Collin Chen

Controlling murine and rat chronic pain through A3 adenosine receptor activation

Clinical management of chronic neuropathic pain is limited by marginal effectiveness and unacceptable side effects of current drugs. We demonstrate A3 adenosine receptor (A3AR) agonism as a new target‐based therapeutic strategy. The development of mechanoallodynia in a well‐characterized mouse model of neuropathic pain following chronic constriction injury of the sciatic nerve was rapidly and dose‐depend‐ently reversed by the A3AR agonists: IB‐MECA, its 2‐chlorinated analog (Cl‐IB‐MECA), and the structurally distinct MRS1898. These effects were naloxone insensitive and thus are not opioid receptor mediated. IB‐MECA was ≥1.6‐fold more efficacious than morphine and >5‐fold more potent. In addition, IB‐MECA was equally efficacious as gabapentin (Neurontin) or amitriptyline, but respectively >350‐ and >75‐fold more potent. Besides its potent standalone ability to reverse established mechanoallodynia, IB‐MECA significantly increased the antiallodynic effects of all 3 analgesics. Moreover, neuropathic pain development in rats caused by widely used chemotherapeutics in the taxane (paclitaxel), platinum‐complex (oxaliplatin), and proteasome‐inhibitor (bortezomib) classes was blocked by IB‐MECA without antagonizing their antitumor effect. A3AR agonist effects were blocked with A3AR antagonist MRS1523, but not with A1AR (DPCPX) or A2AAR (SCH‐442416) antagonists. Our findings provide the scientific rationale and pharmacological basis for therapeutic development of A3AR agonists for chronic pain.—Chen, Z., Janes, K., Chen, C., Doyle, T., Bryant, L., Tosh, D.K., Jacobson, K.A., Salvemini, D. Controlling murine and rat chronic pain through A3 adenosine receptor activation. FASEB J. 26, 1855‐1865 (2012). www.fasebj.org

The Development and Maintenance of Paclitaxel-induced Neuropathic Pain Require Activation of the Sphingosine 1-Phosphate Receptor Subtype 1

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a critical dose-limiting side effect of many chemotherapeutic agents, including paclitaxel. Results: Spinal activation of the S1P-to-S1PR1 axis contributes to the development and maintenance of paclitaxel-induced neuropathic pain through enhanced neuroinflammatory processes. Conclusion: Inhibition of S1PR1 blocks and reverses paclitaxel-induced neuropathic pain without interfering with anticancer effects. Significance: Targeting the S1PR1 signaling pathway could be an effective approach for the treatment of CIPN. The ceramide-sphingosine 1-phosphate (S1P) rheostat is important in regulating cell fate. Several chemotherapeutic agents, including paclitaxel (Taxol), involve pro-apoptotic ceramide in their anticancer effects. The ceramide-to-S1P pathway is also implicated in the development of pain, raising the intriguing possibility that these sphingolipids may contribute to chemotherapy-induced painful peripheral neuropathy, which can be a critical dose-limiting side effect of many widely used chemotherapeutic agents. We demonstrate that the development of paclitaxel-induced neuropathic pain was associated with ceramide and S1P formation in the spinal dorsal horn that corresponded with the engagement of S1P receptor subtype 1 (S1PR1)-dependent neuroinflammatory processes as follows: activation of redox-sensitive transcription factors (NFκB) and MAPKs (ERK and p38) as well as enhanced formation of pro-inflammatory and neuroexcitatory cytokines (TNF-α and IL-1β). Intrathecal delivery of the S1PR1 antagonist W146 reduced these neuroinflammatory processes but increased IL-10 and IL-4, potent anti-inflammatory/neuroprotective cytokines. Additionally, spinal W146 reversed established neuropathic pain. Noteworthy, systemic administration of the S1PR1 modulator FTY720 (Food and Drug Administration-approved for multiple sclerosis) attenuated the activation of these neuroinflammatory processes and abrogated neuropathic pain without altering anticancer properties of paclitaxel and with beneficial effects extended to oxaliplatin. Similar effects were observed with other structurally and chemically unrelated S1PR1 modulators (ponesimod and CYM-5442) and S1PR1 antagonists (NIBR-14/15) but not S1PR1 agonists (SEW2871). Our findings identify for the first time the S1P/S1PR1 axis as a promising molecular and therapeutic target in chemotherapy-induced painful peripheral neuropathy, establish a mechanistic insight into the biomolecular signaling pathways, and provide the rationale for the clinical evaluation of FTY720 in chronic pain patients.

Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor infiltrating CD8+ T cells

Berrien-Elliott and colleagues report that combination checkpoint blockade induced expression of T-bet and Eomes but only T-bet was required to restore CD8+ antitumor effector function, leading to a >95% cure rate in leukemia-bearing mice given this immunotherapy regimen. Coinhibitory receptor blockade is a promising strategy to boost T-cell immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for advanced mechanistic understanding to improve patient outcomes and uncover clinically relevant biomarkers of treatment efficacy. However, the T-cell–intrinsic signaling pathways engaged during checkpoint blockade treatment are not well defined, particularly for combination approaches. Using a murine model to study how effector CD8+ T-cell responses to tumors may be enhanced in a tolerizing environment, we identified a critical role for the T-box transcription factor T-bet. Combination blockade of CTLA-4, PD-1, and LAG-3 induced T-bet expression in responding tumor/self-reactive CD8+ T cells. Eradication of established leukemia using this immunotherapy regimen depended on T-bet induction, which was required for IFNγ production and cytotoxicity by tumor-infiltrating T cells, and for efficient trafficking to disseminated tumor sites. These data provide new insight into the success of checkpoint blockade for cancer immunotherapy, revealing T-bet as a key transcriptional regulator of tumor-reactive CD8+ T-cell effector differentiation under otherwise tolerizing conditions. Cancer Immunol Res; 3(2); 116–24. ©2014 AACR.

Inflammation programs self-reactive CD8+ T cells to acquire T-box-mediated effector function but does not prevent deletional tolerance

CD8+ T cells must detect foreign antigens and differentiate into effector cells to eliminate infections. But, when self‐antigen is recognized instead, mechanisms of peripheral tolerance prevent acquisition of effector function to avoid autoimmunity. These distinct responses are influenced by inflammatory and regulatory clues from the tissue environment, but the mechanism(s) by which naive T cells interpret these signals to generate the appropriate immune response are unclear. The identification of the molecules operative in these cell‐fate decisions is crucial for developing new treatment options for patients with cancer or autoimmunity, where manipulation of T cell activity is desired to alter the course of disease. With the use of an in vivo murine model to examine CD8+ T cell responses to healthy self‐tissue, we correlated self‐tolerance with a failure to induce the T‐box transcription factors T‐bet and Eomes. However, inflammation associated with acute microbial infection induced T‐bet and Eomes expression and promoted effector differentiation of self‐reactive T cells under conditions that normally favor tolerance. In the context of a Listeria infection, these functional responses relied on elevated T‐bet expression, independent of Eomes. Alternatively, infection with LCMV induced higher Eomes expression, which was sufficient in the absence of T‐bet to promote effector cytokine production. Our results place T‐box transcription factors at a molecular crossroads between CD8+ T cell anergy and effector function upon recognition of peripheral self‐antigen, and suggest that inflammation during T cell priming directs these distinct cellular responses.

Complications of double free flap and free flap combined with locoregional flap in head and neck reconstruction: A systematic review

The purpose of this clinical review was to assess the feasibility of reconstructing complex head and neck defects with 2 or more free flaps simultaneously.

Titanium Mesh Nasal Repair without Nasal Lining

Abstract The objective of this study was to describe outcomes for patients who underwent titanium mesh reconstruction of full‐thickness nasal defects without internal lining repair. This is a retrospective cohort study. Patients with through‐and‐through nasal defects were identified at a single academic institution between 2008 and 2016. Nasal reconstruction was performed with either titanium mesh and external skin reconstruction without repair of the intranasal lining or traditional three‐layer closure. Five patients underwent titanium mesh reconstruction and 11 underwent traditional three‐layer repair. Median follow‐up was 11 months (range, 2‐66 months). The only significant difference between groups was older age in patients undergoing titanium reconstruction (mean, 81 vs. 63 years; difference of 18; 95% confidence interval [CI], 4‐32 years). Defect extent including overall size and structures removed was similar between groups (p > 0.05). Paramedian forehead flap was the most common external reconstruction in both groups (100% for titanium mesh and 73% for three‐layer closure). Time under anesthesia was significantly shorter for titanium mesh reconstruction (median, 119 vs. 314 minutes; difference of 195; 95% CI, 45‐237). Estimated blood loss and length of hospital stay were similar between groups (p > 0.05). Complication rates were substantial although not significantly different, 40 and 36% in titanium and three‐layer reconstruction, respectively (p > 0.05). All patients with complications after titanium reconstruction had prior or postoperative radiotherapy. Titanium mesh reconstruction of through‐and‐through nasal defects can successfully be performed without reconstruction of the intranasal lining, significantly decreasing operative times. This reconstructive technique may not be suitable for patients who undergo radiotherapy.

Comprehensive Algorithm for Nasal Ala Reconstruction: Utility of the Auricular Composite Graft

Defects of the nasal ala are challenging to reconstruct, given its complex three-dimensional structure. Successful repair of these defects needs to provide aesthetic symmetry and preserve nasal function. A wide variety of reconstructive options have been described for nasal ala defects, ranging from skin grafts to locoregional flaps, and also includes the auricular composite graft. However, there are currently no comprehensive guidelines for nasal ala repair, and the versatile role of the auricular composite graft has not been well defined. In this review, we aim to provide a comprehensive algorithm to guide repair of nasal ala defects. Additionally, we compare our experience using the auricular composite graft with the available literature to better define its utility in nasal ala repair.

Complications and Reoperations in Mandibular Angle Fractures

Importance Mandible angle fractures can be repaired in a variety of ways, with no consensus on the outcomes of complications and reoperation rates. Objectives To analyze patient, injury, and surgical factors, including approach to the angle and plating technique, associated with postoperative complications, as well as the rate of reoperation with regard to mandible angle fractures. Design, Setting, and Participants Retrospective cohort study analyzing the surgical outcomes of patients with mandible angle fractures between January 1, 2000, and December 31, 2015, who underwent open reduction and internal fixation. Patients were eligible if they were aged 18 years or older, had 3 or less mandible fractures with 1 involving the mandibular angle, and had adequate follow-up data. Patients with comminuted angle fractures, bilateral angle fractures, and multiple surgical approaches were excluded. A total of 135 patients were included in the study. All procedures were conducted at a single, large academic hospital located in an urban setting. Main Outcomes and Measures Major complications and reoperation rates. Major complications included in this study were nonunion, malunion, severe malocclusion, severe infection, and exposed hardware. Results Of 135 patients 113 (83.7%) were men; median age was 29 years (range, 18-82 years). Eighty-seven patients (64.4%) underwent the transcervical approach and 48 patients (35.6%) received the transoral approach. Fifteen (17.2%) patients in the transcervical group and 9 (18.8%) patients in the transoral group experienced major complications (difference, 1%; 95% CI, −8% to 10%). Thirteen (14.9%) patients in the transcervical group and 8 (16.7%) patients in the transoral group underwent reoperations (difference, 2%; 95% CI, −13% to 17%). Active smoking had a significant effect on the rate of major complications (odds ratio, 4.04; 95% CI, 1.07 to 15.34; P = .04). Conclusions and Relevance During repair of noncomminuted mandibular angle fractures, both of the commonly used approaches—transcervical and transoral—can be used during treatment with equal rates of complication and risk of reoperation. For a patient undergoing surgery for mandibular angle fracture, smoking status is more likely to predict surgical outcomes rather than how the surgeon chooses to approach and fixate the fracture. Level of Evidence 3.

Mixed Clinical Response After Total Thyroidectomy in Two Patients with Hashimoto's Encephalopathy

Importance: Hashimoto’s encephalopathy (HE) is currently treated with medical therapy. Only one case of thyroidectomy as treatment for HE has been presented in the literature. We present two patients with distinct manifestations of (HE) who underwent thyroidectomy after minimal response to medical management. Observations: Patient 1 is a 71 year-old female who presented with motor restlessness. She had persistently elevated antithyroid antibodies. After thyroidectomy, her symptoms were only mildly improved. Iodine-123 thyroid scan revealed a small remnant of thyroid tissue. Her antithyroid antibodies remained elevated. Patient 2 is a 60 year-old female with previous diagnosis of (HE) who presented with recurrent seizures. She had a history of elevated antithyroid antibodies. After thyroidectomy, she no longer had seizures, and her antithyroid antibodies normalized. Conclusions and relevance: Patient 1 did not improve as quickly as patient 2. A possible explanation for this is the thyroid tissue remnant found in the first patient during a follow-up iodine-123 thyroid scan; the remnant could be responsible for persistently elevated antithyroid antibodies. The degree or pattern of preoperative antithyroid antibody elevation does not seem to be predictive of postoperative response. Thyroidectomy is a reasonable treatment option for the severely symptomatic patient who has failed medical therapy with steroids, IVIG, and plasmapharesis.