Pregnancy: a stepping-stone to sepsis

The physiological shifts during pregnancy predispose women to a ten-fold higher risk of developing sepsis, a life-threatening condition characterised by a maladapted host-response to infection. We present a comprehensive synthesis of maternal immunity during pregnancy, addressing whether altered set-points in immune homeostasis lower the tipping point for sepsis. This close interconnection between maternal immunity and sepsis makes clinical diagnosis highly challenging and translates to delayed antibiotics or overuse. We propose further understanding of the maternal immune set-point changes are vital for tailoring the right diagnostic tools for maternal sepsis and may unravel pathophysiological pathways that predispose an individual to sepsis.

Off-tumor IDO1 target engagements determine the cancer-immune set point and predict the immunotherapeutic efficacy

BackgroundIndoleamine-2,3-dioxygenase 1 (IDO1) has been intensively pursued as a therapeutic target to reverse the immunosuppressive cancer-immune milieu and promote tumor elimination. However, recent failures of phase III clinical trials with IDO1 inhibitors involved in cancer immunotherapies highlight the urgent need to develop appropriate methods for tracking IDO1 when the cancer-immune milieu is therapeutically modified.MethodsWe utilized a small-molecule radiotracer, 11C-l-1MTrp, to quantitatively and longitudinally visualize whole-body IDO1 dynamics. Specifically, we first assessed 11C-l-1MTrp in mice-bearing contralateral human tumors with distinct IDO1 expression patterns. Then, we applied 11C-l-1MTrp to longitudinally monitor whole-body IDO1 variations in immunocompetent melanoma-bearing mice treated with 1-methyl-l-tryptophan plus either chemotherapeutic drugs or antibodies targeting programmedcell death 1 and cytotoxic T-lymphocyte-associated protein 4.Results11C-l-1MTrp positron emission tomography (PET) imaging accurately delineated IDO1 expression in xenograft mouse models. Moreover, we were able to visualize dynamic IDO1 regulation in the mesenteric lymph nodes (MLNs), an off-tumor IDO1 target, where the percentage uptake of 11C-l-1MTrp accurately annotated the therapeutic efficacy of multiple combination immunotherapies in preclinical models. Remarkably, 11C-l-1MTrp signal intensity in the MLNs was inversely related to the specific growth rates of treated tumors, suggesting that IDO1 expression in the MLNs can serve as a new biomarker of the cancer-immune set point.ConclusionsPET imaging of IDO1 with 11C-l-1MTrp is a robust method to assess the therapeutic efficacy of multiple combinatorial immunotherapies, improving our understanding of the merit and challenges of IDO1 regimens. Further validation of this animal data in humans is ongoing. We envision that our results will provide a potential precision medicine paradigm for noninvasive visualizing each patient’s individual response in combinatorial cancer immunotherapy, and tailoring optimal personalized combination strategies.

THE COMPUTATIONAL CONTENT OF INTRINSIC DENSITY

In a previous article, the author introduced the idea of intrinsic density—a restriction of asymptotic density to sets whose density is invariant under computable permutation. We prove that sets with well-defined intrinsic density (and particularly intrinsic density 0) exist only in Turing degrees that are either high (${\bf{a}}\prime { \ge _{\rm{T}}}\emptyset \prime \prime$) or compute a diagonally noncomputable function. By contrast, a classic construction of an immune set in every noncomputable degree actually yields a set with intrinsic lower density 0 in every noncomputable degree.We also show that the former result holds in the sense of reverse mathematics, in that (over RCA0) the existence of a dominating or diagonally noncomputable function is equivalent to the existence of a set with intrinsic density 0.