An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia

Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, β-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine β-hydroxylase (DBH)–deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophage-sympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients.

Cancer-associated cachexia (CAC) is an energy balance disorder causing unintended loss of body weight due to depletion of white adipose tissue (WAT) and skeletal muscle. This multiorgan and multifactorial syndrome affects up to 80% of cancer patients and is responsible for more than 20% of cancer-associated deaths (1). CAC impedes the effectiveness of anticancer therapies and drastically lowers patients’ quality of life (2).A long list of tumor-borne, often proinflammatory factors, including interleukin-6 (IL-6) (3), parathyroid hormone–related protein (PTHrP) (4), leukemia inhibitory factor (LIF) (5), zinc α-glycoprotein (6), or growth differentiation factor-15 (GDF-15) (7), trigger CAC in mouse models. However, the signaling cascades and catabolic mechanisms that lead to adipose- and muscle tissue wasting remain insufficiently understood (8, 9). IL-6 and PTHrP are among the best studied of these “cachexokines.” Their presence or absence is decisive for the development of CAC in cancer patients and animal models (4, 10–13). Thus, treatment with neutralizing antibodies against IL-6, the IL-6 receptor, or PTHrP ameliorates CAC in various mouse models of CAC (3, 4, 14, 15).CAC-associated WAT atrophy results from a metabolic switch toward decreased lipid synthesis and excessive degradation of lipid stores via enhanced triglyceride degradation (lipolysis) (9, 16). Induced lipolysis is observed in both humans and mice with CAC (17, 18). The absence of metabolic lipases at least partially ameliorates cachexia in murine cancer models (19). The metabolic or catabolic fates of lipolytic products, namely fatty acids (FAs) and glycerol, have not been fully clarified. These may provide energy and/or biosynthetic substrates for cancer cells to promote tumor growth or can be reesterified in WAT, creating an adenosine-triphosphate (ATP)-consuming futile metabolic cycle. Both of these pathways would contribute to the eventual loss of WAT during CAC (20).Another important catabolic pathway in CAC involves the direct oxidation of FAs and glycerol in adipose tissue. This process is promoted by the conversion of white to beige adipocytes called “WAT browning.” During WAT browning, adipocytes adopt a multilocular lipid droplet morphology; express genes that are typical for brown adipocytes, such as uncoupling protein-1 (UCP-1); exhibit elevated substrate oxidation rates; and dissipate energy as heat (21). WAT browning occurs in carcinogen-induced cancer models and genetically engineered mouse models as well as syngeneic and xenogeneic transplant models of murine cancers (3, 4, 22) and depends on the presence of cachexokines. WAT browning also occurs in humans suffering CAC or severe burn trauma (3, 23–25), but the cellular and molecular mechanisms underlying catabolic WAT remodeling in CAC remain unclear.Here, we demonstrate that a macrophage-sympathetic neuron signaling axis generates a high β-adrenergic tone resulting in beige adipogenesis, increased lipid degradation, and WAT atrophy in murine models of CAC. This mechanism triggering hypermetabolism in CAC may offer targets for prevention or treatment of the disease.     

Eating Disorder Day Programs: Is There a Best Format?

The use of a Day Program (DP) format (i.e., intensive daily treatment with no overnight admission) has been shown to be an effective treatment for eating disorders (EDs). The disadvantages, however, include higher cost than outpatient treatment (including costs of meals and staff), greater disruption to patients’ lives, and the use of a highly structured and strict schedule that may interrupt the development of patients’ autonomy in taking responsibility for their recovery. This study investigated whether reducing costs of a DP and the disruption to patients’ lives, and increasing opportunity to develop autonomy, impacted clinical outcomes. Three sequential DP formats were compared in the current study: Format 1 was the most expensive (provision of supported dinners three times/week and extended staff hours); Format 2 included only one dinner/week and provision of a take-home meal. Both formats gave greater support to patients who were not progressing well (i.e., extended admission and extensive support from staff when experiencing feelings of suicidality or self-harm). Format 3 did not provide this greater support but established pre-determined admission lengths and required the patient to step out of the program temporarily when feeling suicidal. Fifty-six patients were included in the analyses: 45% were underweight (body mass index (BMI) < 18.5), 96.4% were female, 63% were given a primary diagnosis of anorexia nervosa (or atypical anorexia nervosa), and mean age was 25.57 years. Clinical outcomes were assessed using self-reported measures of disordered eating, psychosocial impairment, and negative mood, but BMI was recorded by staff. Over admission, 4- and 8-week post-admission, and discharge there were no significant differences between any of the clinical outcomes across the three formats. We can tentatively conclude that decreasing costs and increasing the opportunities for autonomy did not negatively impact patient outcomes, but future research should seek to replicate these results in other and larger populations that allow conclusions to be drawn for different eating disorder diagnostic groups.     

Anti-inflammatory therapeutic approaches to reduce acute atherosclerotic complications

Cardiovascular diseases, including atherosclerosis and the dreaded complication myocardial infarction, represent the major cause of death in western countries. It is now generally accepted that chemokines tightly control and modulate all the events which lead to initiation and progression of cardiovascular diseases, making them very attractive therapeutic targets for the pharmaceutical industry. Various studies showed until now the effects of antagonizing/ neutralizing chemokines or blocking chemokine receptors on cardiovascular pathology. The modulation of the CCL2/CCR2, CCL5/CCR1-CCR5, CXCL12/CXCR4 pathways by preventing receptor--ligand interaction, chemokine-glycosaminoglycan interaction, heteromerization, or interfering with the signaling pathways has proven to have high potential in future drug development. However, while trying to understand the effects of individual chemokines, the biologic consequences of multiple and concomitant chemokine expression on leukocyte migration and function should be taken into account as well. Therefore, many aspects should be considered and carefully scrutinized, when devising therapeutic strategies.     

Dentoskeletal effects of a removable appliance for expansion of the maxillary arch: a postero-anterior cephalometric study

The aim of this study was to evaluate the dentoskeletal effects of early treatment in the primary or early mixed dentition with a removable appliance with expansion springs, assessed on postero-anterior (PA) cephalograms, in patients with a unilateral posterior crossbite when compared with untreated subjects. The treatment group consisted of 23 subjects, 8 males, and 15 females treated with a removable appliance for the expansion of the maxillary arch. The mean age at the start of expansion (T1) was 6 years 2 +/- 17 months, and 8 years +/- 18 months at the end of active therapy and after 1 year of retention (T2), with an observation interval of 22 +/- 7 months. The control group comprised 20 subjects (9 males and 11 females) with an untreated unilateral posterior crossbite. Their mean age was 5 years 9 +/- 15 months at the first observation and 7 years and 4 +/- 16 months at the second examination. The interval between the two observations was 18 +/- 7 months. Nine skeletal and two dental measurements on the transverse plane were assessed. The data from the two groups were compared by means of a Student's t-test for independent samples (P < 0.05). Positive dental and skeletal effects induced by the therapy were observed at T2. The width of the upper dental arch and that of the skeletal maxillary transverse dimension were significantly greater (P < 0.001) in the treatment group when compared with the controls.     

Dermatologic toxicity from immune checkpoint blockade therapy with an interstitial granulomatous pattern

Immunotherapies targeting cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) and the programmed cell death 1 (PD‐1) receptor and its ligand (PD‐L1) have showed significant therapeutic benefit in patients with clinically advanced solid malignancies, including melanoma. However, immune‐related adverse events (irAE) are common, and novel dermatologic toxicities continue to emerge as more patients are treated with immunotherapy. Here we describe a patient treated with combination immunotherapy of ipilimumab and pembrolizumab, who developed asymptomatic erythematous patches on both legs. Histopathologic examination revealed a cutaneous interstitial granulomatous dermatitis. Notably, our patient did not require cessation of immunotherapy for these lesions, which subsequently remained stable, while the patient's melanoma remained controlled. This case expands the dermatologic toxicity profile of immune checkpoint blockade, as recognition of such toxicities is critical to optimal patient management.