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Background: Nasopharyngeal carcinoma (NPC) is a malignant tumor of the nasopharynx. Objective: Here, we aimed to understand better the molecular basis for arctigenin (ARG)’s ability to promote NPC 5-8F cell invasion. Methods: We tested the effects of several doses of ARG on 5-8F cells that had been cultured in vitro. We estimated the metabolic activity of cells by The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay. We examined the influence on cell invasion, and migration using Transwell Evaluation. Real-time polymerase chain reaction analysis was used to determine the relative amounts of epidermal growth factor receptor (EGFR), Janus kinase 2 (JAK2) , and transcriptional activator 3 (STAT 3) mRNA expression. Using western blotting, we looked at the level of phosphorylation of specific proteins like EGFR, phosphorylated EGFR, JAK2, and STAT 3. Results: Our findings revealed that ARG inhibited NPC 5-8F cell development in a dose-and time-dependent manner. The invasiveness and mobility of 5-8F cells were significantly suppressed when ARG was overexpressed in a tumor development model. Expression levels of EGFR, JAK2, and STAT 3 mRNA were considerably low in the experimental group. As a consequence of being treated with ARG, lower levels of EGFR, p-EGFR, p-JAK2, and p-STAT3 expression were observed. Conclusion: These results suggest that ARG may prevent NPC 5-8F cells from proliferating, migrating, and invading other tissues. There are a few potential molecular pathways, two of which are the inhibition of EGFR phosphorylation and the reduction of levels of phospho-JAK2 and phospho-STAT3.

Densitometry analysis of the six chemokine array signals identified in Figure 1A was performed and normalized to the average intensity of 3 controls.

A. Close up views of the photomicrographs from Figure 4 show an association between the PC-3 cells and the wild type DRG neurites (Figure 4A), but fewer associations between the PC-3 cells and CCL2 -/- DRG neurites (Figure 4B). B. DRG's were harvested from wild type and CCL2 -/- mice and explanted in 15µl of growth-factor reduced Matrigel. Photographs were taken every other day. Neurite outgrowth rate was measured by measuring the area covered by the neurites and subtracting the center of the DRG (MetaMorph, Molecular Devices, Sunnyvale, CA).

A. A schematic of the DRG and cancer cell co-culture model depicts that cancer cells initially attach to DRG neurites. Over time, the cancer cells migrate along the neurites towards the DRG and also proliferate. B. Close up views of the photomicrographs from Figure 3 show an association between the shControl PC-3 cells and the DRG neurites (Figure 3A), but fewer associations between the shCCR-2 PC-3 cells and DRG neurites (Figure 3B).

PC-3 migration towards DRG as the attractant is reduced by the addition of anti-CCL2 neutralizing antibody at 10 μg/ml to the DRG. In contrast, the addition of non-specific rat IgG at 10 μg/ml shows no inhibitory effects (* p

Sciatic nerve invasion length based on MRI imaging depicted in Figure 5 was assessed for mice injected with shControl or shCCR2 PC-3 cells. Images showing a thickened sciatic nerve were selected and analyzed with ImageJ (* p

As a general sensory disorder, hearing loss was a major concern worldwide. Autophagy is a common cellular reaction to stress that degrades cytoplasmic waste through the lysosome pathway. Autophagy not only plays major roles in maintaining intracellular homeostasis but is also involved in the development and pathogenesis of many diseases. In the auditory system, several studies revealed the link between autophagy and hearing protection. In this review, we aimed to establish the correlation between autophagy and hair cells (HCs) from the aspects of ototoxic drugs, aging, and acoustic trauma and discussed whether autophagy could serve as a potential measure in the protection of HCs.

Surgical treatment of vertigo is performed with in-depth study of inner ear diseases. Achieving an effective control of vertigo symptoms while reducing damage to hearing and reducing surgical complications is the principle followed by scholars studying surgical modalities. Semicircular canal occlusion is aimed at treatment of partial peripheral vertigo disease and has attracted the attention of scholars because of the above advantages. This article provides a review of the origins of semicircular canal occlusion, related basic research, clinical applications, and the effects of surgery on vestibular and hearing function.

Management of early stage glottic carcinoma involving the anterior commissure is challenging.This study aimed to evaluate the efficacy of a thyroid cartilage window (TCW) technique for transoral laser resection of early glottic cancer with involvement of the anterior commissure.Twenty-one patient who underwent a TCW technique for transoral resection early glottic carcinoma involving the anterior commissure, were retrospectively analyzed. The technical nuances, organ preservation rate and voice outcomes, local and regional recurrence, and perioperative comorbidities, were assessed.All 21 patients underwent a TCW technique for resection, both the organ preservation rate and negative margin achieved 100%. The local control rate achieved 100%, and the 5 years recurrence free survival was 90.5%. For two patients with subglottic involvement (9.5%), regional recurrence with confirmation of a positive pre-laryngeal lymph node was observed. Postoperative granuloma was detected in all 21 patients, 13 of whom spontaneously disappeared (61.9%); whereas the remaining 8 patients (38.1%) demonstrated a consistent presence of granuloma more than 12 weeks, and they accepted surgical extirpation of granuloma under surface anesthesia. The laryngeal web developed in all 21 patients, while no dyspnea and local recurrence were present. By comparison with preoperative baseline, postoperative self-assessment voice demonstrated a significant improvement (TCW technique is a valuable means for transoral resection of early glottic laryngeal cancer involving the anterior commissure, with acceptable voice quality and seemingly low comorbidities.

Foxg1 plays important roles in regeneration of hair cell (HC) in the cochlea of neonatal mouse. Here, we used Sox9-CreER to knock down Foxg1 in supporting cells (SCs) in the utricle in order to investigate the role of Foxg1 in HC regeneration in the utricle. We found Sox9 an ideal marker of utricle SCs and bred Sox9CreER/+Foxg1loxp/loxp mice to conditionally knock down Foxg1 in utricular SCs. Conditional knockdown (cKD) of Foxg1 in SCs at postnatal day one (P01) led to increased number of HCs at P08. These regenerated HCs had normal characteristics, and could survive to at least P30. Lineage tracing showed that a significant portion of newly regenerated HCs originated from SCs in Foxg1 cKD mice compared to the mice subjected to the same treatment, which suggested SCs trans-differentiate into HCs in the Foxg1 cKD mouse utricle. After neomycin treatment in vitro, more HCs were observed in Foxg1 cKD mice utricle compared to the control group. Together, these results suggest that Foxg1 cKD in utricular SCs may promote HC regeneration by inducing trans-differentiation of SCs. This research therefore provides theoretical basis for the effects of Foxg1 in trans-differentiation of SCs and regeneration of HCs in the mouse utricle.

OBJECTIVE: To study the application value of humidified high flow nasal cannula (HHFNC) combined with visual laryngoscopy in the arytenoid cartilage dislocation. METHODS: Twenty-nine patients with arytenoid cartilage dislocation were randomly double-blind into HHFNC group and general nasal catheter oxygen suction group, and the intraoperative and postoperative evaluation indicators, anesthesia-related indicators and postoperative vocal cord were compared. RESULTS: There were statistically significant differences in intraoperative blood oxygen saturation, microstream end-tidal carbon dioxide partial pressure EtCO(2), respiratory rate and respiratory intervention times between the two groups (P < 0.05), and statistically significant differences in postoperative heart rate, oxygen saturation and respiratory rate (P < 0.05). After reduction, the voice disturbance index, the degree of voice abnormality, rough voice, breath sound, powerless pronunciation and catatonic pronunciation changed significantly after operation. CONCLUSION: HHFNC combined with visual laryngoscopy in the arytenoid cartilage dislocation has high anesthetic safety, good cooperation of patients, and good surgical effect.

To investigate the therapeutic effect of the stromal vascular fraction gel (SVF gel) in unilateral vocal fold paralysis.A retrospective study was performed on 22 patients who underwent SVF gel autotransplantation for unilateral vocal fold paralysis between June 2017 and December 2018. Fat was removed from the medial thigh under anesthesia and the SVF gel was prepared using standard techniques and injected using a suspension microlaryngoscopy. The SVF gel was transplanted into the vocal fold muscle and the paraglottic space, and subjective and perceptual assessments, aerodynamic and acoustic assessments, and a videostroboscopic assessment were evaluated pre- and postoperatively at 1day, 12 months and 18 months.The GRBAS evaluation results showed that the voice quality of the patients at 12 and 18 months after the operation was significantly improved, and voice analysis showed that in males maximum speech time (MPT) increased and the normalized noise energy decreased 1 day after surgery. The voice quality parameters at 12 months and 18 months after surgery improved significantly compared to preoperatively (P0.05), except for the fundamental frequency (F0), at 12 months, which was similar to the values before surgery. In females, the MPT and amplitude (shimmer) at 1 day after the surgery were significantly different from before the surgery, and the MPT, fundamental frequency (jitter), shimmer, and normalized noise energy at 12 months and 18 months after the surgery were significantly improved compared to before the surgery while the F0 was not significant.SVF gel autotransplantation can effectively improve the voice quality in unilateral vocal fold paralysis, and the long-term effect is stable.

Objective. To treat children with acute nonsuppurative otitis media induced by acute upper respiratory tract infection of varying severity and evaluate its therapeutic effects. Materials and Methods. Patients from the emergency department with acute nonsuppurative otitis media were followed up between September 2015 and December 2018. A total of 420 patients were classified into grades I to III according to tympanic membrane intactness and systemic reactions and treated according to grading. Results. Grade I patients showed no significant difference in the recovery of acute symptoms whether antibiotics are used or not. Grade II patients, after 3 months of follow-up, showed no tympanic membrane perforation, and 9 cases of binaural B-type children did not improve but were cured by operation. In grade III patients, after treatment for 4 hours in the experimental group 3, the earache subsided, 1 case had tympanic membrane perforation, and the patients recovered after 2 weeks (64/92) and after 3 months (28/92) of drug treatment. After treatment for 4 h in the control group 3, the earache eased, and 3 patients developed tympanic membrane perforation and were treated for 3 months. 4 binaural B-type children did not improve but recovered after surgical treatment. Conclusion. Grade I patients could be closely followed up by clinical observation. For anti-inflammatory patients with grade II disease, treatment has therapeutic significance. For patients with grade III, some patients still have TMP, but the use of cephalosporin third-generation drugs plus an appropriate amount of hormone therapy is effective in reducing symptoms and tympanic local reactions.

OBJECTIVE: To establish the murine models of allergic airway inflammation, and to investigate the biological rhythm expression of substance P in it. METHOD: Eighty-four BALB/c mice were divided into 14 groups, which were airway inflammation groups(0: 00 group, 04: 00 group, 08: 00 group, 12: 00 group, 16: 00 group, 20: 00 group, 24: 00 group) and normal control groups(0: 00 group, 04: 00 group, 08: 00 group, 12: 00 group, 16: 00 group, 20: 00 group, 24: 00 group). The allergic airway inflammation models of mice were established by intraperitoneal injection of ovalbumin(OVA), nasal challenge and aerosol inhalation with OVA. The plasma substance P levels were measured by ELISA. The expression of substance P in nasal mucosa, left lung tissue and left bronchial tissue during different time periods was obversed with RT-PCR and immunohistochemical technique. RESULT: In allergic airway inflammation groups, the plasma substance P levels were higher than in normal control groups(P < 0.05), and 0: 00 group(321.99±28.93) pg/mL, 04: 00 group(310.76±25.31) pg/mL and 24: 00 group(335.62±28.29) pg/mL were higher than other experimental groups(P < 0.05). The expression of substance P mRNA in nasal mucosa, left lung tissue and left bronchial tissue was higher than control groups(P < 0.01). By observing immunohistochemical sections, the expression of substance P in allergic airway inflammation groups was higer than control groups. CONCLUSION: The expression of substance P is high in allergic airway inflammation mice and the peaks are during 04: 00-08: 00 in the early morning, which may provide new basis for treating allergic airway inflammation.

The hair cells that reside in the cochlear sensory epithelium are the fundamental sensory structures responsible for understanding the mechanical sound waves evoked in the environment. The intense damage to these sensory structures may result in permanent hearing loss. The present strategies to rehabilitate the hearing function include either hearing aids or cochlear implants that may recover the hearing capability of deaf patients to a limited extent. Therefore, much attention has been paid on developing regenerative therapies to regenerate/replace the lost hair cells to treat the damaged cochlear sensory epithelium. The stem cell therapy is a promising approach to develop the functional hair cells and neuronal cells from endogenous and exogenous stem cell pool to recover hearing loss. In this review, we specifically discuss the potential of different kinds of stem cells that hold the potential to restore sensorineural hearing loss in mammals and comprehensively explain the current therapeutic applications of stem cells in both the human and mouse inner ear to regenerate/replace the lost hair cells and spiral ganglion neurons.

OBJECTIVE Detection rate and isolation yield of circulating tumor cell (CTC) are low in squamous cell carcinoma of head and neck (SCCHN) with in vitro approaches due to limited sample volumes. In this study, we applied the CellCollector to capture CTC in vivo from peripheral blood. METHODS In total, the study included 22 cases with 37 times of detection. All of the patients were newly diagnosed with locally advanced or metastatic SCCHN, including laryngocarcinoma (40.9%, 9/22) and hypopharyngeal carcinoma (59.1%, 13/22). All patients received CTC analysis before treatment. Three patients received induction chemotherapy. Sixteen patients received surgical therapy, of which 13 patients received postoperative detection. Two patients received both induction chemotherapy and surgery treatment. Patients underwent two successive CellCollector applications 24 h before and 7 d after surgical therapy. Nine healthy volunteers were enrolled as the control group. Epidermal growth factor receptor variant type III (EGFRVIII) expression was analyzed with fluorescent dye labeled antibody. RESULTS With CellCollector isolation, 72.7% (16/22) of the patients were positive for ≥1 CTC (CTC; range, 1-17 cells) before treatments and 46.7% (7/15) of patients were CTC positive for ≥1 CTC (CTC; range, 1-29 cells) after surgical therapy. Moreover, the detection rate of CellCollector (82.4%, 14/17; CTC count range, 0-17) in advanced SCCHN (stage III-IV) was much higher than that in early stages (stage I-II, 40.0%, 2/5; CTC count range, 0-2) (P

The transplantation of neural stem cells (NSCs) has become an emerging treatment for neural degeneration. A key factor in such treatments is to manipulate NSC behaviors such as proliferation and differentiation, resulting in the eventual regulation of NSC fate. Novel bionanomaterials have shown usefulness in guiding the proliferation and differentiation of NSCs due to the materials’ unique morphological and topological properties. Among the nanomaterials, graphene has drawn increasing attention for neural regeneration applications based on the material’s excellent physicochemical properties, surface modifications, and biocompatibility. In this review, we summarize recent works on the use of graphene-based biomaterials for regulating NSC behaviors and the potential use of these materials in clinical treatment. We also discuss the limitations of graphene-based nanomaterials for use in clinical practice. Finally, we provide some future prospects for graphene-based biomaterial applications in neural regeneration.

Graphene-based nanocomposites have attracted more and more attention recently in the field of biology and biomedicine. Graphene and its derivatives have been integrated with drugs, nucleic acids, antibodies, and other molecules. And these materials could be use as nanocomposite carriers or scaffold materials taking advantages of their enormous specific surface area, good elasticity and ductility, excellent biocompatibility, and outstanding mechanical strength. In addition, these composites have strong near-infrared absorbance and can act as photothermal agents to kill target cells through physical or chemical mechanisms. Along with significant advances in cell and organ transplantation, many of these materials have been explored in recent years for use in tissue engineering and regenerative medicine. Tissue engineering includes bone, nerve, heart, and muscle tissue engineering based on two-dimensional and three-dimensional graphene-based matrices or scaffolds possessing certain mechanical strengths and electrical conductivities, and the aim is to produce bioactive tissues to replace or repair natural tissue by promoting osteogenic, neuronal, and myogenic differentiation and myocardial cell growth. In this review, the basic properties of graphene-based complexes are systematically described and the biomedical applications of graphene-based materials in vivo and in vitro are summarized. This review first discusses the safety of graphene-based materials in terms of their biocompatibility and toxicity, and then it discusses these materials’ applications in biosensing, photothermal therapy, stem cell culture, and tissue engineering. This review therefore provides a comprehensive understanding of graphene and its derivatives and their present and future applications.

Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression.

An external approach for resection of sinonasal tumors is associated with increased morbidity. Therefore, we employed a modified transnasal endoscopic maxillectomy combined with pre and/or postoperative radiotherapy for early stage maxillary carcinomas. It aims to evaluate our early experience with endoscopic resection of selected malignant sinonasal tumors. The medical and radiology records of patients who underwent endonasal endoscopic resection of malignant sinonasal tumors between 2008 and 2012 were retrospectively reviewed. Ten cases of selected malignant tumor were performed to resect by modified transnasal endoscopic maxillectomy. All the patients were without evidence of disease at a mean follow-up of 26.8 months. No major complications were recorded. The mean hospitalization stay was 6.6 days. In very carefully selected cases of malignant tumors, modified transnasal endoscopic maxillectomy is acceptable. The postoperative complication rate is low, cosmetic outcome is excellent and patients do not require a long hospitalization.

The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)α1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRα1 released by nerves enhances PNI, even in the absence of cancer cell GFRα1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRα1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRα1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRα1(+/-) mice compared with GFRα1(+/+) mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRα1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRα1 expression, suggesting an alternate source of GFRα1 in PNI. These findings collectively demonstrate that GFRα1 released by nerves enhances PNI through GDNF-RET signaling and that GFRα1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior.

Salivary gland carcinomas are relatively rare malignant tumors, accounting for less than 5% of all cancers of the head and neck.1 They encompass a wide spectrum of histologic abnormalities with varied biologic behavior. Initial therapy of localized disease consists of complete surgical excision. The risk of recurrence and metastasis is significantly higher in patients with locally advanced salivary carcinomas. Individuals with high-grade salivary carcinomas have a 5-year survival of roughly 40%; those with low-and intermediate-grade tumors have a 5-year survival of 85% to 90%.2,3 For these patients, complete surgical resection followed by postoperative radiation therapy is recommended.4 Unfortunately, patients with recurrent and/or unresectable disease have few effective treatment options. Clinical trials exploring the role of chemotherapy in the management of salivary gland carcinomas failed to show survival benefit.1 Chemotherapy, therefore, is generally reserved as a palliative measure for patients with symptoms and/or rapid disease progression. Clearly, novel therapies are needed to improve outcomes for patients with salivary carcinomas. Oncolytic viruses have emerged as versatile therapeutic agents that can selectively infect, replicate within, and ultimately lyse a host cancer cell. A variety of viruses have been reported5–7 to possess on-colytic antitumoral activity, including herpes simplex type 1, adenovirus, reovirus, vesicular stomatitis virus, measles virus, poliovirus, West Nile virus, and New-castle disease virus. Vaccinia virus, which is a double-stranded DNA member of the genus Orthopoxvirus, has many unique characteristics that make it an excellent tool in cancer treatment. In addition to its natural tropism for tumor tissues and its abilities for efficient entry, replication, and lysis, vaccinia virus has a remarkable safety record in its historical widespread human application as a vaccine for smallpox. The vaccinia replication cycle occurs exclusively in the cytoplasm, which eliminates the possibility of chromosomal integration.7 Furthermore, there are many Food and Drug Administration–approved antiviral agents available to limit viral spread and control the unlikely possibility of viral toxicity.8 Consequently, several recombinant vaccinia viruses have been constructed and studied in preclinical and clinical phase 1 settings.8,9 Recombinant, replication-competent vaccinia virus (GLV-1h68) has been reported10–16 as effective in breast cancer, thyroid cancer, mesothelioma, pancreatic cancer, prostate cancer, human hepatocellular carcinoma, and head and neck cancer models. The aim of this study was to assess the usefulness of GLV-1h68 as a therapeutic agent against salivary gland carcinoma in vitro and in vivo. Murine flank and orthotopic parotid tumor models were used.

Background Approximately one fourth of bone and soft-tissue sarcomas recur after prior treatment. GLV-1h68 is a recombinant, replication-competent vaccinia virus that has been shown to have oncolytic effects against many human cancer types. We sought to determine whether GLV-1h68 could selectively target and lyse a panel of human bone and soft-tissue sarcoma cell lines in vitro and in vivo . Methods GLV-1h68 was tested in a panel of four cell lines including: fibrosarcoma HT-1080, osteosarcoma U-2OS, fibrohistiocytoma M-805, and rhabdomyosarcoma HTB-82. Gene expression, infectivity, viral proliferation, and cytotoxicity were characterized in vitro . HT-1080 xenograft flank tumors grown in vivo were injected intratumorally with a single dose of GLV-1h68. Results All four cell lines supported robust viral transgene expression in vitro . At a multiplicity of infection (MOI) of five, GLV-1h68 was cytotoxic to three cell lines, resulting in >80% cytotoxicity over 7 d. In vivo , a single injection of GLV-1h68 into HT-1080 xenografts exhibited localized intratumoral luciferase activity peaking at d 2–4, with gradual resolution over 8 d and no evidence of spread to normal tissues. Treated animals exhibited near-complete tumor regression over a 28-d period without observed toxicity. Conclusion GLV-1h68 has potent direct oncolytic effects against human sarcoma in vitro and in vivo . Recombinant vaccinia oncolytic virotherapy could provide a new platform for the treatment of patients with bone and soft tissue sarcomas. Future clinical trials investigating oncolytic vaccinia as a therapy for sarcomas are warranted.

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Perineural invasion (PNI) is the ability of cancer cells to invade in, around, and along nerves. PNI is widely recognized as an adverse pathologic feature of many malignancies. Glial-derived neurotrophic factor (GDNF) is secreted by nerve and glial cells, and is important in neural development. We previously showed that GDNF activation of the RET/GFR-alpha tyrosine kinase in cancer cells induces chemotaxis towards nerves and PNI. Cdc42 is a member of the Rho family of G proteins and a key regulator of cell polarity. We demonstrate here that GDNF-mediated activation of RET/GFR-alpha leads to activation of Cdc42 as a mediator of cancer cell chemotaxis and PNI. Exposure of MiaPaCa2 cells to GDNF or dorsal root ganglia (DRG) activates Cdc42. SiRNA inhibition of Cdc42 impairs MiaPaCa2 chemotaxis towards GDNF or DRG in Boyden chamber assays. SiRNA inhibition of RET decreases Cdc42 activity under GDNF stimulation and MiaPaCa2 chemotaxis. To study dynamic interactions between nerves and cancer cells in vitro, we used a DRG and cancer cell co-culture model of PNI in matrigel. Analysis of individual cell trajectories reveals that cell velocity remains unchanged, while directional migration is disrupted with shRNA inhibition of Cdc42. The disruption of directional response impairs the ability of shRNA Cdc42 MiaPaCa2 cells to migrate along neurites, as visualized by time lapse microscopy and measured by area of PNI. MRI imaging of live mice with sciatic nerves injected with shRNA Cdc42 MiaPaCa2 cells reveals significantly diminished length and volume of PNI as compared with injected shRNA control cancer cells when matched for equivalent overall tumor volume. Murine sciatic nerves injected with shRNA Cdc42 MiaPaCa2 cells exhibited preserved hindlimb and hind paw neurologic function, and diminished perineural invasion by histopathologic examination as compared with shRNA control MiaPaCa2. To identify potential activators of Cdc42 in this model, we performed a comprehensive siRNA screen of guanine nucleotide exchange factors (GEFs), identifying specific GEFs which are necessary for MiaPaCa2 migration towards DRG in Boyden chambers. We identified and validated six GEFs ([FLJ10521][1], DOCK9, ARHGEF7, RASGRF1, ARHGEF5, PLEKHG1) that impair chemotaxis without affecting proliferation. These findings provide novel insights into the molecular mechanisms underlying cancer cell perineural invasion. The RET-GEF-Cdc42 axis may be an attractive target for novel therapies that may potentially interrupt perineural invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 460. doi:1538-7445.AM2012-460 [1]: /lookup/external-ref?link_type=GENPEPT&access_num=FLJ10521&atom=%2Fcanres%2F72%2F8_Supplement%2F460.atom