Author Correction: Autophagy maintains tumour growth through circulating arginine.

In this Letter, 'released' should have been 'regulated' in the sentence starting: 'Deletion of Atg5 in the host similarly regulated circulating arginine and suppressed tumorigenesis...' This has been corrected online.

Autophagy maintains tumour growth through circulating arginine.

Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation1-5. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass1. Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer6,7. Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth1,8. Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly regulated [corrected] circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer.

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.

The Effects of Patient Characteristics on the Management of Subclinical Hypothyroidism: A Survey of Faculty and Trainees.

OBJECTIVE: There is no universal approach to the management of subclinical hypothyroidism (SCH). This study was designed to determine the impact of patient characteristics on management decisions in SCH amongst physician faculty members and trainees. METHODS: An online survey was distributed to faculty members and medical trainees (ie, interns, residents, and fellows) at multiple academic medical centers. The survey included 9 clinical scenarios describing women with SCH with 5 management options sequenced from most "conservative" (no further treatment or monitoring) to most "aggressive" (treatment with levothyroxine). RESULTS: Of the 194 survey respondents, 95 (49.0%) were faculty members and 99 (51.0%) were trainees. Faculty members were more likely to report being "confident" or "very confident" in making the diagnosis of SCH compared to trainees (95.8% vs 46.5%, P < .001). Faculty members were also more likely to consider patient preference for treatment (60.0% vs 32.3%, P < .001). Among all respondents, the clinical factors that resulted in the highest predicted probability of treatment were hypothyroid symptoms (predicted probability [PP] 68.8%, 95% CI [65.7%-71.9%]), thyroid stimulating hormone >10 mIU/L in a 31-year-old (PP 63.9%, 95% CI [60.3%-67.3%]), and the desire for fertility (PP 52.2%, 95% CI [48.6%-56.0%]). In general, faculty members favored more aggressive treatment across all clinical scenarios. CONCLUSION: The presence of symptoms, thyroid stimulating hormone >10 mIU/L, and desire for fertility were most predictive of the decision to treat in SCH. In several clinical scenarios, both trainee and faculty decision-making demonstrated discordance with general SCH management principles.

A survey of cancer patients, caregivers, and providers regarding familiarity, importance, and utilization of supportive and integrative oncology services.

PURPOSE: Supportive and integrative oncology services aim to improve the quality of life of cancer patients. This study characterizes the views of these services among cancer patients, caregivers, and providers at a comprehensive cancer center. METHODS: A cross-sectional survey was administered in 2017-2018. The survey asked about participants' familiarity, perceived importance, use, accessibility, and barriers to 19 supportive and integrative oncology services using a Likert scale. Data were analyzed using the Kruskal-Wallis test and a proportional odds regression model. RESULTS: A total of 976 surveys were obtained (604 patient surveys, 199 caregiver surveys, 173 provider surveys). Patients were mostly female (56.3%), ≥60 years old (59.4%), and Caucasian (66%). Providers were an even distribution of nurses, physicians, and advanced practice providers. Patients felt social work and nutrition services were the most familiar (36.4% and 34.8%) and the most important (46.3% and 54.5%). Caregivers were also most familiar with those two services, but felt that nutrition and learning resources were most important. Social work and nutrition were easiest to access and used the most by both patients and providers. There was a positive correlation between accessibility and perceived importance. Being unaware was the most common barrier identified by patients (38.4%), providers (67.1%), and caregivers (33.7%). CONCLUSION: Social work and nutrition services were most familiar to respondents, and also generally the most important, accessible, and utilized. Lack of awareness was the most common barrier cited and suggests that increased efforts to educate patients and providers about other services available are needed.

Interest and Willingness to Pay for Integrative Therapies of Patients With Cancer and Caregivers.

PURPOSE: Complementary and integrative medicine (CIM) services are more prevalent in cancer centers but continue to be underutilized by patients. This study examines perspectives from patients and caregivers about these services being offered at a comprehensive cancer center. METHODS: Patients and caregivers were surveyed about their familiarity, interest, and experience with five CIM therapies: acupuncture, massage, meditation, music therapy, and yoga. Respondents were asked about their interest in and/or paying for these services at baseline, when recommended by their medical team, and when offered in a clinical trial. Respondents were also asked about perceived barriers to accessing these services. Chi-squared tests were performed to explore associations between past experience, interest levels, and willingness to pay. RESULTS: A total of 576 surveys were obtained (464 patients and 112 caregivers). Most respondents identified as White or Caucasian (65.6%), female (57.2%), had been a patient for < 3 years (74.2%), had some college education (73.8%), and made > $40,000 in US dollars as their annual household income (69.1%). Respondents were most familiar with therapeutic massage (34.2%) and least familiar with acupuncture (20.0%). The average interest in these services increased from 53.3% to 64.1% when recommended by a medical professional. Respondents were most willing to pay $1-60 for therapeutic massage (62.3%) and least willing to pay for meditation (43.7%). The main barriers to accessing CIM services were cost (56.0%) and lack of knowledge (52.1%). CONCLUSION: Overall, a significant proportion of patients and caregivers were unfamiliar with these five integrative therapies. Increasing education, decreasing cost, and a recommendation by medical professionals would improve CIM usage.

Structural and biochemical analysis of phosphoethanolamine methyltransferase from the pine wilt nematode Bursaphelenchus xylophilus.

In free-living and parasitic nematodes, the methylation of phosphoethanolamine to phosphocholine provides a key metabolite to sustain phospholipid biosynthesis for growth and development. Because the phosphoethanolamine methyltransferases (PMT) of nematodes are essential for normal growth and development, these enzymes are potential targets of inhibitor design. The pine wilt nematode (Bursaphelenchus xylophilus) causes extensive damage to trees used for lumber and paper in Asia. As a first step toward testing BxPMT1 as a potential nematicide target, we determined the 2.05 Å resolution x-ray crystal structure of the enzyme as a dead-end complex with phosphoethanolamine and S-adenosylhomocysteine. The three-dimensional structure of BxPMT1 served as a template for site-directed mutagenesis to probe the contribution of active site residues to catalysis and phosphoethanolamine binding using steady-state kinetic analysis. Biochemical analysis of the mutants identifies key residues on the ß1d-α6 loop (W123F, M126I, and Y127F) and ß1e-α7 loop (S155A, S160A, H170A, T178V, and Y180F) that form the phosphobase binding site and suggest that Tyr127 facilitates the methylation reaction in BxPMT1.