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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

Lithography based additive manufacturing techniques, specifically digital light processing (DLP), are considered innovative manufacturing techniques for orthopaedic implants because of their potential for construction of complex geometries using polymers, metals, and ceramics. Hydroxyapatite (HA) coupons, printed using DLP, were evaluated for biological performance in supporting viability, proliferation, and osteogenic differentiation of the human cell line U2OS and human mesenchymal stem cells (MSCs) up to 35 days in culture to determine feasibility for future use in development of complex scaffold geometries. Contact angle, profilometry, and scanning electron microscopy (SEM) measurements showed the HA coupons to be hydrophilic, porous, and having micro size surface roughness, all within favourable cell culture ranges. The study found no impact of leachable and extractables form the DLP printing process. Cells seeded on coupons exhibited morphologies comparable to conventional tissue culture polystyrene plates. Cell proliferation rates, as determined by direct cell count and the RealTime-Glo TM MT Cell Viability Assay, were similar on HA coupons and standard tissue culture polystyrene plates). Osteogenic differentiation of human MSCs on HA coupons was confirmed using alkaline phosphatase, Alizarin Red S and von Kossa staining. The morphology of MSCs cultured in osteogenic medium for 14 to 35 days was similar on HA coupons and tissue culture polystyrene plates, with osteogenic (geometric, cuboidal morphology with dark nodules) and adipogenic (lipid vesicles and deposits) features. We conclude that the DLP process and LithaBone HA400 slurry are biocompatible and are suitable for osteogenic applications. Coupons served as an effective evaluation design in the characterization and visualization of cell responses on DLP printed HA material. Results support the feasibility of future technical development for 3D printing of sophisticated scaffold designs, which can be constructed to meet the mechanical, chemical, and porosity requirements of an artificial bone scaffold.

Limited vaccine availability and the potential for resistance to antiviral medications have led to calls for establishing the efficacy of non-pharmaceutical measures for mitigating pandemic influenza. Our objective was to examine if the use of face masks and hand hygiene reduced rates of influenza-like illness (ILI) and laboratory-confirmed influenza in the natural setting. A cluster-randomized intervention trial was designed involving 1,178 young adults living in 37 residence houses in 5 university residence halls during the 2007-2008 influenza season. Participants were assigned to face mask and hand hygiene, face mask only, or control group during the study. Discrete-time survival models using generalized estimating equations to estimate intervention effects on ILI and confirmed influenza A/B infection over a 6-week study period were examined. A significant reduction in the rate of ILI was observed in weeks 3 through 6 of the study, with a maximum reduction of 75% during the final study week (rate ratio [RR] = 0.25, [95% CI, 0.07 to 0.87]). Both intervention groups compared to the control showed cumulative reductions in rates of influenza over the study period, although results did not reach statistical significance. Generalizability limited to similar settings and age groups. Face masks and hand hygiene combined may reduce the rate of ILI and confirmed influenza in community settings. These non-pharmaceutical measures should be recommended in crowded settings at the start of an influenza pandemic. [corrected] Clinicaltrials.gov NCT00490633.

How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can directly elicit AP firing in nociceptive as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory processing. When a person touches a hot saucepan, nerve cells in the skin send a message to the brain that causes the person to pull away quickly. Similar messages alert the brain when the skin comes in contact with an object that is cold or causes pain. These nerve cells also help to transmit information about other sensations like holding a ball. Scientists believe that skin cells may release messages that influence how the nerves in the skin respond to sensations. But it is difficult to distinguish the respective roles of skin cells and nerve cells in experiments because these cells often appear to react at the same time. Researchers have discovered that a technique called optogenetics, which originally developed to study the brain, can help. Optogenetics uses genetic engineering to create skin cells that respond to light instead of touch. Baumbauer, DeBerry, Adelman et al. genetically engineered mice to express a light-sensitive protein in their skin cells. When these skin cells were exposed to light, the mice pulled away just like they would if they were responding to painful contact. This behavior coincided with electrical signals in the nerve cells even though the nerve cells themselves were not light sensitive. In further experiments, mice were genetically engineered to express another protein in their skin cells that prevents the neurons from being able to generate electrical signals. When these skin cells were exposed to light, the surrounding nerve cells produced fewer electrical signals. Together, the experiments show that skin cells are able to directly trigger electrical signals in nerve cells. Baumbauer, DeBerry, Adelman et al.'s findings may help researchers to understand why some patients with particular inflammatory conditions are in pain due to overactive nerve cells.

Background. During the influenza A(H1N1) pandemic, antiviral prescribing was limited, vaccines were not available early, and the effectiveness of nonpharmaceutical interventions (NPIs) was uncertain. Our study examined whether use of face masks and hand hygiene reduced the incidence of influenza-like illness (ILI). Methods. A randomized intervention trial involving 1437 young adults living in university residence halls during the 2006–2007 influenza season was designed. Residence halls were randomly assigned to 1 of 3 groups—face mask use, face masks with hand hygiene, or control— for 6 weeks. Generalized models estimated rate ratios for clinically diagnosed or survey-reported ILI weekly and cumulatively. Results. We observed significant reductions in ILI during weeks 4–6 in the mask and hand hygiene group, compared with the control group, ranging from 35% (confidence interval [CI], 9%–53%) to 51% (CI, 13%–73%), after adjusting for vaccination and other covariates. Face mask use alone showed a similar reduction in ILI compared with the control group, but adjusted estimates were not statistically significant. Neither face mask use and hand hygiene nor face mask use alone was associated with a significant reduction in the rate of ILI cumulatively. Conclusions. These findings suggest that face masks and hand hygiene may reduce respiratory illnesses in shared living settings and mitigate the impact of the influenza A(H1N1) pandemic. Trial Registration. ClinicalTrials.gov identifier: NCT00490633.

Background The prevalence, symptom course, and shedding in persons infected with the 4 most common human coronaviruses (HCoV)‐229E, HKU1, NL63, and OC43 are poorly described. Objectives We estimate their prevalence and associated symptoms among college students identified via a social network study design. Patients/Methods We collected 1‐3 samples (n = 250 specimens) from 176 participants between October 2012 and January 17, 2013: participants with acute respiratory infection (ARI; cough and body aches or chills or fever/feverishness) and their social contacts. Virus was detected using RT‐PCR. Results 30.4% (76/250) of specimens tested positive for any virus tested, and 4.8% (12/250) were positive for 2 or more viruses. Human coronaviruses (HCoVs [22.0%; 55/250]), rhinovirus (7.6%; 19/250), and influenza A (6.4%; 16/250) were most prevalent. Symptoms changed significantly over time among ARI participants with HCoV: the prevalence of cough and chills decreased over 6 days (P = .04, and P = .01, respectively), while runny nose increased over the same period (P = .02). HCoV‐NL63 was the most frequent virus detected 6 days following symptom onset (8.9%), followed by rhinovirus (6.7%). Conclusions During a 3‐month period covering a single season, HCoVs were common, even among social contacts without respiratory symptoms; specific symptoms may change over the course of HCoV‐associated illness and were similar to symptoms from influenza and rhinovirus.

Inflammatory pain is thought to arise from increased transmission from nociceptors and recruitment of 'silent' afferents. To evaluate inflammation-induced changes, mice expressing GCaMP3 in cutaneous sensory neurons were generated and neuronal responses to mechanical stimulation in vivo before and after subcutaneous infusion of an 'inflammatory soup' (IS) were imaged in an unanesthetized preparation. Infusion of IS rapidly altered mechanical responsiveness in the majority of neurons. Surprisingly, more cells lost, rather than gained, sensitivity and 'silent' afferents that were mechanically insensitive and gained mechanosensitivity after IS exposure were rare. However, the number of formerly 'silent' afferents that became mechanosensitive was increased five fold when the skin was heated briefly prior to infusion of IS. These findings suggest that pain arising from inflamed skin reflects a dramatic shift in the balance of sensory input, where gains and losses in neuronal populations results in novel output that is ultimately interpreted by the CNS as pain.

In adult mammals, the phenotype of half of all pain-sensing (nociceptive) sensory neurons is tonically modulated by growth factors in the glial cell line-derived neurotrophic factor (GDNF) family that includes GDNF, artemin (ARTN) and neurturin (NRTN). Each family member binds a distinct GFRα family co-receptor, such that GDNF, NRTN and ARTN bind GFRα1, -α2, and -α3, respectively. Previous studies revealed transcriptional regulation of all three receptors in following axotomy, possibly in response to changes in growth factor availability. Here, we examined changes in the expression of GFRα1-3 in response to injury in vivo and in vitro. We found that after dissociation of adult sensory ganglia, up to 27% of neurons die within 4 days (d) in culture and this can be prevented by nerve growth factor (NGF), GDNF and ARTN, but not NRTN. Moreover, up-regulation of ATF3 (a marker of neuronal injury) in vitro could be prevented by NGF and ARTN, but not by GDNF or NRTN. The lack of NRTN efficacy was correlated with rapid and near-complete loss of GFRα2 immunoreactivity. By retrogradely-labeling cutaneous afferents in vivo prior to nerve cut, we demonstrated that GFRα2-positive neurons switch phenotype following injury and begin to express GFRα3 as well as the capsaicin receptor, transient receptor potential vanilloid 1(TRPV1), an important transducer of noxious stimuli. This switch was correlated with down-regulation of Runt-related transcription factor 1 (Runx1), a transcription factor that controls expression of GFRα2 and TRPV1 during development. These studies show that NRTN-responsive neurons are unique with respect to their plasticity and response to injury, and suggest that Runx1 plays an ongoing modulatory role in the adult.

Bladder-innervating primary sensory neurons mediate reflex-driven bladder function under normal conditions, and contribute to debilitating bladder pain and/or overactivity in pathological states. The goal of this study was to examine the respective roles of defined subtypes of afferent neurons in bladder sensation and function via direct optogenetic activation. To accomplish this goal, we generated transgenic lines that express a Channelrhodopsin-2-eYFP fusion protein (ChR2-eYFP) in two distinct populations of sensory neurons: TRPV1-lineage neurons ( ;Ai32, the majority of nociceptors) and Na 1.8 neurons ( ;Ai32, nociceptors and some mechanosensitive fibers). In spinal cord, eYFP+ fibers in ;Ai32 mice were observed predominantly in dorsal horn (DH) laminae I-II, while in ;Ai32 mice they extended throughout the DH, including a dense projection to lamina X. Fiber density correlated with number of retrogradely-labeled eYFP+ dorsal root ganglion neurons (82.2% ;Ai32 vs. 62% ;Ai32) and degree of DH excitatory synaptic transmission. Photostimulation of peripheral afferent terminals significantly increased visceromotor responses to noxious bladder distension (30-50 mmHg) in both transgenic lines, and to non-noxious distension (20 mmHg) in ;Ai32 mice. Depolarization of ChR2+ afferents in ;Ai32 mice produced low- and high-amplitude bladder contractions respectively in 53% and 27% of stimulation trials, and frequency of high-amplitude contractions increased to 60% after engagement of low threshold (LT) mechanoreceptors by bladder filling. In ;Ai32 mice, low-amplitude contractions occurred in 27% of trials before bladder filling, which was pre-requisite for light-evoked high-amplitude contractions (observed in 53.3% of trials). Potential explanations for these observations include physiological differences in the thresholds of stimulated fibers and their connectivity to spinal circuits.

Recent advances in cancer neuroscience necessitate the systematic analysis of neural influences in cancer as potential therapeutic targets in oncology. Here, we outline recommendations for future preclinical and translational research in this field.