IDO1 Is a Therapeutic Target for Pancreatic Cancer-Associated Depression.

Metabolites of tryptophan degradation are known to alter mood. Their effects have only been superficially examined in the context of pancreatic cancer. Herein, we study the role of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme important in the conversion of tryptophan to kynurenine, in a murine model of pancreatic cancer-associated depression. Behavioral tests (open field, forced swim, tail suspension, and elevated plus maze) and biochemical assays (LC-MS metabolomics) were used to characterize a depressive-phenotype in tumor-bearing mice (relative to non-tumor-bearing mice). In addition, we determine whether pharmacologic blockade of IDO1 affects mood in tumor-bearing mice. Immunocompetent mice bearing orthotopic pancreatic tumors exhibit depressive-like behavior relative to non-tumor-bearing mice. Pancreatic tumors strongly express IDO1. Consequently, serum kynurenine levels in tumor-bearing mice are elevated relative to non-tumor-bearing mice. Tumor-bearing mice treated with epacadostat, an IDO1 inhibitor, exhibited improved mood relative to mice receiving vehicle. There was a 95% reduction in serum kynurenine levels in mice receiving epacadostat relative to mice treated with vehicle. As confirmatory evidence of on-target activity, tumors of mice treated with epacadostat exhibited a compensatory increase in IDO1 protein levels. Escitalopram, an approved antidepressant, was ineffective at improving mood in tumor-bearing mice as measured by behavioral assays and did not affect kynurenine levels. Neither epacadostat, nor escitalopram, affected overall survival relative to vehicle. Mice with pancreatic cancer exhibit depressive-like behavior. Epacadostat was effective as an antidepressant for pancreatic cancer-associated depression in mice. These data offer a rationale to consider IDO1 inhibition as a therapeutic strategy to mitigate depressive symptoms in patients with pancreatic cancer.

Prodromal depression and anxiety are associated with worse treatment compliance and survival among patients with pancreatic cancer.

OBJECTIVE: To determine the frequency of depression or anxiety preceding a diagnosis of pancreatic cancer (PC). Further, to examine the association of PC-associated depression or anxiety with treatment compliance and survival. METHODS: 856 patients with PC from a single institution were identified using International Classification of Diseases (ICD) codes. For each case, two non-cancer age- and sex-matched controls were included. Dates of depression or anxiety diagnosis identified using ICD codes were compared to the date of PC diagnosis. The medical record was queried to further explore psychiatric symptoms. Multivariable analyses were performed to examine if prediagnosis depression or anxiety was associated with receipt of treatment or survival. RESULTS: A greater proportion of patients with PC experienced depression or anxiety in the year preceding diagnosis than the overall frequency in controls (4.6% vs. 2.6%, p = 0.005) based on ICD codes. Patients with PC exhibited signs of prodromal depression or anxiety based on ICD codes, clinical documentation of psychiatric symptoms, or initiation of new psychiatric medications more often than controls (20.7% vs. 6.7%, p < 0.001). Prediagnosis depression or anxiety was associated with a reduced likelihood of receiving chemotherapy (OR = 0.58, p = 0.04). There was an associated decrease in overall survival among patients with metastatic disease who experienced depression or anxiety before PC diagnosis (HR = 1.32, p = 0.04). CONCLUSIONS: The frequency of depression or anxiety among patients with PC was higher than the general population. Prediagnosis psychiatric symptoms were associated with reduced chemotherapy utilization and worse overall survival. Thus, timely identification and treatment of these symptoms may improve outcomes.

Sub-10 fs Intervalley Exciton Coupling in Monolayer MoS2 Revealed by Helicity-Resolved Two-Dimensional Electronic Spectroscopy.

The valley pseudospin at the K and K' high-symmetry points in monolayer transition metal dichalcogenides (TMDs) has potential as an optically addressable degree of freedom in next-generation optoelectronics. However, intervalley scattering and relaxation of charge carriers leads to valley depolarization and limits practical applications. In addition, enhanced Coulomb interactions lead to pronounced excitonic effects that dominate the optical response and initial valley depolarization dynamics but complicate the interpretation of ultrafast spectroscopic experiments at short time delays. Employing broadband helicity-resolved two-dimensional electronic spectroscopy (2DES), we observe ultrafast (∼10 fs) intervalley coupling between all A and B valley exciton states that results in a complete breakdown of the valley index in large-area monolayer MoS2 films. These couplings and subsequent dynamics exhibit minimal excitation fluence or temperature dependence and are robust toward changes in sample grain size and inherent strain. Our observations strongly suggest that this direct intervalley coupling on the time scale of optical excitation is an inherent property of large-area MoS2 distinct from dynamic carrier or exciton scattering, phonon-driven processes, and multiexciton effects. This ultrafast intervalley coupling poses a fundamental challenge for exciton-based valleytronics in monolayer TMDs and must be overcome to fully realize large-area valleytronic devices.

A Retrospective Case Study into the Effect of Hoof Lesions on the Lying Behaviour of Holstein-Friesian in a Loose-Housed System.

The association between hoof lesions and lying behaviour was assessed on a Holstein-Friesian dairy farm in England. Twenty-nine cows were included in the study. Cows with claw horn disruption lesions (CHDL, n = 8), soft tissue lesions (STL, n = 6), and no lesions (NL, n = 15) were assessed. Data were collected on parity, days in milk (DIM), and mobility scores. Cows were trimmed and treated, and lesions were recorded by a professional foot trimmer. Lying behaviour was assessed before and after claw trimming. The milking herd (n = 96) prevalence of lameness was 32.3%. Mobility was scored using the Agriculture and Horticulture Development Board (AHDB) Mobility Scoring system. Mobility scores were significantly different across lesions groups (p = 0.022). CHDL cows had a mean mobility score of 2.0 ± 0.9 (mean ± SD), STL were scored 1.2 ± 1.3, and NL cows were 0.9 ± 0.7. CHDL were associated with longer lying times (15.00 ± 1.04 h/d; p = 0.0006) and shorter standing times (9.68 ± 2.38 h/d; p = 0.0351) compared with NL lying times (11.77 ± 1.67 h/d) and standing times (12.21 ± 1.67 h/d). STL cows spent significantly less time lying (11.30 ± 2.44; p = 0.0013) than CHDL but not NL cows. No significant differences were found with any of the other lying behaviours. After trimming, CHDL cows spent significantly less time lying down than before trimming (13.66 ± 0.98; p = 0.0125). Cows with NL spent significantly more time lying down (12.57 ± 1.90; p = 0.0398) and had a shorter minimum lying bout duration (0.17 ± 0.09; p = 0.0236) after trimming. In conclusion, lying behaviour in dairy cattle was impacted by type of hoof lesions and hoof trimming.