Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo.

Knockdown of GH receptor (GHR) in melanoma cells in vitro downregulates ATP-binding cassette-containing (ABC) transporters and sensitizes them to anti-cancer drug treatments. Here we aimed to determine whether a GHR antagonist (GHRA) could control cancer growth by sensitizing tumors to therapy through downregulation of ABC transporters in vivo. We intradermally inoculated Fluc-B16-F10 mouse melanoma cells into GHA mice, transgenic for a GHR antagonist (GHRA), and observed a marked reduction in tumor size, mass and tumoral GH signaling. Moreover, constitutive GHRA production in the transgenic mice significantly improved the response to cisplatin treatment by suppressing expression of multiple ABC transporters and sensitizing the tumors to the drug. We confirmed that presence of a GHRA and not a mere absence of GH is essential for this chemo-sensitizing effect using Fluc-B16-F10 allografts in GH knockout (GHKO) mice, where tumor growth was reduced relative to that in GH-sufficient controls but did not sensitize the tumor to cisplatin. We extended our investigation to hepatocellular carcinoma (HCC) using human HCC cells in vitro and a syngeneic mouse model of HCC with Hepa1-6 allografts in GHA mice. Gene expression analyses and drug-efflux assays confirm that blocking GH significantly suppresses the levels of ABC transporters and improves the efficacy of sorafenib towards almost complete tumor clearance. Human patient data for melanoma and HCC show that GHR RNA levels correlate with ABC transporter expression. Collectively, our results validate in vivo that combination of a GHRA with currently available anti-cancer therapies can be effective in attacking cancer drug resistance.

Vessel wall MR imaging of central nervous system vasculitis: a systematic review.

PURPOSE: Beyond vessel wall enhancement, little is understood about vessel wall MR imaging (VW-MRI) features of vasculitis affecting the central nervous system (CNS). We reviewed vessel wall MR imaging patterns of inflammatory versus infectious vasculitis and also compared imaging patterns for intracranial versus extracranial arteries of the head and neck. METHODS: Studies reporting vasculitis of the CNS/head and neck and included MR imaging descriptions of vessel wall features were identified by searching PubMed, Scopus, Cochrane, Web of Science, and EMBASE up to June 10, 2020. From 6065 publications, 115 met the inclusion criteria. Data on study characteristics, vasculitis type, MR details, and VW-MRI descriptions were extracted. RESULTS: Studies used VW-MRI for inflammatory (64%), infectious (17%), or both inflammatory and infectious vasculitides (19%). Vasculitis affecting intracranial versus extracranial arteries were reported in 58% and 39% of studies, respectively. Commonly reported VW-MRI features were vessel wall enhancement (89%), thickening (72%), edema (10%), and perivascular enhancement (16%). Inflammatory vasculitides affecting the intracranial arteries were less frequently reported to have vessel wall thickening (p = 0.006) and perivascular enhancement (p = 0.001) than extracranial arteries. Varicella zoster/herpes simplex vasculitis (VZV/HSV, 45%) and primary angiitis of the CNS (PACNS, 22%) were the most commonly reported CNS infectious and inflammatory vasculitides, respectively. Patients with VZV/HSV vasculitis more frequently showed decreased or resolution of vessel wall enhancement after therapy compared to PACNS (89% versus 59%). CONCLUSIONS: To establish imaging biomarkers of vessel wall inflammation in the CNS, VW-MRI features of vasculitis accounting for disease mechanism and anatomy should be better understood.

Assessment of Psychological Factors in Short-Stay Total Hip Arthroplasty Protocol.

BACKGROUND: Several variables are known to correlate with the successful completion of short-stay total hip arthroplasty (THA) protocols. The role of psychological factors remains unclear. We investigated the interaction between patient-reported measures of psychological fitness and successful completion of a short-stay THA protocol. METHODS: We performed a prospective cohort study of patients undergoing elective anterior total hip arthroplasty enrolled in a short-stay protocol (success defined as LOS ≤1 midnight versus failed, LOS >1 midnight). Psychological fitness was measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) domains for self-efficacy, depression, anxiety, emotional support, and the ability to participate in social roles. PROMIS scores, patient demographics, and surgical factors were assessed for a relationship with failure to complete short-stay protocol. RESULTS: Patients that failed to complete the short-stay protocol had higher mean pre-operative PROMIS depression scores (50.8 vs 47.1, P = .025) and anxiety scores (53.6 vs 49.2, P = .008) and higher postoperative PROMIS depression (48.19 vs 43.49, P = .003) and anxiety scores (51.7 vs 47.1, P = .01). Demographic and surgical variables did not correlate with the successful completion of the short-stay protocol. That seventy-six percent of the patients did not adhere to the short-stay protocol was due to the inability to complete a physical therapy standardized safety assessment. CONCLUSION: Higher levels of preoperative and postoperative anxiety and depression in otherwise psychologically healthy patients, is associated with an increased risk of failure to complete a short-stay protocol following THA. Targeted interventions are needed to facilitate rapid recovery in patients with psychological barriers to early mobilization.

Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo.

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH; high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO; high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.

Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIM) are characterized by muscle inflammation and weakness, myositis-specific autoantibodies (MSAs), and extramuscular organ damage. The role of neutrophil dysregulation and neutrophil extracellular traps (NETs) in IIM is unclear. We assessed whether pathogenic neutrophil subsets (low-density granulocytes [LDGs]) and NETs were elevated in IIM, associated with clinical presentation and MSAs, and their effect on skeletal myoblasts and myotubes. Circulating NETs and LDGs were quantified and correlated with clinical measures. Specific MSAs were tested for their ability to induce NETs. NETs and neutrophil gene expression were measured in IIM biopsies. Whether NETs damage skeletal myoblasts and myotubes was tested. Circulating LDGs and NETs were increased in IIM. IIM LDGs had an enhanced ability to form NETs. LDGs and NETs correlated with IIM disease activity and muscle damage. The serum MSA anti-MDA5 correlated with circulating and tissue NETs and directly enhanced NET formation. An enhanced neutrophil gene signature was present in IIM muscle and associated with muscle injury and tissue IFN gene signatures. IIM NETs decreased the viability of myotubes in a citrullinated histone-dependent manner. Dysregulated neutrophil pathways may play pathogenic roles in IIM through their ability to directly injure muscle cells and other affected tissues.