A Breakdown in Cooperativity Leads to Cardiac Identity Crisis.

Using induced pluripotent stem cells, Ang et al. elucidate how a mutation in the transcription factor GATA4 causes congenital heart disease. They find that, although the recruitment of GATA4 to cardiac super-enhancers is retained, it no longer functions in partnership with another key transcription factor, leading to misexpression of non-cardiomyocyte genes.

Mechanical Skin Injury Promotes Food Anaphylaxis by Driving Intestinal Mast Cell Expansion.

Mast cell (MC) mediator release after crosslinking of surface-bound IgE antibody by ingested antigen underlies food allergy. However, IgE antibodies are not uniformly associated with food allergy, and intestinal MC load is an important determinant. Atopic dermatitis (AD), characterized by pruritis and cutaneous sensitization to allergens, including foods, is strongly associated with food allergy. Tape stripping mouse skin, a surrogate for scratching, caused expansion and activation of small intestinal MCs, increased intestinal permeability, and promoted food anaphylaxis in sensitized mice. Tape stripping caused keratinocytes to systemically release interleukin-33 (IL-33), which synergized with intestinal tuft-cell-derived IL-25 to drive the expansion and activation of intestinal type-2 innate lymphoid cells (ILC2s). These provided IL-4, which targeted MCs to expand in the intestine. Duodenal MCs were expanded in AD. In addition to promoting cutaneous sensitization to foods, scratching may promote food anaphylaxis in AD by expanding and activating intestinal MCs.

Braveheart, a long noncoding RNA required for cardiovascular lineage commitment.

Long noncoding RNAs (lncRNAs) are often expressed in a development-specific manner, yet little is known about their roles in lineage commitment. Here, we identified Braveheart (Bvht), a heart-associated lncRNA in mouse. Using multiple embryonic stem cell (ESC) differentiation strategies, we show that Bvht is required for progression of nascent mesoderm toward a cardiac fate. We find that Bvht is necessary for activation of a core cardiovascular gene network and functions upstream of mesoderm posterior 1 (MesP1), a master regulator of a common multipotent cardiovascular progenitor. We also show that Bvht interacts with SUZ12, a component of polycomb-repressive complex 2 (PRC2), during cardiomyocyte differentiation, suggesting that Bvht mediates epigenetic regulation of cardiac commitment. Finally, we demonstrate a role for Bvht in maintaining cardiac fate in neonatal cardiomyocytes. Together, our work provides evidence for a long noncoding RNA with critical roles in the establishment of the cardiovascular lineage during mammalian development.

Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy.

The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-ß superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.

Discovery adductomics provides a comprehensive portrait of tissue-, age- and sex-specific DNA modifications in rodents and humans.

DNA damage causes genomic instability underlying many diseases, with traditional analytical approaches providing minimal insight into the spectrum of DNA lesions in vivo. Here we used untargeted chromatography-coupled tandem mass spectrometry-based adductomics (LC-MS/MS) to begin to define the landscape of DNA modifications in rat and human tissues. A basis set of 114 putative DNA adducts was identified in heart, liver, brain, and kidney in 1-26-month-old rats and 111 in human heart and brain by 'stepped MRM' LC-MS/MS. Subsequent targeted analysis of these species revealed species-, tissue-, age- and sex-biases. Structural characterization of 10 selected adductomic signals as known DNA modifications validated the method and established confidence in the DNA origins of the signals. Along with strong tissue biases, we observed significant age-dependence for 36 adducts, including N2-CMdG, 5-HMdC and 8-Oxo-dG in rats and 1,N6-ϵdA in human heart, as well as sex biases for 67 adducts in rat tissues. These results demonstrate the potential of adductomics for discovering the true spectrum of disease-driving DNA adducts. Our dataset of 114 putative adducts serves as a resource for characterizing dozens of new forms of DNA damage, defining mechanisms of their formation and repair, and developing them as biomarkers of aging and disease.

An insulin-regulated arrestin domain protein controls hepatic glucagon action.

Glucagon signaling is essential for maintaining normoglycemia in mammals. The arrestin fold superfamily of proteins controls the trafficking, turnover, and signaling of transmembrane receptors as well as other intracellular signaling functions. Further investigation is needed to understand the in vivo functions of the arrestin domain-containing 4 (ARRDC4) protein family member and whether it is involved in mammalian glucose metabolism. Here, we show that mice with a global deletion of the ARRDC4 protein have impaired glucagon responses and gluconeogenesis at a systemic and molecular level. Mice lacking ARRDC4 exhibited lower glucose levels after fasting and could not suppress gluconeogenesis at the refed state. We also show that ARRDC4 coimmunoprecipitates with the glucagon receptor, and ARRDC4 expression is suppressed by insulin. These results define ARRDC4 as a critical regulator of glucagon signaling and glucose homeostasis and reveal a novel intersection of insulin and glucagon pathways in the liver.

Restoration of Cardiomyogenesis in Aged Mouse Hearts by Voluntary Exercise.

BACKGROUND: The human heart has limited capacity to generate new cardiomyocytes and this capacity declines with age. Because loss of cardiomyocytes may contribute to heart failure, it is crucial to explore stimuli of endogenous cardiac regeneration to favorably shift the balance between loss of cardiomyocytes and the birth of new cardiomyocytes in the aged heart. We have previously shown that cardiomyogenesis can be activated by exercise in the young adult mouse heart. Whether exercise also induces cardiomyogenesis in aged hearts, however, is still unknown. Here, we aim to investigate the effect of exercise on the generation of new cardiomyocytes in the aged heart. METHODS: Aged (20-month-old) mice were subjected to an 8-week voluntary running protocol, and age-matched sedentary animals served as controls. Cardiomyogenesis in aged hearts was assessed on the basis of 15N-thymidine incorporation and multi-isotope imaging mass spectrometry. We analyzed 1793 cardiomyocytes from 5 aged sedentary mice and compared these with 2002 cardiomyocytes from 5 aged exercised mice, followed by advanced histology and imaging to account for ploidy and nucleation status of the cell. RNA sequencing and subsequent bioinformatic analyses were performed to investigate transcriptional changes induced by exercise specifically in aged hearts in comparison with young hearts. RESULTS: Cardiomyogenesis was observed at a significantly higher frequency in exercised compared with sedentary aged hearts on the basis of the detection of mononucleated/diploid 15N-thymidine-labeled cardiomyocytes. No mononucleated/diploid 15N-thymidine-labeled cardiomyocyte was detected in sedentary aged mice. The annual rate of mononucleated/diploid 15N-thymidine-labeled cardiomyocytes in aged exercised mice was 2.3% per year. This compares with our previously reported annual rate of 7.5% in young exercised mice and 1.63% in young sedentary mice. Transcriptional profiling of young and aged exercised murine hearts and their sedentary controls revealed that exercise induces pathways related to circadian rhythm, irrespective of age. One known oscillating transcript, however, that was exclusively upregulated in aged exercised hearts, was isoform 1.4 of regulator of calcineurin, whose regulation and functional role were explored further. CONCLUSIONS: Our data demonstrate that voluntary running in part restores cardiomyogenesis in aged mice and suggest that pathways associated with circadian rhythm may play a role in physiologically stimulated cardiomyogenesis.

Are NCI Cancer Centers Providing Adolescents and Young Adults With Cancer Focused Clinical Services? A National Survey.

BACKGROUND: This study sought to evaluate the current services and delivery models of adolescent and young adult oncology (AYAO)-specific programs at NCI-designated Cancer Centers (NCI-CCs). PATIENTS AND METHODS: NCI, academic, and community cancer centers were electronically sent surveys from October to December 2020 and administered via REDCap. RESULTS: Survey responses were received from 50 of 64 (78%) NCI-CCs, primarily completed by pediatric oncologists (53%), adult oncologists (11%), and social workers (11%). Half (51%) reported an existing AYAO program, with most (66%) started within the past 5 years. Although most programs combined medical and pediatric oncology (59%), 24% were embedded within pediatrics alone. Most programs saw patients aged 15 (55%) to 39 years (66%) mainly via outpatient clinic consultation (93%). Most centers reported access to a range of medical oncology and supportive services, but dedicated services specifically for adolescent and young adults (AYAs) were available at a much lower extent, such as social work (98% vs 58%) and psychology (95% vs 54%). Although fertility preservation was offered by all programs (100%), only two-thirds of NCI centers (64%) reported providing sexual health services to AYAs. Most NCI-CCs (98%) were affiliated with a research consortium, and a lesser extent (73%) reported collaboration between adult and pediatric researchers. Nearly two-thirds (60%) reported that AYA oncology care was important/very important to their respective institution and reported providing good/excellent care to AYAs with cancer (59%), but to a lesser extent reported good/excellent research (36%), sexual health (23%), and education of staff (21%). CONCLUSIONS: Results of this first-ever national survey to assess AYAO programs showed that only half of NCI-CCs report having a dedicated AYAO program, and that areas of improvement include staff education, research, and sexual health services for patients.

Associations between symptoms with healthcare utilization and death in advanced cancer patients.

INTRODUCTION: There is limited data about assessments that are associated with increased utilization of medical services among advanced oncology patients (AOPs). We aimed to identify factors related to healthcare utilization and death in AOP. METHODS: AOPs at a comprehensive cancer center were enrolled in a Center for Medicare and Medicaid Innovation program. Participants completed the Edmonton Symptom Assessment Scale (ESAS) and the Functional Assessment of Cancer Therapy-General (FACT-G) scale. We examined factors associated with palliative care (PC), acute care (AC), emergency room (ER), hospital admissions (HA), and death. RESULTS: In all, 817 AOPs were included in these analyses with a median age of 69. They were generally female (58.7%), white (61.4%), stage IV (51.6%), and represented common cancers (31.5% GI, 25.2% thoracic, 14.3% gynecologic). ESAS pain, anxiety, and total score were related to more PC visits (B=0.31, 95% CI [0.21, 0.40], p<0.001; B=0.24 [0.12, 0.36], p<0.001; and B=0.038 [0.02, 0.06], p=0.001, respectively). Total FACT-G score and physical subscale were related to total PC visits (B=-0.021 [-0.037, -0.006], p=0.008 and B=-0.181 [-0.246, -0.117], p<0.001, respectively). Lower FACT-G social subscale scores were related to more ER visits (B=-0.03 [-0.53, -0.004], p=0.024), while increased tiredness was associated with fewer AC visits (B=-0.039 [-0.073, -0.006], p=0.023). Higher total ESAS scores were related to death within 30 days (OR=0.87 [0.76, 0.98], p=0.027). CONCLUSIONS: The ESAS and FACT-G assessments were linked to PC and AC visits and death. These assessments may be useful for identifying AOPs that would benefit from routine PC.

Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver.

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show that Arrdc3 is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction in Arrdc3 messenger RNA, while, conversely, mice with liver-specific KO of Arrdc3 (L-Arrdc3 KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus, Arrdc3 is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

Molecular mechanisms of heart regeneration.

The adult mammalian heart is incapable of clinically relevant regeneration. The regenerative deficit in adult mammalian heart contrasts with the fetal and neonatal heart, which demonstrate substantial regenerative capacity after injury. This deficiency in adult mammals is attributable to the lack of resident stem cells after birth, combined with an inability of pre-existing cardiomyocytes to complete cytokinesis. Studies of neonatal heart regeneration in mammals suggest that latent regenerative potential can be re-activated. Dissecting the cellular and molecular mechanisms that promote cardiomyocyte proliferation is key to stimulating true regeneration in adult humans. Here, we review recent advances in our understanding of cardiomyocyte proliferation that suggest molecular approaches to heart regeneration.

The Role of the Microbiome in Gastroentero-Pancreatic Neuroendocrine Neoplasms (GEP-NENs).

Gut microbiome balance plays a key role in human health and maintains gut barrier integrity. Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. Fecal samples were collected and compared with matched healthy control samples using logistic regression distances utilizing R package MatchIt (version 4.2.0, Daniel E. Ho, Stanford, CA, USA). We examined differences in microbiome profiles between GEP-NENs and control samples using small subunit (SSU) rRNA (16S), ITS1, ITS4 genomic regions for their ability to accurately characterize bacterial and fungal communities. We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Gut samples of 34 patients (12 males, 22 females, median age 64 years) with metastatic GEP-NENs (22 small bowel, 10 pancreatic, 1 gall bladder, and 1 unknown primary) were analyzed. Twenty-nine patients had well differentiated GEP-neuroendocrine tumors (GEP-NETs), (G1 = 14, G2 = 12, G3 = 3) and five patients had poorly differentiated GEP-neuroendocrine carcinomas (GEP-NECs). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. Patients with GEP-NECs had significantly enriched populations of specific bacteria and fungi (such as Enterobacter hormaechei, Bacteroides fragilis and Trichosporon asahii) compared to those with GEP-NETs (p = 0.048, 0.0022 and 0.034, respectively). In addition, higher grade GEP-NETs were associated with significantly higher Bacteroides fragilis (p = 0.022), and Eggerthella lenta (p = 0.00018) species compared to lower grade tumors. There were substantial differences associated with dietary habits and therapeutic responses. This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. There were significant differences between GEP-NETs and GEP-NECs, supporting the role of the gut microbiome in the pathogenesis of these two distinct entities.

IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation.

Chronic inflammation's tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. Studying the transition from acute, tumor-suppressive to chronic, tumor-promoting allergic contact dermatitis (ACD) revealed how tumor-promoting chronic inflammation develops. Epidermis-derived interleukin (IL)-33 up-regulation and its induction of regulatory T cell (Treg) accumulation in the skin preceded the transition from acute to chronic ACD and triggered the tumor-promoting immune environment in chronic ACD. Mice lacking IL-33 were protected from chronic ACD and its skin cancer sequela compared with wild-type controls (P = 0.0002). IL-33's direct signaling onto Tregs was required for the development of the tumor-promoting immune environment in the skin. IL-33-Treg signaling was also required for chronic colitis and its associated colorectal cancer development in a colitis model (P < 0.0001). Significantly increased IL-33 and Tregs marked the perilesional skin and colon in patients with cancer-prone chronic inflammatory diseases. Our findings elucidate the role of the IL-33/Treg axis in creating a tumor-promoting immune environment in chronic inflammatory diseases and suggest therapeutic targets for cancer prevention and treatment in high-risk patients.

The perspectives of oncology healthcare providers on the role of palliative care in a comprehensive cancer center.

BACKGROUND: Palliative care (PC) is an essential part of oncologic care, but its optimal role within a cancer center remains unclear. This study examines oncology healthcare providers' perspectives about the role of PC at a comprehensive cancer center (CCC). METHODS: Physicians, nurses, and other oncology healthcare providers at a CCC were surveyed for their opinions about the role of inpatient and outpatient PC, preferences for PC services, and barriers to referral. Chi-squared tests and multiple regression analyses were performed to explore associations. RESULTS: We received 137/221 completed questionnaires (61% response rate). Respondents were generally female (78%), had ≤ 10 years of service (69%), and included physicians (32%), nurses (32%), and advanced practice providers (17%). Most respondents (82%) agreed that more patients could benefit from PC. They also agreed that PC is beneficial for both outpatient and inpatient management of complex pain (96 and 88%), complex symptoms (84 and 74%), and advanced cancer patients (80 and 64%). Transition to hospice (64 vs. 42%, p = 0.007) and goals of care (62 vs. 49%, p = 0.011) provided by PC services were more valued by respondents for the inpatient than for the outpatient setting. Barriers to utilizing PC included lack of availability, unsure of when to refer, and poor communication. The majority of respondents (83%) preferred a cancer focused PC team to provide high-quality care. CONCLUSIONS: Overall, the majority of oncology health care providers believe that more patients could benefit from PC, but opinions vary regarding the roles of inpatient and outpatient PC. Barriers and areas for improvement include availability, referral process, and improved communication.

Black race is independently associated with underutilization of transplantation for clinical T1 hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. Operative management of early disease includes ablation, resection, and transplantation. We compared the operative management of early-stage HCC in patients stratified by race. METHODS: We identified patients with cT1 HCC and Charlson-Deyo score 0-1 in the National Cancer Database (2004-2016). We compared operative/non-operative management by race, adjusting for clinicodemographic variables. We performed marginal standardization of logistic regression to ascertain adjusted probabilities of resection or transplantation in patients under 70 years of age with insurance. RESULTS: A total of 25,029 patients were included (White = 20,410; Black = 4619). After adjusting for clinico demographic variables, Black race was associated with a lower likelihood of undergoing operative intervention (OR 0.89,p = 0.009). Black patients were more likely to undergo resection (OR 1.23,p < 0.001) and less likely to undergo transplantation (OR 0.60,p < 0.001). Marginal standardization models demonstrated Black race was associated with increased probability of resection in patients >50yrs, with private insurance/Medicare, and lower probability of transplantation regardless of age or insurance payor. CONCLUSION: Black race is associated with lower rates of hepatic transplantation and higher rates of hepatic resection for early HCC regardless of age or insurance payor. The etiology of these disparities is multifactorial and correcting the root causes represents a critical area for improvement.

Inhibition of mTOR Signaling Enhances Maturation of Cardiomyocytes Derived From Human-Induced Pluripotent Stem Cells via p53-Induced Quiescence.

BACKGROUND: Current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells (iPSCs) are capable of generating highly pure cardiomyocyte populations as determined by expression of cardiac troponin T. However, these cardiomyocytes remain immature, more closely resembling the fetal state, with a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared with adult cardiomyocytes. Immaturity of iPSC-derived cardiomyocytes may be a significant barrier to clinical translation of cardiomyocyte cell therapies for heart disease. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of rapamycin (mTOR)-signaling pathway plays a key role in nutrient sensing and growth. We hypothesized that transient inhibition of the mTOR-signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation. METHODS: Cardiomyocytes were differentiated from 3 human iPSC lines using small molecules to modulate the Wnt pathway. Torin1 (0 to 200 nmol/L) was used to inhibit the mTOR pathway at various time points. We quantified contractile, metabolic, and electrophysiological properties of matured iPSC-derived cardiomyocytes. We utilized the small molecule inhibitor, pifithrin-α, to inhibit p53 signaling, and nutlin-3a, a small molecule inhibitor of MDM2 (mouse double minute 2 homolog) to upregulate and increase activation of p53. RESULTS: Torin1 (200 nmol/L) increased the percentage of quiescent cells (G0 phase) from 24% to 48% compared with vehicle control (P<0.05). Torin1 significantly increased expression of selected sarcomere proteins (including TNNI3 [troponin I, cardiac muscle]) and ion channels (including Kir2.1) in a dose-dependent manner when Torin1 was initiated after onset of cardiomyocyte beating. Torin1-treated cells had an increased relative maximum force of contraction, increased maximum oxygen consumption rate, decreased peak rise time, and increased downstroke velocity. Torin1 treatment increased protein expression of p53, and these effects were inhibited by pifithrin-α. In contrast, nutlin-3a independently upregulated p53, led to an increase in TNNI3 expression and worked synergistically with Torin1 to further increase expression of both p53 and TNNI3. CONCLUSIONS: Transient treatment of human iPSC-derived cardiomyocytes with Torin1 shifts cells to a quiescent state and enhances cardiomyocyte maturity.

Prevalence of potential interactions of medications, including herbs and supplements, before, during, and after chemotherapy in patients with breast and prostate cancer.

BACKGROUND: The use of herbs and supplements (HS) is common among patients with cancer, yet limited information exists about potential medication interactions (PMIs) with HS use around chemotherapy. METHODS: Patients with breast or prostate cancer who had recently finished chemotherapy at 2 academic medical centers were surveyed by telephone. Interviewers inquired about all medications, including HS, before, during, and after chemotherapy. Micromedex, Lexicomp, and Natural Medicines Comprehensive Database interaction software programs were used to determine PMIs. RESULTS: A total of 67 subjects (age range, 39-77 years) were evaluated in this study. Participants were primarily White patients (73%) with breast cancer (87%). The median number of medications was 11 (range, 2-28) during the entire study and was highest during chemotherapy (7; range, 2-22). Approximately four-fifths (84%) used HS. A total of 1747 PMIs were identified, and they represented 635 unique PMIs across all 3 timeframes, with most occurring during chemotherapy. Prescription-related PMIs (70%) were the most common type, and they were followed by HS-related (56%) and anticancer treatment-related PMIs (22%). Approximately half of the PMIs (54%) were categorized as moderate interactions, and more than one-third (38%) were categorized as major interactions. Patient use of HS increased from 51% during chemotherapy to 66% after chemotherapy, and this correlated with an increased prevalence of HS PMIs (46% to 60%). HS users were more likely to be at risk for a major PMI than non-HS users (92% vs 70%; P = .038). CONCLUSIONS: The use of HS remains prevalent among patients with cancer and may place them at risk for PMIs both during chemotherapy and after the completion of treatment. LAY SUMMARY: This study evaluates the risk of potential medication interactions for patients with breast or prostate cancer undergoing chemotherapy. The results show that patients often use herbs and supplements during treatment. Prescription medications are most often associated with medication interactions, which are followed by herb and supplement-related interactions. More than one-third of potential medication interactions are considered major. Patients should be educated about the risk of herb and supplement-related medication interactions during treatment.

Steady-state and regenerative hematopoiesis occurs normally in mice in the absence of GDF11.

Tightly regulated production of mature blood cells is essential for health and survival in vertebrates and dependent on discrete populations of blood-forming (hematopoietic) stem and progenitor cells. Prior studies suggested that inhibition of growth differentiation factor 11 (GDF11) through soluble activin receptor type II (ActRII) ligand traps or neutralizing antibodies promotes erythroid precursor cell maturation and red blood cell formation in contexts of homeostasis and anemia. As Gdf11 is expressed by mature hematopoietic cells, and erythroid precursor cell expression of Gdf11 has been implicated in regulating erythropoiesis, we hypothesized that genetic disruption of Gdf11 in blood cells might perturb normal hematopoiesis or recovery from hematopoietic insult. Contrary to these predictions, we found that deletion of Gdf11 in the hematopoietic lineage in mice does not alter erythropoiesis or erythroid precursor cell frequency under normal conditions or during hematopoietic recovery after irradiation and transplantation. In addition, although hematopoietic cell-derived Gdf11 may contribute to the pool of circulating GDF11 protein during adult homeostasis, loss of Gdf11 specifically in the blood system does not impair hematopoietic stem cell function or induce overt pathological consequences. Taken together, these results reveal that hematopoietic cell-derived Gdf11 is largely dispensable for native and transplant-induced blood formation.

NCCN Guidelines® Insights: Palliative Care, Version 2.2021.

Palliative care has evolved to be an integral part of comprehensive cancer care with the goal of early intervention to improve quality of life and patient outcomes. The NCCN Guidelines for Palliative Care provide recommendations to help the primary oncology team promote the best quality of life possible throughout the illness trajectory for each patient with cancer. The NCCN Palliative Care Panel meets annually to evaluate and update recommendations based on panel members' clinical expertise and emerging scientific data. These NCCN Guidelines Insights summarize the panel's recent discussions and highlights updates on the importance of fostering adaptive coping strategies for patients and families, and on the role of pharmacologic and nonpharmacologic interventions to optimize symptom management.

Nanoscale Technologies for Prevention and Treatment of Heart Failure: Challenges and Opportunities.

The adult myocardium has a limited regenerative capacity following heart injury, and the lost cells are primarily replaced by fibrotic scar tissue. Suboptimal efficiency of current clinical therapies to resurrect the infarcted heart results in injured heart enlargement and remodeling to maintain its physiological functions. These remodeling processes ultimately leads to ischemic cardiomyopathy and heart failure (HF). Recent therapeutic approaches (e.g., regenerative and nanomedicine) have shown promise to prevent HF postmyocardial infarction in animal models. However, these preclinical, clinical, and technological advancements have yet to yield substantial enhancements in the survival rate and quality of life of patients with severe ischemic injuries. This could be attributed largely to the considerable gap in knowledge between clinicians and nanobioengineers. Development of highly effective cardiac regenerative therapies requires connecting and coordinating multiple fields, including cardiology, cellular and molecular biology, biochemistry and chemistry, and mechanical and materials sciences, among others. This review is particularly intended to bridge the knowledge gap between cardiologists and regenerative nanomedicine experts. Establishing this multidisciplinary knowledge base may help pave the way for developing novel, safer, and more effective approaches that will enable the medical community to reduce morbidity and mortality in HF patients.