PURPOSE OF REVIEWHematopoietic stem cells (HSCs) are defined by their ability to self-renew and differentiate to replenish all blood lineages throughout adult life. Under homeostasis, the majority of ...HSCs are quiescent, and few stem cells are cycling to sustain hematopoiesis. However, HSCs can be induced to proliferate and differentiate in response to stress signals produced during infection, inflammation, chemotherapy, radiation, bone marrow transplantation, and aging. Recent evidence suggests that acute and chronic stress impact the number and function of HSCs including their ability to repopulate and produce mature cells. This review will focus on how chronic stress affects HSC biology and methods to mitigate HSC loss during chronic hematopoietic stress.
RECENT FINDINGSQuiescent HSCs exit dormancy, divide, and differentiate to maintain steady-state hematopoiesis. Under conditions of acute stress including infection or blood loss some HSCs are pushed into division by cytokines and proinflammatory stimuli to differentiate and provide needed myeloid and erythroid cells to protect and reconstitute the host; after which, hematopoiesis returns to steady-state with minimal loss of HSC function. However, under conditions of chronic stress including serial bone marrow transplantation (BMT), chronic inflammation, and genotoxic stress (chemotherapy) and aging, HSCs are continuously induced to proliferate and undergo accelerated exhaustion. Recent evidence demonstrates that ablation of inhibitor of DNA binding 1 (Id1) gene can protect HSCs from exhaustion during chronic proliferative stress by promoting HSC quiescence.
SUMMARYIncreasing our understanding of the molecular processes that protect HSCs from chronic proliferative stress could lead to therapeutic opportunities to prevent accelerated HSC exhaustion during physiological stress, genotoxic stress, BMT, and aging.
Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of ...suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.
Display omitted
•CD276/B7-H3 is broadly overexpressed in both cancer cells and tumor vasculature•Both angiogenic and non-angiogenic tumor vasculature express CD276•Anti-CD276-drug conjugates display potent anti-tumor and anti-metastatic activity•Pyrrolobenzodiazepine dimers are optimal warheads for targeting tumor vasculature
Seaman et al. show that CD276 is broadly overexpressed in cancer cells and tumor vascular cells and demonstrate anti-CD276-drug conjugates as promising anti-cancer reagents. The drug selected for conjugation is important because tumor vascular cells can be resistant to a drug to which tumor cells are sensitive.
Lymphoid tissue inducer (LTi) cells are regarded as a subset of innate lymphoid cells (ILCs). However, these cells are not derived from the ILC common progenitor, which generates other ILC subsets ...and is defined by the expression of the transcription factor PLZF. Here, we examined transcription factor(s) determining the fate of LTi progenitors versus non-LTi ILC progenitors. Conditional deletion of Gata3 resulted in the loss of PLZF+ non-LTi progenitors but not the LTi progenitors that expressed the transcription factor RORγt. Consistently, PLZF+ non-LTi progenitors expressed high amounts of GATA3, whereas GATA3 expression was low in RORγt+ LTi progenitors. The generation of both progenitors required the transcriptional regulator Id2, which defines the common helper-like innate lymphoid progenitor (ChILP), but not cytokine signaling. Nevertheless, low GATA3 expression was necessary for the generation of functionally mature LTi cells. Thus, differential expression of GATA3 determines the fates and functions of distinct ILC progenitors.
Display omitted
•High GATA3 expression is required for the development of non-LTi ILC progenitors•GATA3 is dispensable for the development of RORγt-expressing LTi progenitors•Low GATA3 expression is essential for the acquisition of LTi cell function•GATA3 and Id2 determine ILC lineage fates before cytokine-mediated ILC maturation
Lymphoid tissue inducer (LTi) cells are regarded as a subset of innate lymphoid cells (ILCs). Zhong et al. show that the generation of both non-LTi and LTi progenitors requires the transcriptional regulator Id2, but is distinguished by the differential requirement for the transcription factor GATA3. Their findings suggest that non-LTi ILCs are the bona fide innate counterparts of CD4+ T effector cells.
The actin cytoskeleton plays a central role in establishing cell polarity and shape during embryonic morphogenesis. Daam1, a member of the Formin family of actin cytoskeleton regulators, is a ...Dvl2-binding protein that functions in the Wnt/Planar Cell Polarity (PCP) pathway. To examine the role of the Daam proteins in mammalian development, we generated Daam-deficient mice by gene targeting and found that Daam1, but not Daam2, is necessary for fetal survival. Embryonic development of Daam1 mutants was delayed most likely due to functional defects in the labyrinthine layer of the placenta. Examination of Daam2 and Daam1/2 double mutants revealed that Daam1 and Daam2 are functionally redundant during placental development. Of note, neural tube closure defects (NTD), which are observed in several mammalian PCP mutants, are not observed in Wnt5a or Daam1 single mutants, but arise in Daam1;Wnt5a double mutants. These findings demonstrate a unique function for Daam genes in placental development and are consistent with a role for Daam1 in the Wnt/PCP pathway in mammals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hypothesis Our hypothesis was that in patients undergoing shoulder arthroplasty, a prospective randomized trial would find no significant differences in average daily pain scores of those treated ...with interscalene nerve block (INB) vs. local liposomal bupivacaine (LB). Methods Sixty patients undergoing primary shoulder arthroplasty were assessed for eligibility. Study arms included either intraoperative local infiltration of LB (20 mL bupivacaine/20 mL saline) or preoperative INB, with a primary outcome of postoperative average daily visual analog scale scores for 4 days. Secondary outcomes assessed included opioid consumption, length of stay, and complications. Randomization was by a computerized algorithm. Only the observer was blinded to the intervention. Results Three patients were excluded, all before randomization. A total of 57 patients were analyzed. Outcomes showed a significant increase in pain in the LB group between 0 and 8 hours postoperatively (mean standard deviation 5.3 2.2 vs. 2.5 3.0; P = .001). A significant increase in intravenous morphine equivalents was found in the INB group at 13 to 16 hours (mean standard deviation 1.2 0.9 vs. 0.6 0.7; P = .01). No significant differences were found in any variable after postoperative day 0 between the 2 groups. Conclusion An increase in early postoperative pain on the day of surgery was found with LB, whereas the INB group required more narcotics at the end of the day. After the day of surgery, there were no significant differences found in any variables. These findings suggest that LB provides similar overall pain relief as INB, with no increase in complications or length of stay and a decrease in narcotic requirements on the day of surgery.
Defining mechanisms that maintain tissue stem cells during homeostasis, stress, and aging is important for improving tissue regeneration and repair and enhancing cancer therapies. Here, we show that ...Id1 is induced in hematopoietic stem cells (HSCs) by cytokines that promote HSC proliferation and differentiation, suggesting that it functions in stress hematopoiesis. Genetic ablation of Id1 increases HSC self-renewal in serial bone marrow transplantation (BMT) assays, correlating with decreases in HSC proliferation, mitochondrial biogenesis, and reactive oxygen species (ROS) production. Id1−/− HSCs have a quiescent molecular signature and harbor less DNA damage than control HSCs. Cytokines produced in the hematopoietic microenvironment after γ-irradiation induce Id1 expression. Id1−/− HSCs display a blunted proliferative response to such cytokines and other inducers of chronic proliferation including genotoxic and inflammatory stress and aging, protecting them from chronic stress and exhaustion. Thus, targeting Id1 may be therapeutically useful for improving HSC survival and function during BMT, chronic stress, and aging.
Display omitted
•Id1−/− HSCs have enhanced self-renewal potential and are maintained during BMT•Id1−/− HSCs show reduced oxidative stress and increased quiescence after BMT•Id1−/− HSCs are protected from inflammatory cytokine-induced proliferative stress•Id1−/− HSCs are protected from exhaustion by chronic inflammatory stress and aging
Singh et al. show that Id1 is an important mediator of stress hematopoiesis. They found that Id1 deletion protects HSCs from exhaustion in multiple paradigms of chronic and physiologically relevant stress and promotes their quiescence, suggesting that targeting Id1 may improve HSC survival and function during chronic stress and aging.
Defining mechanism(s) that maintain tissue stem quiescence is important for improving tissue regeneration, cell therapies, aging, and cancer. We report here that genetic ablation of Id2 in adult ...hematopoietic stem cells (HSCs) promotes increased HSC activation and differentiation, which results in HSC exhaustion and bone marrow failure over time. Id2J/J HSCs showed increased cycling, ROS production, mitochondrial activation, ATP production, and DNA damage compared with Id2+'+ HSCs, supporting the conclusion that Id2J/J HSCs are less quiescent. Mechanistically, HIF-1a expression was decreased in Id2J/J HSCs, and stabilization of HIF-1a in Id2J/J HSCs restored HSC quiescence and rescued HSC exhaustion. Inhibitor of DNA binding 2 (ID2) promoted HIF-1a expression by binding to the von Hippel-Lindau (VHL) protein and interfering with proteasomal degradation of HIF-1a. HIF-1a promoted Id2 expression and enforced a positive feedback loop between ID2 and HIF-1a to maintain HSC quiescence. Thus, sustained ID2 expression could protect HSCs during stress and improve HSC expansion for gene editing and cell therapies.
Several genes implicated in autism spectrum disorder (ASD) are chromatin regulators, including POGZ. The cellular and molecular mechanisms leading to ASD impaired social and cognitive behavior are ...unclear. Animal models are crucial for studying the effects of mutations on brain function and behavior as well as unveiling the underlying mechanisms. Here, we generate a brain specific conditional knockout mouse model deficient for Pogz, an ASD risk gene. We demonstrate that Pogz deficient mice show microcephaly, growth impairment, increased sociability, learning and motor deficits, mimicking several of the human symptoms. At the molecular level, luciferase reporter assay indicates that POGZ is a negative regulator of transcription. In accordance, in Pogz deficient mice we find a significant upregulation of gene expression, most notably in the cerebellum. Gene set enrichment analysis revealed that the transcriptional changes encompass genes and pathways disrupted in ASD, including neurogenesis and synaptic processes, underlying the observed behavioral phenotype in mice. Physiologically, Pogz deficiency is associated with a reduction in the firing frequency of simple and complex spikes and an increase in amplitude of the inhibitory synaptic input in cerebellar Purkinje cells. Our findings support a mechanism linking heterochromatin dysregulation to cerebellar circuit dysfunction and behavioral abnormalities in ASD.
Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. BRCA1- and BRCA2-mutated cells, ...which are homologous recombination (HR) deficient, are hypersensitive to PARPi through the mechanism of synthetic lethality. Here we examine the effect of PARPi on HR-proficient cells. Olaparib pretreatment, PARP1 knockdown or Parp1 heterozygosity of Brca2(cko/ko) mouse embryonic stem cells (mESCs), carrying a null (ko) and a conditional (cko) allele of Brca2, results in viable Brca2(ko/ko) cells. PARP1 deficiency does not restore HR in Brca2(ko/ko) cells, but protects stalled replication forks from MRE11-mediated degradation through its impaired recruitment. The functional consequence of Parp1 heterozygosity on BRCA2 loss is demonstrated by a significant increase in tumorigenesis in Brca2(cko/cko) mice. Thus, while olaparib efficiently kills BRCA2-deficient cells, we demonstrate that it can also contribute to the synthetic viability if PARP is inhibited before BRCA2 loss.
Background:
Medial ulnar collateral ligament (UCL) reconstruction is a common procedure performed on professional pitchers in Major League Baseball (MLB). Although a great deal is known about primary ...reconstruction, much less is known about revision reconstruction.
Purpose/Hypothesis:
The purpose of this study was to evaluate statistical performance, return to play, and career longevity in MLB pitchers after revision UCL surgery, with the hypothesis that pitching performance and career longevity will decline after revision surgery.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
A total of 33 MLB pitchers who underwent revision UCL reconstruction surgery (UCL-R group) were identified and compared with 33 age- and position-matched controls (CTL group). Return to play, total years played, and statistical performance were evaluated and compared with controls.
Results:
After revision surgery, 65.5% of UCL-R pitchers returned to the MLB level. On average, the UCL-R pitchers played 0.8 years less in the majors (P < .01) than did the control pitchers. The UCL-R pitchers who returned to the MLB level had a similar earned run average (UCL-R: 4.88, CTL: 4.76, P = .82) and walks/hits per innings pitched (UCL-R: 1.58, CTL: 1.44, P = .22) compared with the control pitchers. There were significant declines, however, in terms of innings pitched (UCL-R: 36.95, CTL: 75.00, P < .01), walks per 9 innings (UCL-R: 4.75, CTL: 3.49, P < .01), and wins (UCL-R: 1.88, CTL: 4.10, P < .01) as well as nonsignificant declines in wins above replacement (UCL-R: 0.25, CTL: 0.62, P = .06) and runs above replacement (UCL-R: 3.26, CTL: 6.91, P = .07).
Conclusion:
MLB pitchers who undergo UCL-R have a low rate of return to MLB play and have shortened careers after return. Pitchers who returned to the MLB level maintained performance in several statistics such as earned run average and walks/hits per innings pitched; however, pitchers returned with a significantly decreased workload.
PDF
