Merkel cell carcinoma (MCC) is a polyomavirus-associated skin cancer that is frequently lethal and lacks established prognostic biomarkers. This study sought to identify biomarkers that improve ...prognostic accuracy and provide insight into MCC biology.
Gene expression profiles of 35 MCC tumors were clustered based on prognosis. The cluster of genes overexpressed in good-prognosis tumors was tested for biologic process enrichment. Relevant mRNA expression differences were confirmed by quantitative polymerase chain reaction and immunohistochemistry. An independent set of 146 nonoverlapping MCC tumors (median follow-up, 25 months among 116 living patients) was employed for biomarker validation. Univariate and multivariate Cox regression analyses were performed.
Immune response gene signatures were prominent in patients with good prognoses. In particular, genes associated with cytotoxic CD8+ lymphocytes were overexpressed in tumors from patients with favorable prognoses. In the independent validation set, cases with robust intratumoral CD8+ lymphocyte infiltration had improved outcomes (100% MCC-specific survival, n = 26) compared with instances characterized by sparse infiltration (60% survival, n = 120). Only stage and intratumoral CD8 infiltration (but not age, sex, or CD8+ lymphocytes localized to the tumor-stroma interface) were significant in both univariate and multivariate Cox regression analyses. Notably, traditional histologic identification of tumor-infiltrating lymphocytes was not a significant independent predictor of survival.
Intratumoral CD8+ lymphocyte infiltration can be readily assessed on paraffin-embedded tissue, is independently associated with improved MCC-specific survival, and therefore, may provide prognostic information that enhances established MCC staging protocols.
BACKGROUND: Isotretinoin is an effective treatment for nodulocystic acne. Outside of required pregnancy testing, laboratory monitoring suggested by the manufacturers is vague. Dermatologists, ...therefore, monitor a variety of tests with variable frequency. Despite intense monitoring, the majority of patients do not have gross laboratory abnormalities that warrant changes in management. OBJECTIVE: To survey US dermatologists regarding laboratory monitoring practices while prescribing isotretinoin. METHODS: An online survey sent via e-mail to members of the American Academy of Dermatology. RESULTS: 12,396 surveys were sent with a response rate of ~19%. At baseline >60% of responders check a CBC, LFTs, and a lipid panel. 74% check a monthly lipid panel and LFTs, while 57% check a monthly CBC. 75% report stopping isotretinoin when AST or ALT values reach 3 times normal; 89% report stopping at 4 times normal. When triglycerides reach 4 times normal, 72% stop the medication. CONCLUSIONS: There is no consensus on isotretinoin monitoring tests and frequency, though the majority of dermatologists surveyed monitor a lipid panel and LFTs. J Drugs Dermatol. 2017;16(6):557-564..
This study evaluated how preparing for an interval workout, while wearing a cooling vest, affects core temperature (Tc), heart rate (HR), and interval time in long-distance runners. Nineteen male ...collegiate cross-country runners exercised under two different conditions: (a) wearing a Nike PreCool™ ice vest for one hour prior to the workout (30 minutes resting with the vest and 30 minutes while performing their warm-up); and (b) a control condition utilizing a traditional warm-up. Subjects performed 8 × 1000 m intervals. HR and Tc were measured prior to warm-up, immediately before the first interval, and after each interval. Tc measured before the first interval was significantly lower in the vest condition (difference = 0.37° ± 0.2°C). Differences persisted through the sixth interval. Differences in HR and interval times were nonsignificant between conditions for all intervals Wearing an ice vest prior to and during warm-up effectively lowers Tc during long-distance interval training.
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type (AMPA-type) glutamate receptors (AMPARs) play an important role in plasticity at central synapses. Although there is anatomical evidence for ...AMPAR expression in the peripheral nervous system, the functional role of such receptors in vivo is not clear. To address this issue, we generated mice specifically lacking either of the key AMPAR subunits, GluA1 or GluA2, in peripheral, pain-sensing neurons (nociceptors), while preserving expression of these subunits in the central nervous system. Nociceptor-specific deletion of GluA1 led to disruption of calcium permeability and reduced capsaicin-evoked activation of nociceptors. Deletion of GluA1, but not GluA2, led to reduced mechanical hypersensitivity and sensitization in models of chronic inflammatory pain and arthritis. Further analysis revealed that GluA1-containing AMPARs regulated the responses of nociceptors to painful stimuli in inflamed tissues and controlled the excitatory drive from the periphery into the spinal cord. Consequently, peripherally applied AMPAR antagonists alleviated inflammatory pain by specifically blocking calcium-permeable AMPARs, without affecting physiological pain or eliciting central side effects. These findings indicate an important pathophysiological role for calcium-permeable AMPARs in nociceptors and may have therapeutic implications for the treatment chronic inflammatory pain states.
Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in ...cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐1+/− mice, which are animal correlates of human PRG‐1+/mut carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases.
Synopsis
Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders.
The human PRG‐1 SNP (R345T), present in a monoallelic variant, abolished PRG‐1 function by impeding its ability for LPA internalization due to altered glycosylation.
Monoallelic PRG‐1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress‐related behaviors, an endophenotype of psychiatric disorders.
Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild‐type levels, opening a new therapeutic perspective for stress‐related mental dysfunctions.
Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG‐1. A common loss‐of‐function SNP in PRG‐1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders.
Purpose: Reducing body temperature before exercise is called precooling. Past research suggests that reducing body core temperature (Tc) slightly can result in improved running performance. This ...study evaluated the effects that warming up, while wearing a cooling vest prior to an interval workout, had on Tc, and interval time in long-distance runners. Methods: Nineteen healthy male collegiate cross-country runners were recruited for this study. Each subject warmed up and exercised under two different conditions: (a) an experimental condition in which subjects wore a Nike PreCool® ice vest during warm-up and (b) a control condition. Subjects performed a warm-up followed by running eight 1000 m intervals separated by 90 s of rest. Heart rate (HR) and Tc were measured prior to warm-up, just prior to start of the first interval, and after each interval. Results: Tc measured directly prior to the first interval was significantly lower in the vest condition than the non-vest condition (difference = 0.37°C; P < 0.05). This difference persisted through the end of the sixth interval. Tc rose at a faster rate in the non-vest condition, though this difference was not significant (P = 0.07). Differences in HR and interval times were found to be nonsignificant between conditions for all intervals. Conclusion: Wearing an ice vest prior to and during warm-up effectively lowers Tc during long-distance interval training.
Peripheral injury or inflammation leads to a release of mediators capable of binding to a variety of ion channels and receptors. Among these are the 7-transmembrane receptors (G protein-coupled ...receptors) coupling to G(s), G(i/o), G₁₂/₁₃, or G(q/11) G proteins. Each of the G protein-coupled receptor pathways is involved in nociceptive modulation and pain processing, but the relative contribution of individual signaling pathways in vivo has not yet been worked out. The G(q)/G₁₁ signaling branch is of particular interest because it leads to the activation of phospholipase C-β, protein kinase C, the release of calcium from intracellular stores, and it modulates extracellular regulated kinases. To investigate the contribution of the entire G(q/11)-signaling pathway in nociceptors towards regulation of pain, we generated double-deficient mice lacking G(q/11) selectively in nociceptors using a conditional gene-targeting approach. We observed that nociceptor-specific loss of G(q) and G₁₁ results in reduced pain hypersensitivity following paw inflammation or spared nerve injury. Surprisingly, our behavioral and electrophysiological experiments also indicated defects in basal mechanical sensitivity in G(q/11) mutant mice, suggesting a novel function for G(q/11) in tonic modulation of acute nociception. Patch-clamp recordings revealed changes in voltage-dependent tetrodotoxin-resistant and tetrodotoxin-sensitive sodium channels in nociceptors upon a loss of G(q/11), whereas potassium currents remained unchanged. Our results indicate that the functional role of the G(q)/G₁₁ branch of G-protein signaling in nociceptors in vivo not only spans sensitization mechanisms in pathological pain states, but is also operational in tonic modulation of basal nociception and acute pain.
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