Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive solid tumors with a dismal prognosis and an increasing incidence. At the time of diagnosis, more than 85% of patients are ...in an unresectable stage. For these patients, chemotherapy can prolong survival by only a few months. Unfortunately, in recent decades, no groundbreaking therapies have emerged for PDAC, thus raising the question of how to identify novel therapeutic druggable targets to improve prognosis. Recently, the tumor microenvironment and especially its neural component has gained increasing interest in the pancreatic cancer field. A histological hallmark of PDAC is perineural invasion (PNI), whereby cancer cells invade surrounding nerves, providing an alternative route for metastatic spread. The extent of PNI has been positively correlated with early tumor recurrence and reduced overall survival. Multiple studies have shown that mechanisms involved in PNI are also involved in tumor spread and pain generation. Targeting these pathways has shown promising results in alleviating pain and reducing PNI in preclinical models. In this review, we will describe the mechanisms and future treatment strategies to target this mutually trophic interaction between cancer cells to open novel avenues for the treatment of patients diagnosed with PDAC.
Smart Glasses such as Google Glass are mobile computers combining classical Head-Mounted Displays (HMD) with several sensors. Therefore, contact-free, sensor-based experiments can be linked with ...relating, near-eye presented multiple representations. We will present a first approach on how Smart Glasses can be used as an experimental tool for head-centered, context-aware, wearable-technology-enhanced, and inquiry-based learning in physics education. Therefore, we developed an app that is based on the Google Glass platform and designed to perform educational physical experiments on the topic of acoustics. Its initial application is intended for high-school students whose task is to study the relationship between the frequency of the sound generated by hitting a glass of water and the amount of water in the glass. The core idea is to have Google Glass automatically measure both the water fill level with the camera and the sound frequency with the microphone, and incrementally generate a fill level/frequency graph in the HMD. We designed an educational setting and studied its effect on cognitive and affective variables with an intervention-control-group design. While the intervention group analyzed the fill level/frequency relationship with the Google Glass platform, control group 1 worked on the phenomenon using the same platform implemented on a tablet PC. Control group 2 analyzed the phenomenon using a tablet PC with a typical mobile-based education platform. We used a two-way ANCOVA to study learning outcome, wondering, curiosity, cognitive load, and experimentation time as dependent variables of 46 high-school eighth-graders together with group membership and gender influence as independent variables. While the positive effects of using Google Glass as a mobile lab on wondering and curiosity as well as a positive trend for experimentation time were detected, no differences were analyzed for learning achievement. Although students have a higher cognitive load when working with Google Glass compared to other devices, the cognitive load level is very low in general.
Abdominal pain, diarrhea with weight loss, and endocrine insufficiency represent the dominant symptoms of chronic pancreatitis (CP). High intensity of pain and constant pain have been shown to reduce ...quality of life in CP and may result in disability and increased health resource utilization. Various basic challenges and unanswered questions still exist regarding the treatment of pain in CP. Recently, limited evidence has been gained that early surgery for painful disease might be associated with better treatment results. Thus, timing of pancreatic surgery in painful disease represents a major issue that needs to be clarified in future studies. In this context, surveillance of patients is necessary in clinical practice. It appears that a generally accepted classification of the disease represents a major requirement for inter-institutional comparison of data with future progress in clinical research. Among recently proposed classification systems, the M-ANNHEIM classification system of CP with its recently presented M-ANNHEIM Surgery Score might be a useful tool to picture the course of the disease and to monitor treatment results. Future research is required to clarify the possible role of this system in the management of pain in CP. In the present article, we provide an overview of current status, challenges, and unanswered questions in the treatment of pain in CP, and we demonstrate the potential benefits of the M-ANNHEIM classification system in the management of painful CP.
Several guidelines recommend the risk-adapted monitoring of patients with chronic pancreatitis (CP). However, dedicated risk stratification is widely missing in CP. Elderly-CP (disease onset with 60 ...or more years of age) may represent a subgroup of CP subjects with a distinct course of disease.
We aimed to investigate the clinical presentation of elderly-CP, and if elderly-CP requires an adapted monitoring.
Seven hundred forty one patients with CP were analyzed in a multicenter (Mannheim/Germany, n = 537; Gießen/Germany, n = 100; Donetsk/Ukraine, n = 104), cross-sectional, retrospective study and classified according to the M-ANNHEIM classification.
The frequency of elderly-CP was 20% (148/741). In comparison with non-elderly-CP, elderly-CP was less frequently caused by alcohol and nicotine dependency or genetic mutations. In contrast, the frequency of efferent duct abnormalities (p = 0.009, chi-square test) and idiopathic CP (p < 0.0001, chi-square test) increased significantly. The presence of multiple risk factors was found less frequently in elderly-CP than in non-elderly patients (p < 0.0001; chi-square test). Furthermore, elderly-CP was associated with increased rates of pseudocysts (p = 0.0002; chi-square test), endocrine insufficiency (p = 0.001; chi-square test), and the absence of pain (p = 0.04; chi-square test) in the first year of the disease.
In elderly-CP, the course of disease significantly differs from non-elderly-CP. Therefore, individualized monitoring strategies for elderly-CP might be necessary.
In addition to the poor prognosis, excruciating abdominal pain is a major challenge in pancreatic cancer. Neurotropism appears to be the underlying mechanism leading to neuronal invasion. However, ...there is a lack of animal models suitable for translationally bridging in vitro findings with clinical trials. We characterized KPC (Kras
; Trp53
; P48-Cre) and KPPC (Kras
; Trp53
; P48-Cre) mice with genetically determined pancreatic ductal adenocarcinoma (PDAC) and compared them with an orthotopic pancreatic cancer mouse model, healthy littermates and human tissue. We analyzed behavioral correlates of cancer-associated pain and well-being, and studied neuronal remodeling and cytokine expression. Histologically, we found similarities between KPC and KPPC tissue with human samples. Compared to healthy littermates, we detect nerve fiber hypertrophy, which was not restricted to a certain fiber type. Interestingly, while KPPC mice showed significantly reduced well-being, KPC mice emerged to be better suited for studying long-lasting cancer pain that emerges over a slow course of tumor progression. To address the neuroinflammatory correlate of loss of well-being, we studied cytokine levels in KPPC mice and observed a significant upregulation of CXCL16, TNFRSF5, CCL24, CXCL1, CCL22, CLL20 and CX2CL1. In summary, we demonstrate that the KPC mouse model is best suited to studying cancer pain, whereas the KPPC model can be employed to study cancer-associated reduction in well-being.
Axonal sodium channels are attractive targets for chronic pain treatment, and recent evidence suggests that specific targeting of the slow inactivation of sodium channels (NaV) might exert analgesic ...effects. Using a human-like animal model, the pig, we compared changes in the conductive properties of different C-fiber classes on acute administration of lidocaine (nonselective NaV blocker) and lacosamide (selective enhancer of NaV slow inactivation).
Single-fiber extracellular recordings from saphenous nerves were performed. We classified C-fibers according to mechanical responsiveness and amount of activity-dependent slowing (ADS) of conduction velocity. Lidocaine (4 mM; 100 μL), lacosamide (4 mM; 100 μL), or saline was injected intradermally at the stimulation site, and changes of fibers' conductive properties were assessed.
Conduction latencies evoked by lidocaine were more prominent in mechanosensitive (5.5%± 2.1%) than in mechano-insensitive nociceptors (2.5% ± 1%), whereas lacosamide increased conduction latencies to a greater extent in the mechano-insensitive (3% ± 1%) than in mechanosensitive C-nociceptors (2% ± 0.9%). Lidocaine, but not lacosamide, increased electrical thresholds in all mechanosensitive, but not in the mechano-insensitive, C-fibers. Lacosamide blocked conduction and, in addition, reduced ADS in mechano-insensitive nociceptors significantly more than in mechanosensitive nociceptors (ΔADS: 2.4% ± 0.5% vs 1.6% ± 0.5%), whereas lidocaine had opposite effects. Saline had no significant effect on the conductive properties of C-fibers.
Local application of test compounds in pig skin allows for functional assessment of steady-state and use-dependent modulation of sodium channels in nociceptive and nonnociceptive C-fibers. Increased analgesic specificity might derive from selective enhancement of slow inactivation of sodium channels.
Intracutaneous nerve growth factor reduces the activity-dependent slowing of conduction of the mechano-insensitive C-fibers. This long-term change of axonal characteristics might contribute to ...hyperalgesia. Parts of this study have been published in abstract form (Obreja et al., Society for Neuroscience Meeting, 2008, Washington, 668.5).
Nerve growth factor (NGF) induces acute sensitization of nociceptive sensory endings and long-lasting hyperalgesia. NGF modulation of sodium channel expression might contribute to neurotrophin-induced hyperalgesia. Here, we investigated NGF-evoked changes of the activity-dependent slowing of conduction in porcine C-fibers. Animals received intradermal injections of NGF (2
μg or 8
μg) or saline in both hind limbs. Extracellular recordings from the saphenous nerves were performed 1
week later. Based on sensory thresholds and electrically induced activity-dependent slowing (ADS) of axonal conduction, C-fibers were classified as mechano-sensitive afferents, mechano-insensitive afferents, cold nociceptors, and sympathetic efferents. NGF (2
μg) increased conduction velocity in C-fibers from 1.0
±
0.05
m/s to 1.2
±
0.07
m/s. In mechano-insensitive afferents, NGF (8
μg) reduced activity-dependent slowing of conduction, from 5.3
±
0.2% to 3.2
±
0.5% (0.125–0.5
Hz stimulation) and from 28.5
±
1.3% to 20.9
±
1.9% (2
Hz stimulation), such that ADS no longer differentiated between mechano-sensitive and mechano-insensitive fibers. Accordingly, the number of fibers with pronounced ADS decreased but more units with pronounced ADS were mechano-sensitive. Spontaneously active C-fibers were increased above the control level (1%) by NGF 8
μg (8%). The results demonstrate that NGF changes the functional axonal characteristics of mechano-insensitive C-fibers and enhances spontaneous activity thereby possibly contributing to hyperalgesia.
When traveling by rail, you might have experienced the following phenomenon: The train enters a tunnel, and after some seconds a noticeable pressure change occurs, as perceived by your ears or even ...by a rapid wobbling of the train windows. The basic physics is that pressure waves created by the train travel down the tunnel, are reflected at its other end, and travel back until they meet the train again. Here we will show (i) how this effect can be well understood as a kind of large-scale outdoor case of a textbook paradigm, and (ii) how, e.g., a prediction of the tunnel length from the inside of a moving train on the basis of this model can be validated by means of a mobile phone measurement.
Der Beitrag erläutert ein Nutzungskonzept für Smartphones und Tablets als physikalische Experimentiermittel (iMobilePhysics, kurz: iMP) und ordnet zwei Realisierungsbeispiele dieses Konzept für ...Schule und Hochschule an Hand von Designkriterien in den Rahmen des Mobile Assisted Seamless Learning (MSL) ein. Zu den Beispielen werden Studien zur Lernwirksamkeit und Akzeptanz der medienbasierten Lehransätze dargestellt. Die Ergebnisse liefern den Begründungsrahmen, mobiles Experimentieren mit Smartphone und Tablets zur Unterstützung von MSL in die schulische und universitäre Lehre, insbesondere in die Lehramtsausbildung einzubinden. 12.08.2016 | Michael Hirth, Jochen Kuhn, Andreas Müller, Matthias Rohs & Pascal Klein (Kaiserslautern, Genf)
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