Rapid Autopsy to Define Dendritic Cell Spatial Distribution and T Cell Association in Lung Adenocarcinoma.

Immunotherapy response is associated with the presence of conventional dendritic cells (cDCs). cDC type 1 (cDC1) is critically important for CD8+ T cell activation, cDC type 2 (cDC2) regulates CD4+ T cell responses, and mature regulatory cDCs may dampen T cell responses in the tumor microenvironment (TME). However, we lack a clear understanding of cDC distribution in the human TME, cDC prevalence in metastatic sites, and cDC differences in early- versus late-stage disease.

Effects of noninvasive neuromodulation targeting the spinal cord on early learning of force control by the digits.

Aims: Control of finger forces underlies our capacity for skilled hand movements acquired during development and reacquired after neurological injury. Learning force control by the digits, therefore, predicates our functional independence. Noninvasive neuromodulation targeting synapses that link corticospinal neurons onto the final common pathway via spike-timing-dependent mechanisms can alter distal limb motor output on a transient basis, yet these effects appear subject to individual differences.

Force oscillations underlying precision grip in humans with lesioned corticospinal tracts.

Stability of precision grip depends on the ability to regulate forces applied by the digits. Increased frequency composition and temporal irregularity of oscillations in the force signal are associated with enhanced force stability, which is thought to result from increased voluntary drive along the corticospinal tract (CST). There is limited knowledge of how these oscillations in force output are regulated in the context of dexterous hand movements like precision grip, which are often impaired by CST damage due to stroke.

Cost-Effectiveness of Universal Screening for Blunt Cerebrovascular Injury: A Markov Analysis.

Background: Blunt cerebrovascular injury (BCVI) is a significant cause of morbidity and mortality after blunt trauma. Numerous screening strategies exist, although which is used is institution- and physician-dependent. We sought to identify the most cost-effective screening strategy for BCVI, hypothesizing that universal screening would be optimal among the screening strategies studied.

Metabolomics and Physiological Approach to Understand Allelopathic Effect of Horseradish Extract on Onion Root and Lettuce Seed as Model Organism.

In the present study, we assessed the allelopathic effects of various concentrations (0%, 0.1%, 0.2%, and 0.

Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans.

Background: Transcutaneous stimulation of the external ear is thought to recruit afferents of the auricular vagus nerve, providing a means to activate noradrenergic pathways in the central nervous system. Findings from human studies examining the effects of auricular stimulation on noradrenergic biomarkers have been mixed, possibly relating to the limited and variable parameter space explored to date.

Objective: We tested the extent to which brief pulse trains applied to locations of auricular innervation (canal and concha) elicit acute pupillary responses (PRs) compared to a sham location (lobe).

Hydrogel-based electrodes for selective cervical vagus nerve stimulation.

Electrical vagus nerve stimulation (VNS) has the potential to treat a wide variety of diseases by modulating afferent and efferent communication to the heart, lungs, esophagus, stomach, and intestines. Although distal vagal nerve branches, close to end organs, could provide a selective therapeutic approach, these locations are often surgically inaccessible. In contrast, the cervical vagus nerve has been targeted for decades using surgically implantable helix electrodes to treat epileptic seizures and depression; however, to date, clinical implementation of VNS has relied on an electrode with contacts that fully wrap around the nerve, producing non-selective activation of the entire nerve.

ICOS agonism by JTX-2011 (vopratelimab) requires initial T cell priming and Fc cross-linking for optimal T cell activation and anti-tumor immunity in preclinical models.

Immunotherapy checkpoint inhibitors, such as antibodies targeting PD-1 and CTLA-4, have demonstrated the potential of harnessing the immune system to treat cancer. However, despite encouraging results particularly with respect to survival, only a minority of patients benefit from these therapies. In clinical studies aimed at understanding changes in the immune system following immunotherapy treatment, ICOS (Inducible T cell CO-Stimulator) was shown to be significantly up-regulated on CD4+ T cells and this was associated with clinical activity, indicating that ICOS stimulatory activity may be beneficial in the treatment of solid tumors.

Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates.

Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps >2 to 3 centimeters is autografting; however, autografting can result in neuroma formation, loss of sensory function at the donor site, and increased operative time. To address the need for a synthetic nerve conduit to treat large nerve gaps, we investigated a biodegradable poly(caprolactone) (PCL) conduit with embedded double-walled polymeric microspheres encapsulating glial cell line-derived neurotrophic factor (GDNF) capable of providing a sustained release of GDNF for >50 days in a 5-centimeter nerve defect in a rhesus macaque model.

Demonstration of allelopathy of horseradish root extract on lettuce seed.

Allelopathy plays crucial roles in invasive plant viability and agricultural production systems. However, there is no well-established hands-on learning activity to teach the concept of allelopathy. Nor is there an activity which allows students to gain knowledge about glucosinolates and their corresponding enzyme, myrosinase, which are present in almost all Brassica crops.

Cytotoxic T lymphocyte antigen-4 blockade enhances antitumor immunity by stimulating melanoma-specific T-cell motility.

It is now clear that anti-CTLA-4 (α-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-cell function or by depletion of regulatory T cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a "go" signal to effector T cells, thus interrupting T-cell receptor signaling and subsequent T-cell activation. We examined the behavior of melanoma-specific CD8+ pmel-1 T cells in the B16/BL6 mouse model using intravital microscopy.

Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.

Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival.

An acellular biologic scaffold promotes skeletal muscle formation in mice and humans with volumetric muscle loss.

Biologic scaffolds composed of naturally occurring extracellular matrix (ECM) can provide a microenvironmental niche that alters the default healing response toward a constructive and functional outcome. The present study showed similarities in the remodeling characteristics of xenogeneic ECM scaffolds when used as a surgical treatment for volumetric muscle loss in both a preclinical rodent model and five male patients. Porcine urinary bladder ECM scaffold implantation was associated with perivascular stem cell mobilization and accumulation within the site of injury, and de novo formation of skeletal muscle cells.

Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.

Treatment with monoclonal antibody specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has emerged as an effective therapy for the treatment of metastatic melanoma. Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression. We demonstrate, however, that the activity of anti-CTLA-4 antibody on the T reg cell compartment is mediated via selective depletion of T reg cells within tumor lesions.

Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication.

The continual interaction of the immune system with a developing tumor is thought to result in the establishment of a dynamic state of equilibrium. This equilibrium depends on the balance between effector and regulatory T-cell compartments. Whereas regulatory T cells can infiltrate and accumulate within tumors, effector T cells fail to efficiently do so.

Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts.

Adoptive transfer of large numbers of tumor-reactive CD8(+) cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8(+) CTLs, with much less emphasis on the role and contribution of CD4(+) T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4(+) T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation.

Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS).

Inducible costimulator (ICOS), a member of the CD28 family of costimulatory molecules, is upregulated on the surface of T cells following T cell activation and upon binding to its ligand (ICOSL), initiates a cascade of events that can shape key aspects of the immune response. Although initial studies focused on determining the role of ICOS in Th1 versus T helper 2 (Th2) responses, new insights into its biology have revealed the contribution of ICOS to germinal center formation and isotype switching, as well as its relevance to the fate and function of effector and regulatory CD4(+) T cells in the response against self (i.e.

Evaluation of tooth-click triggering and speech recognition in assistive technology for computer access.

Background: Computer access can play an important role in employment and leisure activities following spinal cord injury. The authors' prior work has shown that a tooth-click detecting device, when paired with an optical head mouse, may be used by people with tetraplegia for controlling cursor movement and mouse button clicks.

Objective: To compare the efficacy of tooth clicks to speech recognition and that of an optical head mouse to a gyrometer head mouse for cursor and mouse button control of a computer.

Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma.

Interference with inhibitory immunological checkpoints controlling T cell activation provides new opportunities to augment cancer immunotherapies. Whereas cytotoxic T lymphocyte-associated antigen-4 blockade has shown promising preclinical and clinical results, therapeutic CD4(+)CD25(+) T reg cell depletion has failed to consistently enhance immune-based therapies. Using B16/BL6, a transplantable murine melanoma model, we show a dichotomy between the effects of T reg cell depletion on tumor rejection dependent on whether depletion occurs before (prophylactic) or after (therapeutic) tumor engraftment.

Tooth-click control of a hands-free computer interface.

People with severe upper limb paralysis use devices that monitor head movements to control computer cursors. The three most common methods for producing mouse button clicks are dwell-time, sip-and-puff control, and voice-recognition. Here, we tested a new method in which small tooth-clicks were detected by an accelerometer contacting the side of the head.

Innate immune activation and CD4+ T cell priming during respiratory fungal infection.

Aspergillus fumigatus is a mold that causes a spectrum of diseases, including lethal lung infections in immunocompromised humans and allergic asthma in atopic individuals. T helper 1 (Th1) CD4(+) T cells protect against invasive A. fumigatus infections whereas Th2 CD4(+) T cells exacerbate asthma upon inhalation of A.