Neutrophil extracellular traps induced by chemotherapy inhibit tumor growth in murine models of colorectal cancer.

Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of PIK3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor biopsies from patients treated with the drug combination in a phase II clinical trial. Increased NET levels in tumors were associated with longer progression-free survival. Mechanistically, the drug combination induced the expression of IL-8 preferentially in PIK3CA-mutant CRCs to attract neutrophils into the tumors. Further, the drug combination increased the levels of ROS in neutrophils, thereby inducing NETs. Cathepsin G (CTSG), a serine protease localized in NETs, entered CRC cells through the RAGE cell surface protein. The internalized CTSG cleaved 14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which chemotherapy-induced NETs kill cancer cells.

Challenges in Implementing Guideline on Integrative Oncology and Pain: The Israeli Perspective.

CONTEXT AND OBJECTIVES: To explore the feasibility of implementing the joint guideline on integrative medicine for pain management in oncology, published by the Society for Integrative Oncology (SIO) and the American Society of Clinical Oncology (ASCO), for integrative oncology (IO) services in supportive and palliative care. METHODS: A qualitative research methodology was co-designed by the SIO-ASCO guideline committee, with the Society for Complementary Medicine, Israel Medical Association (IMA). A questionnaire with five open-ended questions exploring barriers and enablers to implementing the guideline was distributed to chairs and board members of nine IMA-affiliated medical societies; four deans of Israeli medical schools; and nurses from the Israeli Society for Oncology Nursing. Respondent narratives were qualitatively analyzed using ATLAS.Ti software for systematic coding. RESULTS: Questionnaires were completed by 52 physicians and nurses from medical oncology, hematology, gynecological oncology, pediatric oncology, palliative medicine, pain, family medicine, internal medicine, and integrative medicine. The SIO-ASCO guidelines were endorsed by nine IMA-affiliated societies. The domains identified included the importance of guideline implementation in clinical practice; barriers and facilitators to implementation; practical aspects required for this implementation (e.g., IO training); clinical indications for referral; budget-related issues; and clinical and administrative models enabling practical implementation of the guideline. CONCLUSION: We found across-the-board consensus among the nine IMA-affiliated societies supporting the current guideline. This, while identifying potential facilitators and barriers in order to address the implementation of the SIO-ASCO guideline recommendations.

Genetic analysis and multimodal imaging identify novel mtDNA 12148T>C leading to multisystem dysfunction with tissue-specific heteroplasmy.

Patients with mitochondrial disorders present with clinically diverse symptoms, largely driven by heterogeneous mutations in mitochondrial-encoded and nuclear-encoded mitochondrial genes. These mutations ultimately lead to complex biochemical disorders with a myriad of clinical manifestations, often accumulating during childhood on into adulthood, contributing to life-altering and sometimes fatal events. It is therefore important to diagnose and characterize the associated disorders for each mitochondrial mutation as early as possible since medical management might be able to improve the quality and longevity of life in mitochondrial disease patients. Here we identify a novel mitochondrial variant in a mitochondrial transfer RNA for histidine (mt-tRNA-his) [m.12148T>C], that is associated with the development of ocular, aural, neurological, renal, and muscular dysfunctions. We provide a detailed account of a family harboring this mutation, as well as the molecular underpinnings contributing to cellular and mitochondrial dysfunction. In conclusion, this investigation provides clinical, biochemical, and morphological evidence of the pathogenicity of m.12148T>C. We highlight the importance of multiple tissue testing and in vitro disease modeling in diagnosing mitochondrial disease.

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.

Improving Quality of Life During Chemotherapy: Cannabinoids, Cryotherapy, and Scalp Cooling.

There have been significant advances in the treatment of cancer in the past decade. However, patients continue to suffer from significant side effects of antineoplastic agents that greatly affect their quality of life (QOL), including chemotherapy-induced nausea and vomiting (CINV), chemotherapy-induced peripheral neuropathy (CIPN), and chemotherapy-induced alopecia (CIA). This review aims to provide an updated overview of emerging strategies for the management and prevention of these immediate and long-lasting side effects. The use of integrative medicine including cannabis continues to evolve in the realm of CINV and cancer-related anorexia. Although no pharmaceutical agent has been approved for the prevention of CIPN, cryotherapy, compression therapy and, more recently, cryocompression therapy have shown benefit in small trials, but there are concerns with tolerability especially related to cryotherapy. More data are necessary to determine an effective and tolerable option to prevent CIPN in large, randomized studies. Scalp cooling (SC), which has a similar mechanism to cryotherapy and compression therapy for CIPN prevention, has proven to be an effective and tolerable approach in randomized studies and has significantly limited CIA, an entity that definitively affects the QOL of patients living with cancer. Taken together, cannabis, cryotherapy, compression and cryocompression therapy, and SC all strive to improve the QOL of patients living with cancer by minimizing the side effects of chemotherapeutic agents.

Integrative Oncology and the Clinical Care Network: Challenges and Opportunities.

Integrative oncology is a new and growing field of cancer care. Integrative oncology is a patient-centered, evidence-based field of comprehensive cancer care that utilizes integrative therapies such as mind-body practices, acupuncture, massage, music therapy, nutrition, and exercise in collaboration with conventional cancer treatments. Patient interest and utilization has been growing over the past two decades. Clinical research has shown the benefits of these approaches to improving symptom management and quality of life, and is now being incorporated into national guidelines from the National Comprehensive Cancer Network (NCCN) and American Society for Clinical Oncology (ASCO). The availability of these services at cancer centers is growing, although the structure and implementation of integrative oncology remains highly variable. This article discusses the benefits of integrative oncology and provides an overview of the current state of integrative oncology programs nationwide. Current challenges and opportunities for cancer centers to provide integrative services is reviewed in the areas of programmatic structure, clinical service, education, and research.

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.

A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides.

Parkinson's disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson's-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.

Retrospective Outcomes of a New Acupuncture Service at a Comprehensive Cancer Center.

Introduction: Among cancer centers, patients' interest in acupuncture is growing, in addition to clinical research in the intervention. Their National Cancer Institute-designated comprehensive cancer center piloted an acupuncture service. Their aim was to assess whether acupuncture impacted patient self-reported symptoms as delivered clinically and discuss their implementation strategy. Methods: Patients undergoing acupuncture at a comprehensive cancer center from June 2019 to March 2020 were asked to complete a modified Edmonton Symptom Assessment Scale (ESAS) before and after each session. The authors evaluated symptom changes after acupuncture in both outpatient and inpatient settings. A change of ≥1 U, on the 0-10 scale, was considered clinically significant. Results: Three hundred and nine outpatient and 394 inpatient acupuncture sessions were provided to patients at the comprehensive cancer center during this period, of which surveys from 186 outpatient (34 patients) and 124 inpatient (57 patients) sessions were available for analysis. The highest pretreatment symptoms reported by outpatients were neuropathy (5.78), pain (5.58), and tiredness (5.59). Outpatients receiving acupuncture reported clinically significant improvements in pain (ESAS score change of -2.97), neuropathy (-2.68), decreased lack of well-being (-2.60), tiredness (-1.85), nausea (-1.83), anxiety (-1.56), activities of daily living issues (-1.32), depression (-1.23), anorexia (-1.19), insomnia (-1.14), and shortness of breath (-1.14). The most severe pretreatment symptoms reported by inpatients were pain (6.90), insomnia (6.16), and constipation (5.44). Inpatients receiving acupuncture reported clinically significant improvements in anxiety (-3.69), nausea (-3.61), insomnia (-3.26), depression (-2.98), pain (-2.77), neuropathy (-2.68), anorexia (-2.20), constipation (-1.95), and diarrhea (-1.26). Conclusion: Both outpatient and inpatient participants in this pilot acupuncture program reported clinically significant improvements in symptoms after a single acupuncture treatment. Some differences between the outpatient and inpatient settings warrant further investigation.

Tissue-embedded stretchable nanoelectronics reveal endothelial cell-mediated electrical maturation of human 3D cardiac microtissues.

Clinical translation of stem cell therapies for heart disease requires electrical integration of transplanted cardiomyocytes. Generation of electrically matured human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is critical for electrical integration. Here, we found that hiPSC-derived endothelial cells (hiPSC-ECs) promoted the expression of selected maturation markers in hiPSC-CMs. Using tissue-embedded stretchable mesh nanoelectronics, we achieved a long-term stable map of human three-dimensional (3D) cardiac microtissue electrical activity. The results revealed that hiPSC-ECs accelerated the electrical maturation of hiPSC-CMs in 3D cardiac microtissues. Machine learning-based pseudotime trajectory inference of cardiomyocyte electrical signals further revealed the electrical phenotypic transition path during development. Guided by the electrical recording data, single-cell RNA sequencing identified that hiPSC-ECs promoted cardiomyocyte subpopulations with a more mature phenotype, and multiple ligand-receptor interactions were up-regulated between hiPSC-ECs and hiPSC-CMs, revealing a coordinated multifactorial mechanism of hiPSC-CM electrical maturation. Collectively, these findings show that hiPSC-ECs drive hiPSC-CM electrical maturation via multiple intercellular pathways.

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.

Proposed Implementation of a Patient-Centered Self-Assessment Tool for Patients with Neuroendocrine Tumors among Academic and Community Practice Sites: The City of Hope Model.

Neuroendocrine tumors are a rare type of cancer found in hormone-producing cells throughout the body. Research on disease-specific patient education assessments in this population is lacking. We previously demonstrated the feasibility and validity of NET VITALS, a patient-centered self-assessment designed to improve patients' knowledge of their neuroendocrine tumor diagnosis/treatment and facilitate communication with their physician. In this report, we provide a brief overview of patient assessments that have been used for patients with neuroendocrine tumors. We summarize NET VITALS and present a proposed infrastructure for its implementation into standard clinical care in both academic and community practice settings at City of Hope. Incorporating NET VITALS into standard of care treatment for patients with neuroendocrine tumors may improve patients' overall clinical care experience.

Functional substitutions of amino acids that differ between GDF11 and GDF8 impact skeletal development and skeletal muscle.

Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGF-ß family proteins that interact with nearly identical signaling receptors and antagonists. However, GDF11 appears to activate SMAD2/3 more potently than GDF8 in vitro and in vivo. The ligands possess divergent structural properties, whereby substituting unique GDF11 amino acids into GDF8 enhanced the activity of the resulting chimeric GDF8. We investigated potentially distinct endogenous activities of GDF11 and GDF8 in vivo by genetically modifying their mature signaling domains. Full recoding of GDF8 to that of GDF11 yielded mice lacking GDF8, with GDF11 levels ∼50-fold higher than normal, and exhibiting modestly decreased muscle mass, with no apparent negative impacts on health or survival. Substitution of two specific amino acids in the fingertip region of GDF11 with the corresponding GDF8 residues resulted in prenatal axial skeletal transformations, consistent with Gdf11-deficient mice, without apparent perturbation of skeletal or cardiac muscle development or homeostasis. These experiments uncover distinctive features between the GDF11 and GDF8 mature domains in vivo and identify a specific requirement for GDF11 in early-stage skeletal development.

Mistletoe lectin inhibits growth of Myc-amplified small-cell lung cancer.

BACKGROUND: Small-cell lung cancer (SCLC) is the deadliest form of lung cancer but lacks targeted therapies. METHODS: We studied the effect of the natural product mistletoe lectin (ML) in pre-clinical models of SCLC, focusing on cell lines with amplification of the myc family oncogenes C-myc and N-myc. RESULTS: We found that ML treatment inhibits growth of SCLC cell lines in culture and induces apoptosis. ML treatment also decreases the expression of the amplified myc proteins. Over-expression of either C-myc or N-myc results in enhanced SCLC cell sensitivity to ML. In a mouse xenograft model of SCLC, treatment with ML results in decreased tumor growth over 4 weeks with evidence of increased apoptosis in tumors from treated animals. CONCLUSION: Overall, our results demonstrate that ML exhibits therapeutic potential in SCLC, that is at least partially dependent on myc protein expression.

Physiological and Pathophysiological Roles of Thioredoxin Interacting Protein: A Perspective on Redox Inflammation and Metabolism.

Significance: Thioredoxin interacting protein (TXNIP) is a member of the arrestin fold superfamily with important cellular functions, including cellular transport, mitochondrial energy generation, and protein cycling. It is the only arrestin-domain protein known to covalently bind to thioredoxin and plays roles in glucose metabolism, inflammation, apoptosis, and cancer. Recent Advances: The crystal structure of the TXNIP-thioredoxin complex provided details about this fascinating interaction. Recent studies showed that TXNIP is induced by endoplasmic reticulum (ER) stress, activates NLR family pyrin domain containing 3 (NLRP3) inflammasomes, and can regulate glucose transport into cells. The tumor suppressor role of TXNIP in various cancer types and the role of TXNIP in fructose absorption are now described. Critical Issues: The influence of TXNIP on redox state is more complex than its interaction with thioredoxin. Future Directions: It is incompletely understood which functions of TXNIP are thioredoxin-dependent. It is also unclear whether TXNIP binding can inhibit glucose transporters without endocytosis. TXNIP-regulated control of ER stress should also be investigated further. Antioxid. Redox Signal. 38, 442-460.