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It is known that transient receptor potential ankyrin 1 (TRPA1) channels, expressed by nociceptors, contribute to neuropathic pain. Here we show that TRPA1 is also expressed in Schwann cells. We found that in mice with partial sciatic nerve ligation, TRPA1 silencing in nociceptors attenuated mechanical allodynia, without affecting macrophage infiltration and oxidative stress, whereas TRPA1 silencing in Schwann cells reduced both allodynia and neuroinflammation. Activation of Schwann cell TRPA1 evoked NADPH oxidase 1 (NOX1)-dependent H 2 O 2 release, and silencing or blocking Schwann cell NOX1 attenuated nerve injury-induced macrophage infiltration, oxidative stress and allodynia. Furthermore, the NOX2-dependent oxidative burst, produced by macrophages recruited to the perineural space activated the TRPA1–NOX1 pathway in Schwann cells, but not TRPA1 in nociceptors. Schwann cell TRPA1 generates a spatially constrained gradient of oxidative stress, which maintains macrophage infiltration to the injured nerve, and sends paracrine signals to activate TRPA1 of ensheathed nociceptors to sustain mechanical allodynia. Following peripheral nerve injury, influx of immune cells to the site may contribute to the development of chronic pain. Here the authors show that TRPA1 is expressed on Schwann cells and contributes to immune cell influx in a mouse model of neuropathic pain.

Pain evoked by visceral inflammation is often ‘referred’ to the somatic level. Transient receptor potential ankyrin 1 (TRPA1) has been reported to contribute to visceral pain-like behavior in dextran sulfate sodium (DSS)-evoked colitis. However, the role of TRPA1 in somatic component of hypersensitivity due to visceral inflammation is unknown. The present study investigated the role of TRPA1 in colitis-evoked mechanical hypersensitivity at the somatic level. Colitis was induced in mice by adding DSS to drinking water for one week. Control and DSS-treated mice were tested for various parameters of colitis as well as mechanical pain sensitivity in abdominal and facial regions. DSS treatment caused mechanical hypersensitivity in the abdominal and facial skin. Pharmacological blockade or genetic deletion of TRPA1 prevented the colitis-associated mechanical hypersensitivity in the abdominal and facial skin areas although the severity of colitis remained unaltered. DSS treatment increased expression of TRPA1 mRNA in cultured dorsal root ganglion (DRG) neurons, but not trigeminal ganglion neurons, and selectively enhanced currents evoked by the TRPA1 agonist, allyl isothiocyanate, in cultured DRG neurons. Our findings indicate that the TRPA1 channel contributes to colitis-associated mechanical hypersensitivity in somatic tissues, an effect associated with upregulation of TRPA1 expression and responsiveness in DRG nociceptors.

In recent years, photobiomodulation (PBM) has been recognized as a physical therapy in wound management. Despite several published research papers, the mechanism underlying photobiomodulation is still not completely understood. The investigation about application of blue light to improve wound healing is a relatively new research area. Tests in selected patients evidenced a stimulation of the healing process in superficial and chronic wounds treated with a blue LED light emitting at 420 nm; a study in animal model pointed out a faster healing process in superficial wound, with an important role of fibroblasts and myofibroblasts. Here, we present a study aiming at evidencing the effects of blue light on the proliferation and metabolism in fibroblasts from healthy skin and keratinocytes. Different light doses (3.43, 6.87, 13.7, 20.6, 30.9 and 41.2 J/cm2) were used to treat the cells, evidencing inhibitory and stimulatory effects following a biphasic dose behavior. Electrophysiology was used to investigate the effects on membrane currents: healthy fibroblasts and keratinocytes showed no significant differences between treated and not treated cells. Raman spectroscopy revealed the mitochondrial Cytochrome C (Cyt C) oxidase dependence on blue light irradiation: a significant decrease in peak intensity of healthy fibroblast was evidenced, while it is less pronounced in keratinocytes. In conclusion, we observed that the blue LED light can be used to modulate metabolism and proliferation of human fibroblasts, and the effects in wound healing are particularly evident when studying the fibroblasts and keratinocytes co-cultures.

Keloids are an exuberant response to wound healing, characterized by an exaggerated synthesis of collagen, probably due to the increase of fibroblasts activity and to the reduction of their apoptosis rate: currently no standard treatments or pharmacological therapies are able to prevent keloid recurrence. To reach this goal, in recent years some physical treatments have been proposed, and among them the PhotoBioModulation therapy (PBM). This work analyses the effects of a blue LED light irradiation (410–430 nm, 0.69 W/cm2 power density) on human fibroblasts, isolated from both keloids and perilesional tissues. Different light doses (3.43–6.87–13.7–20.6–30.9 and 41.2 J/cm2) were tested. Biochemical assays and specific staining were used to assess cell metabolism, proliferation and viability. Micro-Raman spectroscopy was used to explore direct effects of the blue LED light on the Cytochrome C (Cyt C) oxidase. We also investigated the effects of the irradiation on ionic membrane currents by patch-clamp recordings. Our results showed that the blue LED light can modulate cell metabolism and proliferation, with a dose-dependent behavior and that these effects persist at least till 48 h after treatment. Furthermore, we demonstrated that the highest fluence value can reduce cell viability 24 h after irradiation in keloid-derived fibroblasts, while the same effect is observed 48 h after treatment in perilesional fibroblasts. Electrophysiological recordings showed that the medium dose (20.6 J/cm2) of blue LED light induces an enhancement of voltage-dependent outward currents elicited by a depolarizing ramp protocol. Overall, these data demonstrate the potentials that PBM shows as an innovative and minimally-invasive approach in the management of hypertrophic scars and keloids, in association with current treatments.

We have previously shown that a subset of sinonasal intestinal-type adenocarcinomas (ITAC) shows activation of the epidermal growth factor-receptor (EGFR) pathway. In this study we examine the status of the EGFR, KRAS and BRAF genes in a series of sinonasal intestinal (ITAC) and non-intestinal type adenocarcinomas (non-ITAC). Eighteen ITACs and 12 non-ITACs were studied immunohistochemically for EGFR expression. Point mutations were analyzed for EGFR exons 19 and 21, KRAS exon 2 and BRAF exon 15 by direct sequencing. Non-ITACs showed significantly higher expression of EGFR ( p  = 0.015). Mutation analysis revealed one ITAC with EGFR and one ITAC with KRAS mutation, while two non-ITACs presented mutation of BRAF. We conclude that a subset of sinonasal adenocarcinomas shows overexpression of EGFR, while activating mutations of the signaling cascade downstream of EGFR are rare, suggesting that these tumors could be good candidates for anti-EGFR therapies.

Thermal ablation (TA) procedures are effective treatments for several kinds of cancers. In the recent years, several medical imaging advancements have improved the use of image-guided TA. Imaging technique plays a pivotal role in improving the ablation success, maximizing pre-procedure planning efficacy, intraprocedural targeting, post-procedure monitoring and assessing the achieved result. Fusion imaging (FI) techniques allow for information integration of different imaging modalities, improving all the ablation procedure steps. FI concedes exploitation of all imaging modalities’ strengths concurrently, eliminating or minimizing every single modality’s weaknesses. Our work aims to give an overview of FI, explain and analyze FI technical aspects and its clinical applications in ablation therapy and interventional oncology.

It has been hypothesized that the development of sinonasal intestinal-type adenocarcinoma (ITAC) occurs through intestinal metaplasia (IM) of the respiratory and/or glandular epithelium. The aim of this study was to characterize the histological, immunohistochemical, and molecular features of sinonasal IM. Histologic slides from 29 consecutive surgical specimens of ITAC were retrieved. Sections were stained for CDX2, cytokeratin 20 (CK20), MUC2, and p53. The status of TP53 gene exons 4–9 was assessed separately in areas of IM and in ITAC. Foci of IM were detected in eight cases (27.5 %). They were all positive for CK20 and CDX2, while MUC2 was detected in six cases (75 %). In six cases (75 %), the metaplastic foci showed signs of dysplasia, including nuclear enlargement with increased nucleus to cytoplasm ratio, nuclear hyperchromasia, loss of nuclear polarity, and presence of prominent nucleoli. P53 nuclear immunoreactivity was observed in four cases. TP53 gene sequencing was successfully performed in six cases and revealed the same mutation in both IM and ITAC in two cases (c.832C > T and c.215G > C), while another ITAC showed a mutation that was not present in the adjacent IM (c.536A > G). In conclusion, our study suggests a possible clonal relationship between areas of sinonasal IM and ITAC, indicating that IM may represent a precursor lesion of ITAC. Improving the knowledge on the morphological and molecular features of IM is a key step to identify reliable biomarkers to determine the risk of sinonasal ITAC development.

Neuroendocrine neoplasms represent a rare subset of tumors in the sinonasal tract. Combined tumors, with an endocrine and a non-neuroendocrine component, are exceedingly rare, and mainly consist of a combination of neuroendocrine carcinoma with adenocarcinomas. We present the clinico-pathologic and immunohistochemical features of a neuroendocrine carcinoma combined with squamous cell carcinoma, arising in the maxillary sinus. In addition, we evaluated the clonal origin of the two components through analysis of TP53 gene status. Both components were positive for cytokeratins AE1/AE3, while the squamous cell carcinoma was positive for cytokeratin 5/6 and p63, and the neuroendocrine carcinoma showed immunoreactivity for neuron specific enolase, chromogranin, synaptophysin and CD56. In situ hybridization for human papilloma virus and Epstein–Barr virus were negative in both components. A missense mutation in TP53 exon 7 (c.734G>C) and strong nuclear immunostaining for p53 were detected only in the neuroendocrine carcinoma. This suggests that the tumor either derived from one precursor cell with squamous differentiation, which underwent TP53 mutation and acquisition of a neuroendocrine phenotype, or it derived from two separate clones, one with mutated TP53 and neuroendocrine differentiation, and the other with wild type TP53 and squamous differentiation (collision tumor).

To investigate the prevalence, incidence of players reporting shoulder injuries in a non-probability sample of Italian amateur soccer players. We also wanted to explore the characteristics of injuries, predictive factors and differences between men's and women's leagues. Cross-sectional study. Anonymous online survey. Adult athletes playing on a first team of the Italian National Amateur Soccer League. Period prevalence, incidence, and characteristics of players reporting shoulder injuries over a soccer season. Fifty-one out of 431 respondents reported shoulder injuries. The pooled period prevalence was 12.0% (95%CI [9, 15]), with an incidence of .46 (95%CI [.35, .60]) injured/1000 h of players exposure. Goalkeepers were more likely to be injured than outfield players (OR 5.15, 95%CI [2.27, 11.25]). The injury type stated was mainly contusion (n = 22, 43.1%). Among those reporting injuries, thirty-four (66.6%) respondents stated 0–7 days as time loss from sport activity, with no significant difference due to role (p=.161) Shoulder injuries have a relatively low impact on the participation of adult amateur players in soccer activities. Technical and medical staff need to monitor players after an injury to the shoulder in order to provide appropriate training, prevention of complications and educational programs. •Soccer is among the sports activities that often cause acute shoulder injuries.•Information on the characteristics of shoulder injuries in adult players is lacking.•The ratio of injured players per 1000 h of game time to training time was 12:1.•Loss of time from training and competition was mostly limited to seven days.•Adequate training, prevention and education programs are needed for amateur players.

HOX genes encode transcription factors, which play a key role in morphogenesis and cell differentiation during embryogenesis. Several observations indicate that a deregulated expression of these genes may result in tumor development and progression. Actually, several HOX genes are aberrantly expressed in many tumors and cell lines derived from them. Little is known about the expression of HOX genes in brain tumors. In the present work, we study the relative expression of HOX-D genes (D1, D3, D4, D8, D9, D10, D11, D12, D13) with real-time polymerase chain reaction in a group of 14 pediatric low-grade gliomas. We compare the HOX-D expression level of the 14 tumors with the average expression level of six non-neoplastic human brain tissues. HOX-D1 and HOX-D12 resulted over-expressed in neoplastic samples with respect to non-neoplastic brain parenchyma. Conversely, HOX-D3 was expressed at a lower level in gliomas with respect to non-neoplastic brain. HOX-D4, HOX-D11, and HOX-D13 were never expressed. HOX-D8, HOX-D9, and HOX-D10 were exceptionally expressed in non-neoplastic samples and irregularly expressed in tumors. The observation that all but three HOX-D genes studied are expressed with different pattern in neoplastic and non-neoplastic brain tissue may support the hypothesis that HOX-D genes play a role in the pathogenesis of pediatric low-grade gliomas.