Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression.

Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis.

InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma.

Introduction: We are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients.

Manipulating adrenergic stress receptor signalling to enhance immunosuppression and prolong survival of vascularized composite tissue transplants.

Background: Vascularized composite tissue allotransplantation (VCA) to replace limbs or faces damaged beyond repair is now possible. The resulting clear benefit to quality of life is a compelling reason to attempt this complex procedure. Unfortunately, the high doses of immunosuppressive drugs required to protect this type of allograft result in significant morbidity and mortality giving rise to ethical concerns about performing this surgery in patients with non-life-threatening conditions.

Prognostic biomarkers of cutaneous melanoma.

Background/purpose: Melanomas account for only approximately 4% of diagnosed skin cancers in the United States but are responsible for the majority of deaths caused by skin cancer. Both genetic factors and ultraviolet (UV) radiation exposure play a role in the development of melanoma. Although melanomas have a strong propensity to metastasize when diagnosed late, melanomas that are diagnosed and treated early pose a low mortality risk.

AT-RvD1 Mitigates Secondhand Smoke-Exacerbated Pulmonary Inflammation and Restores Secondhand Smoke-Suppressed Antibacterial Immunity.

Cigarette smoke is a potent proinflammatory trigger contributing to acute lung injury and the development of chronic lung diseases via mechanisms that include the impairment of inflammation resolution. We have previously demonstrated that secondhand smoke (SHS) exposure exacerbates bacterial infection-induced pulmonary inflammation and suppresses immune responses. It is now recognized that resolution of inflammation is a bioactive process mediated by lipid-derived specialized proresolving mediators that counterregulate proinflammatory signaling and promote resolution pathways.

Cutaneous Leiomyosarcoma: A SEER Database Analysis.

Background: Cutaneous leiomyosarcoma is a rare dermal neoplasm usually arising from the pilar smooth muscle. It is considered a relatively indolent neoplasm, and there is debate whether designation as sarcoma is appropriate. Owing to some conflicting data in the literature, however, its behavior warrants further clarification.

Recombinant Sialyltransferase Infusion Mitigates Infection-Driven Acute Lung Inflammation.

Inappropriate inflammation exacerbates a vast array of chronic and acute conditions with severe health risks. In certain situations, such as acute sepsis, traditional therapies may be inadequate in preventing severe organ damage or death. We have previously shown cell surface glycan modification by the circulating sialyltransferase ST6Gal-1 regulates inflammatory cell production via a novel extrinsic glycosylation pathway.

Secondhand Smoke Induces Inflammation and Impairs Immunity to Respiratory Infections.

Despite advocacy to reduce smoking-related diseases, >1 billion people worldwide continue to smoke. Smoking is immunosuppressive and an important etiological factor in the development of several human disorders including respiratory diseases like chronic obstructive pulmonary disease. However, there is a critical gap in the knowledge of the role of secondhand smoke (SHS) in inflammation and immunity.

The blood-borne sialyltransferase ST6Gal-1 is a negative systemic regulator of granulopoiesis.

Responding to systemic demands in producing and replenishing end-effector blood cells is predicated on the appropriate delivery and interpretation of extrinsic signals to the HSPCs. The data presented herein implicate the systemic, extracellular form of the glycosyltransferase ST6Gal-1 in the regulation of late-stage neutrophil development. ST6Gal-1 is typically a membrane-bound enzyme sequestered within the intracellular secretory apparatus, but an extracellular form is released into the blood from the liver.

Metastatic melanoma with features of blue nevus and tumoral melanosis identified during pembrolizumab therapy.

Metastatic melanoma may exhibit clinical or histologic features of blue nevus. Pembrolizumab therapy is associated with regression and tumoral melanosis. We report on a man with widespread metastatic melanoma on pembrolizumab therapy in whom a blue-grey papule developed on the left side of his neck that clinically resembled a blue nevus and histologically showed features of both blue nevus and tumoral melanosis.

Leukocyte-borne α(1,3)-fucose is a negative regulator of β2-integrin-dependent recruitment in lung inflammation.

Leukocyte recruitment in inflammation is a multistep, sequential cascade where the initial step is the selectin-dependent tethering, followed by the formation of firmer integrin-mediated adhesive forces leading to extravasation. The α(1,3)-fucose-containing sialyl-Lewis X (sLe) is the archetypical ligand on leukocyte surfaces mediating selectin interactions. Canonically, disruption of α(1,3)-fucose formation ablates selectin-mediated adhesion, dramatically reducing trafficking.

Intraoperative intravital microscopy permits the study of human tumour vessels.

Tumour vessels have been studied extensively as they are critical sites for drug delivery, anti-angiogenic therapies and immunotherapy. As a preclinical tool, intravital microscopy (IVM) allows for in vivo real-time direct observation of vessels at the cellular level. However, to date there are no reports of intravital high-resolution imaging of human tumours in the clinical setting.

Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model.

The chemopreventive actions of vitamin D were examined in the N-nitroso-tris-chloroethylurea (NTCU) mouse model, a progressive model of lung squamous cell carcinoma (SCC). SWR/J mice were fed a deficient diet (D) containing no vitamin D3, a sufficient diet (S) containing 2,000 IU/kg vitamin D3, or the same diets in combination with the active metabolite of vitamin D, calcitriol (C; 80 μg/kg, weekly). The percentage (%) of the mucosal surface of large airways occupied by dysplastic lesions was determined in mice after treatment with a total dose of 15 or 25 μmol NTCU (N).

MMP3-mediated tumor progression is controlled transcriptionally by a novel IRF8-MMP3 interaction.

Interferon regulatory factor-8 (IRF8), originally identified as a leukemic tumor suppressor, can also exert anti-neoplastic activities in solid tumors. We previously showed that IRF8-loss enhanced tumor growth, which was accompanied by reduced tumor-cell susceptibility to apoptosis. However, the impact of IRF8 expression on tumor growth could not be explained solely by its effects on regulating apoptotic response.

Cigarette smoke exposure exacerbates lung inflammation and compromises immunity to bacterial infection.

The detrimental impact of tobacco on human health is clearly recognized, and despite aggressive efforts to prevent smoking, close to one billion individuals worldwide continue to smoke. People with chronic obstructive pulmonary disease are susceptible to recurrent respiratory infections with pathogens, including nontypeable Haemophilus influenzae (NTHI), yet the reasons for this increased susceptibility are poorly understood. Because mortality rapidly increases with multiple exacerbations, development of protective immunity is critical to improving patient survival.