The ability of cells to count and remember their divisions could underlie many alterations that occur during development, aging, and disease. We tracked the cumulative divisional history of ...slow-cycling hematopoietic stem cells (HSCs) throughout adult life. This revealed a fraction of rarely dividing HSCs that contained all the long-term HSC (LT-HSC) activity within the aging HSC compartment. During adult life, this population asynchronously completes four traceable symmetric self-renewal divisions to expand its size before entering a state of dormancy. We show that the mechanism of expansion involves progressively lengthening periods between cell divisions, with long-term regenerative potential lost upon a fifth division. Our data also show that age-related phenotypic changes within the HSC compartment are divisional history dependent. These results suggest that HSCs accumulate discrete memory stages over their divisional history and provide evidence for the role of cellular memory in HSC aging.
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•A rare population of dormant LR-HSCs persists throughout adult life•Only 1% of repopulating cells within the aging HSC compartment are LT-HSCs•LR-HSCs divide symmetrically four times throughout adult life to accumulate with age•HSCs count and retain a memory of their cell division events in vivo
HSCs count and remember the number of times they have divided to limit their cell divisions, a mechanism that may underlie many phenomena associated with HSC aging.
Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we ...review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative.
Metastases are responsible for the majority of cancer-related deaths. Although genomic heterogeneity within primary tumors is associated with relapse, heterogeneity among treatment-naïve metastases ...has not been comprehensively assessed. We analyzed sequencing data for 76 untreated metastases from 20 patients and inferred cancer phylogenies for breast, colorectal, endometrial, gastric, lung, melanoma, pancreatic, and prostate cancers. We found that within individual patients, a large majority of driver gene mutations are common to all metastases. Further analysis revealed that the driver gene mutations that were not shared by all metastases are unlikely to have functional consequences. A mathematical model of tumor evolution and metastasis formation provides an explanation for the observed driver gene homogeneity. Thus, single biopsies capture most of the functionally important mutations in metastases and therefore provide essential information for therapeutic decision-making.
Quiescence is a fundamental property that maintains hematopoietic stem cell (HSC) potency throughout life. Quiescent HSCs are thought to rely on glycolysis for their energy, but the overall metabolic ...properties of HSCs remain elusive. Using combined approaches, including single-cell RNA sequencing (RNA-seq), we show that mitochondrial membrane potential (MMP) distinguishes quiescent from cycling-primed HSCs. We found that primed, but not quiescent, HSCs relied readily on glycolysis. Notably, in vivo inhibition of glycolysis enhanced the competitive repopulation ability of primed HSCs. We further show that HSC quiescence is maintained by an abundance of large lysosomes. Repression of lysosomal activation in HSCs led to further enlargement of lysosomes while suppressing glucose uptake. This also induced increased lysosomal sequestration of mitochondria and enhanced the competitive repopulation ability of primed HSCs by over 90-fold in vivo. These findings show that restraining lysosomal activity preserves HSC quiescence and potency and may be therapeutically relevant.
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•Mitochondrial heterogeneity reveals fundamental metabolic properties of HSCs•Lysosomal repression enhances HSC quiescence and potency•Active, but not quiescent, HSCs use glycolysis as their main source of energy•Label-retaining dormant HSCs and low-MMP HSCs exhibit overlapping molecular signatures
The quiescence and potency of hematopoietic stem cells (HSCs) are thought to be maintained by glycolysis. By exploiting mitochondrial heterogeneity, Liang, Arif, et al. uncover that activated, but not quiescent, HSCs use glycolysis for energy. Quiescence is maintained by an abundance of lysosomes whose repression enhances HSC potency by over 90-fold.
Newly processed global imaging and topographic mapping of Uranus's five major satellites reveal differences and similarities to mid-sized satellites at Saturn and Pluto. Three modes of internal heat ...redistribution are recognized. The broad similarity of Miranda's three oval resurfacing zones to those mapped on Enceladus and (subtly) on Dione are likely due to antipodal diapiric upwelling. Conversely, break-up and foundering of crustal blocks accompanied by extensive (cryo)volcanism is the dominant mode on both Charon and Ariel. Titania's fault network finds parallels on Rhea, Dione, Tethys and possibly Oberon. Differences in the geologic style of resurfacing in the satellite systems (e.g. plains on Charon, Dione, Tethys and perhaps Titania versus ridges on Miranda and Ariel) may be driven by differences in ice composition. Surface processes such as volatile transport may also be indicated by bright and dark materials on Oberon, Umbriel and Charon. The more complete and higher quality observations of the Saturnian and Plutonian mid-sized icy satellites by Cassini and New Horizons reveal a wealth of features and phenomena that cannot be perceived in the more limited Voyager coverage of the Uranian satellites, harbingers of many discoveries awaiting us on a return to Uranus.
This article is part of a discussion meeting issue ‘Future exploration of ice giant systems'.
Reconstructing the evolutionary history of metastases is critical for understanding their basic biological principles and has profound clinical implications. Genome-wide sequencing data has enabled ...modern phylogenomic methods to accurately dissect subclones and their phylogenies from noisy and impure bulk tumour samples at unprecedented depth. However, existing methods are not designed to infer metastatic seeding patterns. Here we develop a tool, called Treeomics, to reconstruct the phylogeny of metastases and map subclones to their anatomic locations. Treeomics infers comprehensive seeding patterns for pancreatic, ovarian, and prostate cancers. Moreover, Treeomics correctly disambiguates true seeding patterns from sequencing artifacts; 7% of variants were misclassified by conventional statistical methods. These artifacts can skew phylogenies by creating illusory tumour heterogeneity among distinct samples. In silico benchmarking on simulated tumour phylogenies across a wide range of sample purities (15-95%) and sequencing depths (25-800 × ) demonstrates the accuracy of Treeomics compared with existing methods.
There are more than 70 distinct sarcomas, and this diversity complicates the development of precision-based therapeutics for these cancers. Prospective comprehensive genomic profiling could overcome ...this challenge by providing insight into sarcomas' molecular drivers. Through targeted panel sequencing of 7494 sarcomas representing 44 histologies, we identify highly recurrent and type-specific alterations that aid in diagnosis and treatment decisions. Sequencing could lead to refinement or reassignment of 10.5% of diagnoses. Nearly one-third of patients (31.7%) harbor potentially actionable alterations, including a significant proportion (2.6%) with kinase gene rearrangements; 3.9% have a tumor mutational burden ≥10 mut/Mb. We describe low frequencies of microsatellite instability (<0.3%) and a high degree of genome-wide loss of heterozygosity (15%) across sarcomas, which are not readily explained by homologous recombination deficiency (observed in 2.5% of cases). In a clinically annotated subset of 118 patients, we validate actionable genetic events as therapeutic targets. Collectively, our findings reveal the genetic landscape of human sarcomas, which may inform future development of therapeutics and improve clinical outcomes for patients with these rare cancers.
The southeastern, middle shelf of the Bering Sea has exhibited extreme variability in sea ice extent, temperature, and the distribution and abundance of species at multiple trophic levels over the ...past four decades. From 1972–2000, there was high interannual variability of areal extent of sea ice during spring (March–April). In 2000, this shifted to a 5-year (2001–2005) period of low ice extent during spring, which transitioned to a 4-year (2007–2010) period of extensive sea ice. High (low) areal extent of sea ice in spring was associated with cold (warm) water column temperatures for the following 6–7 months. The ocean currents also differed between warm and cold years. During cold years, the monthly-mean currents over the shelf were largely westward, while in warm years the direction of currents was more variable, with northward flow during December–February and relatively weak flow during the remainder of the year. The types and abundance of zooplankton differed sharply between warm and cold years. This was especially true during the prolonged warm period (2001–2005) and cold period (2007–2010), and was less evident during the years of high interannual variability. During the warm period, there was a lack of large copepods and euphausiids over the shelf; however, their populations rebounded during cold period. Small crustacean zooplankton taxa did not appear to vary between and warm and cold years. For both walleye pollock and Pacific cod, year-class strength (recruitment) was low during the prolonged warm period, but improved during the following cold period. Year-class strength did not appear to vary as a function of warm and cold years during the period of high year-to-year variability. Also, recruitment of arrowtooth flounder (a predator of pollock and cod) did not appear influenced by the warm or cold years. Finally, the distribution and relative abundance of fin whales appeared to differ in warm and cold years, with fewer whales on the southeastern, middle shelf during warm years.
IMPORTANCE: Posttraumatic stress disorder (PTSD) is prevalent, persistent, and disabling. Although psychotherapy and pharmacotherapy have proven efficacious in randomized clinical trials, geographic ...barriers impede rural veterans from engaging in these evidence-based treatments. OBJECTIVE: To test a telemedicine-based collaborative care model designed to improve engagement in evidence-based treatment of PTSD. DESIGN, SETTING, AND PARTICIPANTS: The Telemedicine Outreach for PTSD (TOP) study used a pragmatic randomized effectiveness trial design with intention-to-treat analyses. Outpatients were recruited from 11 Department of Veterans Affairs (VA) community-based outpatient clinics serving predominantly rural veterans. Inclusion required meeting diagnostic criteria for current PTSD according to the Clinician-Administered PTSD Scale. Exclusion criteria included receiving PTSD treatment at a VA medical center or a current diagnosis of schizophrenia, bipolar disorder, or substance dependence. Two hundred sixty-five veterans were enrolled from November 23, 2009, through September 28, 2011, randomized to usual care (UC) or the TOP intervention, and followed up for 12 months. INTERVENTIONS: Off-site PTSD care teams located at VA medical centers supported on-site community-based outpatient clinic providers. Off-site PTSD care teams included telephone nurse care managers, telephone pharmacists, telepsychologists, and telepsychiatrists. Nurses conducted care management activities. Pharmacists reviewed medication histories. Psychologists delivered cognitive processing therapy via interactive video. Psychiatrists supervised the team and conducted interactive video psychiatric consultations. MAIN OUTCOMES AND MEASURES: The primary outcome was PTSD severity as measured by the Posttraumatic Diagnostic Scale. Process-of-care outcomes included medication prescribing and regimen adherence and initiation of and adherence to cognitive processing therapy. RESULTS: During the 12-month follow-up period, 73 of the 133 patients randomized to TOP (54.9%) received cognitive processing therapy compared with 16 of 132 randomized to UC (12.1%) (odds ratio, 18.08 95% CI, 7.96-41.06; P < .001). Patients in the TOP arm had significantly larger decreases in Posttraumatic Diagnostic Scale scores (from 35.0 to 29.1) compared with those in the UC arm (from 33.5 to 32.1) at 6 (β = −3.81; P = .002) and 12 (β = −2.49; P = .04) months. Patients in the TOP arm also had significantly larger decreases in Posttraumatic Diagnostic Scale scores (from 35.0 to 30.1) compared with those in the UC arm (from 33.5 to 29.1) at 12 months (β = −2.49; P=.04). There were no significant group differences in the number of PTSD medications prescribed and adherence to medication regimens were not significant. Attendance at 8 or more sessions of cognitive processing therapy significantly predicted improvement in Posttraumatic Diagnostic Scale scores (β = −3.86 95% CI, −7.19 to −0.54; P = .02) and fully mediated the intervention effect at 12 months. CONCLUSIONS AND RELEVANCE: Telemedicine-based collaborative care can successfully engage rural veterans in evidence-based psychotherapy to improve PTSD outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00821678
Structural inequities have important implications for the health of marginalized groups. Neighborhood-level redlining and lending bias represent state-sponsored systems of segregation, potential ...drivers of adverse health outcomes. We sought to estimate the effect of redlining and lending bias on breast cancer mortality and explore differences by race.
Using Georgia Cancer Registry data, we included 4,943 non-Hispanic White (NHW) and 3,580 non-Hispanic Black (NHB) women with a first primary invasive breast cancer diagnosis in metro-Atlanta (2010-2014). Redlining and lending bias were derived for census tracts using the Home Mortgage Disclosure Act database. We calculated hazard ratios and 95% confidence intervals (CI) for the associations of redlining, lending bias on breast cancer mortality and estimated race-stratified associations.
Overall, 20% of NHW and 80% of NHB women lived in redlined census tracts, and 60% of NHW and 26% of NHB women lived in census tracts with pronounced lending bias. Living in redlined census tracts was associated with a nearly 1.60-fold increase in breast cancer mortality (hazard ratio = 1.58; 95% CI, 1.37-1.82) while residing in areas with substantial lending bias reduced the hazard of breast cancer mortality (hazard ratio = 0.86; 95% CI, 0.75-0.99). Among NHB women living in redlined census tracts, we observed a slight increase in breast cancer mortality (hazard ratio = 1.13; 95% CI, 0.90-1.42); among NHW women the association was more pronounced (hazard ratio = 1.39; 95% CI, 1.09-1.78).
These findings underscore the role of ecologic measures of structural racism on cancer outcomes.
Place-based measures are important contributors to health outcomes, an important unexplored area that offers potential interventions to address disparities.
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