinical Trials Involving Novel Human Germline-Editing Technology.

Much of the international community opposes editing the human germline. Yet, given enough experience to become better acquainted with strengths and limitations, prominent international figures are cautiously optimistic about using CRISPR-like novel technologies for clinical applications. Not only might such applications be morally (ethically) permissible, but clinical trials for therapeutic aims could be necessary. Here, we assess critical dimensions of early-phase trials deploying germline-editing technologies for "bench-to-bedside" translation. While assuming no overarching position favoring or opposing such research, our discussion primarily focuses on normative considerations. First, we evaluate the imperative of conducting trials to produce reliable, reproducible knowledge and advancement, if possible, for human diseases that are incurable and/or whose treatments are deficient. Second, we address complexities in assessing risk and potential-benefit profiles. Third, we review the moral foundations of trial participation through well-established and accepted bioethical principles: autonomy, nonmaleficence, beneficence, and distributive justice. Finally, we raise critical questions about the scope of regulatory authority and investigator and funder accountability for these applications that could have everlasting impacts.

Reactions to the National Academies/Royal Society Report on Heritable Human Genome Editing.

In September 2020, a detailed report on Heritable Human Genome Editing was published. The report offers a translational pathway for the limited approval of germline editing under limited circumstances and assuming various criteria have been met. In this perspective, some three dozen experts from the fields of genome editing, medicine, bioethics, law, and related fields offer their candid reactions to the National Academies/Royal Society report, highlighting areas of support, omissions, disagreements, and priorities moving forward.

CRISPR Ethics: Moral Considerations for Applications of a Powerful Tool.

With the emergence of CRISPR technology, targeted editing of a wide variety of genomes is no longer an abstract hypothetical, but occurs regularly. As application areas of CRISPR are exceeding beyond research and biomedical therapies, new and existing ethical concerns abound throughout the global community about the appropriate scope of the systems' use. Here we review fundamental ethical issues including the following: 1) the extent to which CRISPR use should be permitted; 2) access to CRISPR applications; 3) whether a regulatory framework(s) for clinical research involving human subjects might accommodate all types of human genome editing, including editing of the germline; and 4) whether international regulations governing inappropriate CRISPR utilization should be crafted and publicized. We conclude that moral decision making should evolve as the science of genomic engineering advances and hold that it would be reasonable for national and supranational legislatures to consider evidence-based regulation of certain CRISPR applications for the betterment of human health and progress.

Human keratinocyte carcinomas have distinct differences in their tumor-associated macrophages.

Cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) have different clinical behaviors, despite both being keratinocyte carcinomas mainly caused by ultraviolet radiation. Whether these distinct features are associated with tumor-associated macrophages (TAMs) is largely unknown. The main goal of this study was to conduct a comprehensive analysis of density and polarization states of TAMs in SCCs versus BCCs. The role of lactic acid in TAM polarization in SCC versus BCC was examined. We found that SCCs have a higher density of CD68 + TAMs compared to BCCs. TAMs in SCCs express higher levels of TAM-associated markers (arginase-1, MMP9, CD40 and CD127) than those in BCCs. Interestingly, differential expression of TAM-associated markers between SCCs and BCCs was reproduced in human monocytic THP-1 cells stimulated with SCC- or BCC-conditioned media. Analysis of soluble factor(s) in these tumors further revealed that SCCs have a significantly higher concentration of lactic acid than BCCs, and lactic acid was sufficient to upregulate TAM markers. Our results demonstrate that TAMs in SCCs versus BCCs differ in density and polarization states, which can be determined by soluble factors including tumor-derived lactic acid. These differences in TAMs may contribute to the distinct clinical behaviors of SCCs versus BCCs. This work was supported by grants from the National Institutes of Health and the Doris Duke Charitable Foundation. RESEARCH IN CONTEXT: Few studies have studied tumor-associated macrophages in the context of SCC versus BCC. It has been demonstrated that macrophages mobilize to the epidermis after being exposed to ultraviolet-B radiation and produce interleukin-10 (IL-10). It has also been shown that the production of IL-10 results in the evasion of T cell-mediated immunity in BCCs and SCCs. However, the relationship between TAMs and the clinical behaviors of SCCs and BCCs remains largely unclear. Our study shows that despite their similar origins, human cutaneous SCCs and BCCs are considerably different in their TAMs. To our knowledge, these results provide the first evidence of differential TAM density and polarization in SCCs versus BCCs, which may contribute to their characteristic clinical behaviors. Future studies are necessary to elucidate the mechanisms by which TAMs influence these cancers with the goal of developing therapies tailored to each type of malignancy.

Do CRISPR Germline Ethics Statements Cut It?

The extraordinary wave of genomic-engineering innovation, driven by CRISPR-Cas9, has sparked worldwide scientific and ethical uncertainty. Great concern has arisen across the globe about whether heritable genome editing should be permissible in humans-that is, whether it is morally acceptable to modify genomic material such that the "edit" is transferable to future generations. Here I examine 61 ethics statements released by the international community within the past 3 years about this controversial issue and consider the statements' overarching positions and limitations. Despite their inability to fully address all important considerations, many of the statements may advance debate and national and international law and public policy.