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Lighting interventions can mitigate fatigue by promoting circadian rhythmicity. We test whether individualized, wearable-based lighting interventions delivered via a mobile app reduce cancer-related fatigue in a randomized controlled trial with 138 breast cancer, prostate cancer, and hematopoietic stem cell transplant patients. Participants are randomized to tailored lighting intervention or control. The primary endpoint is PROMIS fatigue 4a at trial end, with secondary endpoints including change in daily fatigue, sleep, anxiety, depression, physical function, and overall health. Fatigue T-scores at week 11 do not differ between groups but decrease significantly from week 1 to week 11 (3.07 points, p = 0.001) in the intervention group, with a significant final-week treatment effect (p = 0.014). Daily fatigue, anxiety, sleep disturbance, and physical function improve within intervention. Further studies are needed to see if these results generalize in broader cancer care. The trial is registered at ClinicalTrials.gov (trial registration number: NCT04827446)., Competing Interests: Declaration of interests O.W. has given talks at Unilever events and received honorariums/travel expenses; she has also done consulting for Gideon Health. She is the CEO of Arcascope, a company that makes circadian rhythm software. D.B.F. is the CSO of Arcascope. D.B.F. and the University of Michigan are part owners of Arcascope. N.L.H. has received institutional support for the conduct of a clinical trial (Blue Note Therapeutics), receives royalties from UpToDate, and has consulted for AstraZeneca and Myovant Sciences. Z.R.R. has received institutional support from AstraZeneca and consulted for AstraZeneca and Johnson and Johnson., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

The extracellular RNA communication consortium (ERCC) is an NIH-funded program aiming to promote the development of new technologies, resources, and knowledge about exRNAs and their carriers. After Phase 1 (2013-2018), Phase 2 of the program (ERCC2, 2019-2023) aims to fill critical gaps in knowledge and technology to enable rigorous and reproducible methods for separation and characterization of both bulk populations of exRNA carriers and single EVs. ERCC2 investigators are also developing new bioinformatic pipelines to promote data integration through the exRNA atlas database. ERCC2 has established several Working Groups (Resource Sharing, Reagent Development, Data Analysis and Coordination, Technology Development, nomenclature, and Scientific Outreach) to promote collaboration between ERCC2 members and the broader scientific community. We expect that ERCC2's current and future achievements will significantly improve our understanding of exRNA biology and the development of accurate and efficient exRNA-based diagnostic, prognostic, and theranostic biomarker assays., Competing Interests: Crislyn D’Souza-Schorey, Satyajyoti Senapati and Hsueh-Chia Chang hold equity in AgenDx Biosciences. Hsueh-Chia Chang is a cofounder of Aopia Biosciences and holds equity. Daniel T. Chiu has financial interest and is a scientific founder and/or board member of the following companies and their respective affiliates: Micareo, Inc, Lamprogen, Inc, Cellectricon AB, and Fluicell AB. Saumya Das is a founding member of Dyrnamix Inc. that did not play any role in this study. Kendal Van Keuren-Jensen is a board member of Dyrnamix Inc. and HTG that did not play any role in this study. Aleksandar Milosavljevic is a founder of IP Genesis, Inc. that did not play any role in this study. Louise C. Laurent has stock in Illumina, Inc. Anil K. Sood has the following disclosures: Consultant (Merck, Kiyatec), shareholder (BioPath), research funding (MTrap). John Nolan holds equity in Cellarcus Biosciences Inc. L. James Lee holds equity at Spot Biosystems. David A. Routenberg, Sigal Shachar and Alexander K. Tucker-Schwartz are employees of Meso Scale Diagnostics, LLC. Andrey Turchinovich is founder of SciBerg e.Kfm, Mannheim, Germany. Angela M. Zivkovic is cofounder and board member at Innate Biology, Inc., (© 2022 The Author(s).)

Consumer-grade wearables are needed to track disease, especially in the ongoing pandemic, as they can monitor patients in real time. We show that decomposing heart rate from low-cost wearable technologies into signals from different systems can give a multidimensional description of physiological changes due to COVID-19 infection. We find that the separate physiological features of basal heart rate, heart rate response to physical activity, circadian variation in heart rate, and autocorrelation of heart rate are significantly altered and can classify symptomatic versus healthy periods. Increased heart rate and autocorrelation begin at symptom onset, while the heart rate response to activity increases soon after symptom onset and increases more in individuals exhibiting cough. Symptom onset is associated with a blunting of circadian variation in heart rate, as measured by the uncertainty in the phase estimate. This work establishes an innovative data analytic approach to monitor disease progression remotely using consumer-grade wearables., Competing Interests: D.B.F. is the CSO of Arcascope, a company that makes circadian rhythms software. Both he and the University of Michigan are part owners of Arcascope. S.W.C., D.B.F., C.M., and M.T. receive research funding from an Arcascope NIH SBIR grant for a different research project. However, Arcascope did not sponsor the research presented herein. S.S. received Fitbit devices at reduced cost for the Intern Health Study. J.T., C.M., D.B.F., S.W.C., M.T. S.S., Y.F., and C.F. are inventors of intellectual property related to this work, for which the University of Michigan is pursuing intellectual property protections., (© 2022 The Authors.)

Immune checkpoint inhibitors (ICIs) have been a transformational advance in cancer therapy in the past decade. However, ICIs can produce immune-related adverse effects (irAEs), which can lead to both morbidity and premature termination of therapy. Recent studies suggest that the gut microbiota and its metabolites affect ICI efficacy and toxicity. Herein, we review such evidence in the context of ICI-induced colitis. In particular, the short-chain fatty acid butyrate, a microbial metabolite, has known protective effects on the intestine. We discuss how the use of dietary prebiotics, which can be metabolized by bacteria to produce butyrate, can be an intriguing new investigational approach to prevent ICI-associated colitis and lead to improved patient outcomes., Competing Interests: Declaration of Interests No interests are declared., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Whether cell forces or extracellular matrix (ECM) can impact genome integrity is largely unclear. Here, acute perturbations (∼1 h) to actomyosin stress or ECM elasticity cause rapid and reversible changes in lamin-A, DNA damage, and cell cycle. The findings are especially relevant to organs such as the heart because DNA damage permanently arrests cardiomyocyte proliferation shortly after birth and thereby eliminates regeneration after injury including heart attack. Embryonic hearts, cardiac-differentiated iPS cells (induced pluripotent stem cells), and various nonmuscle cell types all show that actomyosin-driven nuclear rupture causes cytoplasmic mis-localization of DNA repair factors and excess DNA damage. Binucleation and micronuclei increase as telomeres shorten, which all favor cell-cycle arrest. Deficiencies in lamin-A and repair factors exacerbate these effects, but lamin-A-associated defects are rescued by repair factor overexpression and also by contractility modulators in clinical trials. Contractile cells on stiff ECM normally exhibit low phosphorylation and slow degradation of lamin-A by matrix-metalloprotease-2 (MMP2), and inhibition of this lamin-A turnover and also actomyosin contractility are seen to minimize DNA damage. Lamin-A is thus stress stabilized to mechano-protect the genome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Marrow-derived macrophages are highly phagocytic, but whether they can also traffic into solid tumors and engulf cancer cells is questionable, given the well-known limitations of tumor-associated macrophages (TAMs). Here, SIRPα on macrophages from mouse and human marrow was inhibited to block recognition of its ligand, the "marker of self" CD47 on all other cells. These macrophages were then systemically injected into mice with fluorescent human tumors that had been antibody targeted. Within days, the tumors regressed, and single-cell fluorescence analyses showed that the more the macrophages engulfed, the more they accumulated within regressing tumors. Human-marrow-derived macrophages engorged on the human tumors, while TAMs were minimally phagocytic, even toward CD47-knockdown tumors. Past studies had opsonized tumors in situ with antibody and/or relied on mouse TAMs but had not injected SIRPα-inhibited cells; also, unlike past injections of anti-CD47, blood parameters remained normal and safe. Consistent with tumor-selective engorge-and-accumulate processes in vivo, phagocytosis in vitro inhibited macrophage migration through micropores that mimic features of dense 3D tissue. Accumulation of SIRPα-inhibited macrophages in tumors favored tumor regression for 1-2 weeks, but donor macrophages quickly differentiated toward non-phagocytic, high-SIRPα TAMs. Analyses of macrophages on soft (like marrow) or stiff (like solid tumors) collagenous gels demonstrated a stiffness-driven, retinoic-acid-modulated upregulation of SIRPα and the mechanosensitive nuclear marker lamin-A. Mechanosensitive differentiation was similarly evident in vivo and likely limited the anti-tumor effects, as confirmed by re-initiation of tumor regression by fresh injections of SIRPα-inhibited macrophages. Macrophage motility, phagocytosis, and differentiation in vivo are thus coupled., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Migration through micron-size constrictions has been seen to rupture the nucleus, release nuclear-localized GFP, and cause localized accumulations of ectopic 53BP1-a DNA repair protein. Here, constricted migration of two human cancer cell types and primary mesenchymal stem cells (MSCs) increases DNA breaks throughout the nucleoplasm as assessed by endogenous damage markers and by electrophoretic "comet" measurements. Migration also causes multiple DNA repair proteins to segregate away from DNA, with cytoplasmic mis-localization sustained for many hours as is relevant to delayed repair. Partial knockdown of repair factors that also regulate chromosome copy numbers is seen to increase DNA breaks in U2OS osteosarcoma cells without affecting migration and with nucleoplasmic patterns of damage similar to constricted migration. Such depletion also causes aberrant levels of DNA. Migration-induced nuclear damage is nonetheless reversible for wild-type and sub-cloned U2OS cells, except for lasting genomic differences between stable clones as revealed by DNA arrays and sequencing. Gains and losses of hundreds of megabases in many chromosomes are typical of the changes and heterogeneity in bone cancer. Phenotypic differences that arise from constricted migration of U2OS clones are further illustrated by a clone with a highly elongated and stable MSC-like shape that depends on microtubule assembly downstream of the transcription factor GATA4. Such changes are consistent with reversion to a more stem-like state upstream of cancerous osteoblastic cells. Migration-induced genomic instability can thus associate with heritable changes., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Recent evidence indicates that mouse and human embryonic stem cells (ESCs) are fixed at different developmental stages, with the former positioned earlier. We show that a narrow concentration of the naturally occurring short-chain fatty acid, sodium butyrate, supports the extensive self-renewal of mouse and human ESCs, while promoting their convergence toward an intermediate stem cell state. In response to butyrate, human ESCs regress to an earlier developmental stage characterized by a gene expression profile resembling that of mouse ESCs, preventing precocious Xist expression while retaining the ability to form complex teratomas in vivo. Other histone deacetylase inhibitors (HDACi) also support human ESC self-renewal. Our results indicate that HDACi can promote ESC self-renewal across species, and demonstrate that ESCs can toggle between alternative states in response to environmental factors.

To initiate a system-level analysis of C. elegans DAF-7/TGF-beta signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-beta pathway components defined a network of 71 interactions among 59 proteins. Coaffinity purification (co-AP) assays in mammalian cells confirmed the overall quality of this network. Systematic perturbations of the network using RNAi, both in wild-type and daf-7/TGF-beta pathway mutant animals, identified nine DAF-7/TGF-beta signaling modifiers, seven of which are conserved in humans. We show that one of these has functional homology to human SNO/SKI oncoproteins and that mutations at the corresponding genetic locus daf-5 confer defects in DAF-7/TGF-beta signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-beta signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules.

Presented in a paper in the September issue of Molecular Cell, Aza-Blanc et al. used an RNA interference-based genetic screen to identify genes that modulate sensitivity to the apoptosis-inducing ligand TRAIL. The age of mammalian cell genetic screens has begun.

Although the mechanism of mammalian apoptosis has not been elucidated, a protease of the CED-3/ICE family is anticipated to be a component of the death machinery. Several lines of evidence predict that this protease cleaves the death substrate poly(ADP-ribose) polymerase (PARP) to a specific 85 kDa form observed during apoptosis, is inhibitable by the CrmA protein, and is distinct from ICE. We cloned a ced-3/ICE-related gene, designated Yama, that encodes a protein identical to CPP32 beta. Purified Yama was a zymogen that, when activated, cleaved PARP to generate the 85 kDa apoptotic fragment. Cleavage of PARP by Yama was inhibited by CrmA but not by an inactive point mutant of CrmA. Furthermore, CrmA blocked cleavage of PARP in cells undergoing apoptosis. We propose that Yama may represent an effector component of the mammalian cell death pathway and suggest that CrmA blocks apoptosis by inhibiting Yama.

Using the cytoplasmic domain of Fas in the yeast two-hybrid system, we have identified a novel interacting protein, FADD, which binds Fas and Fas-FD5, a mutant of Fas possessing enhanced killing activity, but not the functionally inactive mutants Fas-LPR and Fas-FD8. FADD contains a death domain homologous to the death domains of Fas and TNFR-1. A point mutation in FADD, analogous to the lpr mutation of Fas, abolishes its ability to bind Fas, suggesting a death domain to death domain interaction. Overexpression of FADD in MCF7 and BJAB cells induces apoptosis, which, like Fas-induced apoptosis, is blocked by CrmA, a specific inhibitor of the interleukin-1 beta-converting enzyme. These findings suggest that FADD may play an important role in the proximal signal transduction of Fas.