mTOR regulates T cell exhaustion and PD-1-targeted immunotherapy response during chronic viral infection.

T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted CD8+ T cells are maintained by self-renewing stem-like T cells that provide differentiated TIM3+ cells, a part of which possesses effector-like properties. PD-1-targeted therapies enhance T cell response by promoting differentiation of stem-like T cells toward TIM3+ cells, but the role of mTOR during T cell exhaustion remains elusive.

Current Source Density Imaging Using Regularized Inversion of Acoustoelectric Signals.

Acoustoelectric (AE) imaging can potentially image biological currents at high spatial (~mm) and temporal (~ms) resolution. However, it does not directly map the current field distribution due to signal modulation by the acoustic field and electric lead fields. Here we present a new method for current source density (CSD) imaging.

Optimizing drug inhibition of IgE-mediated anaphylaxis in mice.

Background: Administering allergens in increasing doses can temporarily suppress IgE-mediated allergy and anaphylaxis by desensitizing mast cells and basophils; however, allergen administration during desensitization therapy can itself induce allergic responses. Several small molecule drugs and nutraceuticals have been used clinically and experimentally to suppress these allergic responses.

Objectives: This study sought to optimize drug inhibition of IgE-mediated anaphylaxis.

Single-chip holographic beam steering for lidar by a digital micromirror device with angular and spatial hybrid multiplexing.

A digital micromirror device (DMD) based holographic beam steering technique is reported that multiplexes fine-steering binary amplitude gratings with a coarse-steering programmable blazed grating. The angular spatial light modulation (ASLM) technique encodes the spatial pattern of the binary amplitude grating at the same plane as the angular modulation set by a phase map of the DMD-based beam steering technique. The beam steering technique is demonstrated at 532 nm and implemented into a 905 nm lidar system.

Inhibiting Fibronectin Attenuates Fibrosis and Improves Cardiac Function in a Model of Heart Failure.

Background: Fibronectin (FN) polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblasts (MFs) after cardiac injury. We hypothesized that interfering with FN polymerization or its genetic ablation in fibroblasts would attenuate MF and fibrosis and improve cardiac function after ischemia/reperfusion (I/R) injury.

Methods: Mouse and human MFs were used to assess the impact of the FN polymerization inhibitor (pUR4) in attenuating pathological cellular features such as proliferation, migration, extracellular matrix deposition, and associated mechanisms.

NKT cells contribute to basal IL-4 production but are not required to induce experimental asthma.

CD1d-deficiency results in a selective deletion of NKT cells in mice that is reported to prevent murine allergic airway disease (AAD). Because we find 2-3 fold lower basal IL-4 production in CD1d- mice than in wild-type (WT) mice, we hypothesized that the contribution made by NKT cells to AAD would depend on the strength of the stimulus used to induce the disease. Consequently, we compared CD1d-deficient mice to WT mice in the development of AAD, using several models of disease induction that differed in the type and dose of allergen, the site of sensitization and the duration of immunization.

IL-4 and IL-15 promotion of virtual memory CD8 T cells is determined by genetic background.

Virtual memory (VM) CD8 T cells are present in unimmunized mice, yet possess T-cell receptors specific for foreign antigens. To date, VM cells have only been characterized in C57BL/6 mice. Here, we assessed the cytokine requirements for VM cells in C57BL/6 and BALB/c mice.

Replacing tracheostomy with overnight intubation to manage the airway in head and neck oncology patients: towards an improved recovery.

In maxillofacial head and neck oncology, tracheostomy is often used to secure the airway, but not without risk. This study compared the existing practice of two units: one where tracheostomy was routinely done with one where overnight intubation was used. From both units we retrospectively analysed 50 consecutive patients who had intraoral resection, neck dissection, and microvascular reconstruction for head and neck cancer.

Cdc42 regulates neutrophil migration via crosstalk between WASp, CD11b, and microtubules.

Chemotaxis promotes neutrophil participation in cellular defense by enabling neutrophil migration to infected tissue and is controlled by persistent cell polarization. One long-standing question of neutrophil polarity has been how the pseudopod and the uropod are coordinated. In our previous report, we suggested that Rho GTPase Cdc42 controls neutrophil polarity through CD11b signaling at the uropod, albeit through an unknown mechanism.

TGF-β-responsive myeloid cells suppress type 2 immunity and emphysematous pathology after hookworm infection.

Transforming growth factor β (TGF-β) regulates inflammation, immunosuppression, and wound-healing cascades, but it remains unclear whether any of these functions involve regulation of myeloid cell function. The present study demonstrates that selective deletion of TGF-βRII expression in myeloid phagocytes i) impairs macrophage-mediated suppressor activity, ii) increases baseline mRNA expression of proinflammatory chemokines/cytokines in the lung, and iii) enhances type 2 immunity against the hookworm parasite Nippostrongylus brasiliensis. Strikingly, TGF-β-responsive myeloid cells promote repair of hookworm-damaged lung tissue, because LysM(Cre)TGF-βRII(flox/flox) mice develop emphysema more rapidly than wild-type littermate controls.

Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection.

The molecular mechanisms that drive mucosal T helper type 2 (T(H)2) responses against parasitic helminths and allergens remain unclear. In this study, we demonstrate in mice that TFF2 (trefoil factor 2), an epithelial cell-derived repair molecule, is needed for the control of lung injury caused by the hookworm parasite Nippostrongylus brasiliensis and for type 2 immunity after infection. TFF2 is also necessary for the rapid production of IL-33, a T(H)2-promoting cytokine, by lung epithelia, alveolar macrophages, and inflammatory dendritic cells in infected mice.

First do no harm: should routine tracheostomy after oral and maxillofacial oncological operations be abandoned?

Tracheostomy is traditionally used to secure the airway after major oral and maxillofacial oncological operations. In our unit, as an alternative, patients are intubated overnight without tracheostomy. We reviewed the case notes of 55 patients who had had a major intraoral resection, neck dissection, and reconstruction with a free flap.

Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice.

Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models, and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed.

The role of neuropeptide S and neuropeptide S receptor 1 in regulation of respiratory function in mice.

Genome-wide screening and positional cloning have linked neuropeptide S receptor 1 (NPSR1) with asthma and airway hyperresponsiveness. However, the mechanism by which NPSR1 regulates pulmonary responses remains elusive. Because neuropeptide S and its receptor NPSR1 are expressed in brain regions that regulate respiratory rhythm, and Npsr1-deficient mice have impaired stress and anxiety responses, we aimed to investigate whether neuropeptide S and NPSR1 regulate respiratory function through a central-mediated pathway.

Single-fraction image-guided extracranial radiosurgery for recurrent and metastatic abdominal and pelvic cancers: short-term local control, metabolic response, and toxicity.

Purpose: Extracranial radiosurgery (ECRS) is a novel treatment for inoperable recurrent or metastatic abdominopelvic cancers. However, local control, metabolic response, and acute toxicity remain undefined. We therefore analyzed these endpoints in patients treated with single-fraction image-guided ECRS at Emory University.

Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis.

Alternatively activated macrophages prevent lethal intestinal pathology caused by worm ova in mice infected with the human parasite Schistosoma mansoni through mechanisms that are currently unclear. This study demonstrates that arginase I (Arg I), a major product of IL-4- and IL-13-induced alternatively activated macrophages, prevents cachexia, neutrophilia, and endotoxemia during acute schistosomiasis. Specifically, Arg I-positive macrophages promote TGF-beta production and Foxp3 expression, suppress Ag-specific T cell proliferation, and limit Th17 differentiation.

Prognostic accuracy of computed tomography findings for patients with laryngeal cancer undergoing laryngectomy.

Purpose: The indications for upfront laryngectomy in the management of laryngeal cancer are a functionless larynx and extralaryngeal extension. Practically, clinicians rely on imaging to predict which patients will have T4 disease. Our goal was to review the accuracy of preoperative computed tomography (CT) scanning in determining the necessity for initial laryngectomy for advanced laryngeal cancer.

Evaluation of automatic atlas-based lymph node segmentation for head-and-neck cancer.

Purpose: To evaluate if automatic atlas-based lymph node segmentation (LNS) improves efficiency and decreases inter-observer variability while maintaining accuracy.

Methods And Materials: Five physicians with head-and-neck IMRT experience used computed tomography (CT) data from 5 patients to create bilateral neck clinical target volumes covering specified nodal levels. A second contour set was automatically generated using a commercially available atlas.

Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection.

Th2 cells drive protective immunity against most parasitic helminths, but few mechanisms have been demonstrated that facilitate pathogen clearance. We show that IL-4 and IL-13 protect against intestinal lumen-dwelling worms primarily by inducing intestinal epithelial cells (IECs) to differentiate into goblet cells that secrete resistin-like molecule (RELM) beta. RELM-beta is essential for normal spontaneous expulsion and IL-4-induced expulsion of Nippostrongylus brasiliensis and Heligmosomoides polygyrus, which both live in the intestinal lumen, but it does not contribute to immunity against Trichinella spiralis, which lives within IEC.

Thrombosis of the internal jugular vein: A rare but important operative finding.

Free flap reconstruction following the surgical resection of head and neck malignancy optimally utilises the internal jugular vein as the main recipient vessel for venous anastamosis. We describe an unusual case of thrombosis having arisen de novo within the internal jugular vein and identified at the time of neck dissection. We believe this is the first case of this phenomenon in a patient without a history of thrombophilia, distant malignancy, or local invasion by tumour.

Endogenously produced IL-4 nonredundantly stimulates CD8+ T cell proliferation.

T cell proliferation and survival are regulated by the cytokine receptor common gamma-chain-associated cytokines IL-2, IL-7, and IL-15, while IL-4, another gamma-chain-associated cytokine, is thought to primarily affect T cell quality rather than quantity. In contrast, our experiments reveal that endogenously produced IL-4 is a direct, nonredundant, and potent stimulator of CD8(+) T cell proliferation in Ag- and pathogen-induced CD8(+) T cell responses. These stimulatory effects of IL-4 are observed in both BALB/c and C57BL/6 mice and activate both naive and memory/activated phenotype CD8(+) T cells, although the former are stimulated less than are the latter.

IL-10 and TGF-beta redundantly protect against severe liver injury and mortality during acute schistosomiasis.

The cytokines IL-10 and TGF-beta regulate immunity and inflammation. IL-10 is known to suppress the extent of hepatic damage caused by parasite ova during natural infection with Schistosoma mansoni, but the role of TGF-beta is less clear. Cytokine blockade studies in mice revealed that anti-IL-10R mAb treatment during acute infection modestly increased cytokine production and liver damage, whereas selective anti-TGF-beta mAb treatment had marginal effects.