Accessory cells precondition naïve T cells and regulatory T cells for cytokine-mediated proliferation.

Naïve T cells and regulatory T cells, when purified, do not proliferate to the γc-cytokines IL-2, IL-7, or IL-15, despite their expression of cognate cytokine receptors. Dendritic cells (DCs) enabled the T cell proliferation to these cytokines, through cell-to-cell contact, but independent of T cell receptor stimulation. This effect lasted after separation of T cells from DCs, enabling enhanced proliferation of the T cells in DC-depleted hosts. We propose calling this a "preconditioning effect". Interestingly, IL-2 alone was sufficient to induce phosphorylation and nuclear translocation of STAT5 in T cells, but could not activate MAPK and AKT pathways and failed to induce transcription of IL-2 target genes. "Preconditioning" was necessary to activate these two pathways and induced weak Ca2+ mobilization independent of calcium release-activated channels. When preconditioning was combined with IL-2, full activation of downstream mTOR, 4E-BP1 hyperphosphorylation, and prolonged S6 phosphorylation occurred. Collectively, accessory cells provide T cell preconditioning, a unique activation mechanism, controlling cytokine-mediated proliferation of T cells.

IL15 and Anti-PD-1 Augment the Efficacy of Agonistic Intratumoral Anti-CD40 in a Mouse Model with Multiple TRAMP-C2 Tumors.

PURPOSE: IL15 promotes activation and maintenance of natural killer (NK) and CD8+ T effector memory cells making it a potential immunotherapeutic agent for the treatment of cancer. However, monotherapy with IL15 was ineffective in patients with cancer, indicating that it would have to be used in combination with other anticancer agents. The administration of high doses of common gamma chain cytokines, such as IL15, is associated with the generation of "helpless" antigen-nonspecific CD8 T cells. The generation of the tumor-specific cytotoxic T cells can be mediated by CD40 signaling via agonistic anti-CD40 antibodies. Nevertheless, parenteral administration of anti-CD40 antibodies is associated with unacceptable side effects, such as thrombocytopenia and hepatic toxicity, which can be avoided by intratumoral administration. EXPERIMENTAL DESIGN: We investigated the combination of IL15 with an intratumoral anti-CD40 monoclonal antibody (mAb) in a dual tumor TRAMP-C2 murine prostate cancer model and expanded the regimen to include an anti-PD-1 mAb. RESULTS: Here we demonstrated that anti-CD40 given intratumorally not only showed significant antitumor activity in treated tumors, but also noninjected contralateral tumors, indicative of abscopal efficacy. The combination of IL15 with intratumoral anti-CD40 showed an additive immune response with an increase in the number of tumor-specific tetramer-positive CD8 T cells. Furthermore, the addition of anti-PD-1 further improved efficacy mediated by the anti-CD40/IL15 combination. CONCLUSIONS: These studies support the initiation of a clinical trial in patients with cancer using IL15 in association with the checkpoint inhibitor, anti-PD-1, and intratumoral optimized anti-CD40.

Triple combination of BET plus PI3K and NF-κB inhibitors exhibit synergistic activity in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell lymphoproliferative malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL is an orphan disease with no curative drug treatment regimens urgently needing new combination therapy. HTLV-1-infected cells rely on viral proteins, Tax and HBZ (HTLV-1-b-ZIP factor), to activate the transcription of various host genes that are critical for promoting leukemic transformation. Inhibition of bromodomain and extraterminal motif (BET) protein was previously shown to collapse the transcriptional network directed by BATF3 super-enhancer and thereby induced ATL cell apoptosis. In the current work, by using xenograft, ex vivo, and in vitro models, we demonstrated that I-BET762 (BETi) synergized with copanlisib (PI3Ki) and bardoxolone methyl (NF-κBi) to dramatically decrease the growth of ATL cells. Mechanistically, the triple combination exhibited synergistic activity by down-regulating the expression of c-MYC while upregulating the level of the glucocorticoid-induced leucine zipper (GILZ). The triple combination also enhanced apoptosis induction by elevating the expression of active caspase-3 and cleaved PARP. Importantly, the triple combination prolonged the survival of ATL-bearing xenograft mice and inhibited the proliferation of ATL cells from peripheral blood mononuclear cells (PBMCs) of both acute and smoldering/chronic ATL patients. Therefore, our data provide the rationale for a clinical trial exploring the multiagent combination of BET, PI3K/AKT, and NF-κB inhibitors for ATL patients and expands the potential treatments for this recalcitrant malignancy.

Enhanced efficacy of JAK1 inhibitor with mTORC1/C2 targeting in smoldering/chronic adult T cell leukemia.

Adult T-cell leukemia (ATL) is an aggressive T-cell lymphoproliferative malignancy of regulatory T lymphocytes (Tregs), caused by human T-cell lymphotropic virus 1 (HTLV-1). Interleukin 2 receptor alpha (IL-2Rα) is expressed in the leukemic cells of smoldering/chronic ATL patients, leading to constitutive activation of the JAK/STAT pathway and spontaneous proliferation. The PI3K/AKT/mTOR pathway also plays a critical role in ATL cell survival and proliferation. We previously performed a high-throughput screen that demonstrated additive/synergistic activity of Ruxolitinib, a JAK1/2 inhibitor, with AZD8055, an mTORC1/C2 inhibitor. However, effects of unintended JAK2 inhibition with Ruxolitinib limits it therapeutic potential for ATL patients, which lead us to evaluate a JAK1-specific inhibitor. Here, we demonstrated that Upadacitinib, a JAK-1 inhibitor, inhibited the proliferation of cytokine-dependent ATL cell lines and the expression of p-STAT5. Combinations of Upadacitinib with either AZD8055 or Sapanisertib, mTORC1/C2 inhibitors, showed anti-proliferative effects against cytokine-dependent ATL cell lines and synergistic effect with reducing tumor growth in NSG mice bearing IL-2 transgenic tumors. Importantly, the combination of these two agents inhibited ex vivo spontaneous proliferation of ATL cells from patients with smoldering/chronic ATL. Combined targeting of JAK/STAT and PI3K/AKT/mTOR pathways represents a promising therapeutic intervention for patients with smoldering/chronic ATL.

Derivation and internal validation of a multi-biomarker-based cardiovascular disease risk prediction score for rheumatoid arthritis patients.

BACKGROUND: Rheumatoid arthritis (RA) patients have increased risk for cardiovascular disease (CVD). Accurate CVD risk prediction could improve care for RA patients. Our goal is to develop and validate a biomarker-based model for predicting CVD risk in RA patients. METHODS: Medicare claims data were linked to multi-biomarker disease activity (MBDA) test results to create an RA patient cohort with age ≥ 40 years that was split 2:1 for training and internal validation. Clinical and RA-related variables, MBDA score, and its 12 biomarkers were evaluated as predictors of a composite CVD outcome: myocardial infarction (MI), stroke, or fatal CVD within 3 years. Model building used Cox proportional hazard regression with backward elimination. The final MBDA-based CVD risk score was internally validated and compared to four clinical CVD risk prediction models. RESULTS: 30,751 RA patients (904 CVD events) were analyzed. Covariates in the final MBDA-based CVD risk score were age, diabetes, hypertension, tobacco use, history of CVD (excluding MI/stroke), MBDA score, leptin, MMP-3 and TNF-R1. In internal validation, the MBDA-based CVD risk score was a strong predictor of 3-year risk for a CVD event, with hazard ratio (95% CI) of 2.89 (2.46-3.41). The predicted 3-year CVD risk was low for 9.4% of patients, borderline for 10.2%, intermediate for 52.2%, and high for 28.2%. Model fit was good, with mean predicted versus observed 3-year CVD risks of 4.5% versus 4.4%. The MBDA-based CVD risk score significantly improved risk discrimination by the likelihood ratio test, compared to four clinical models. The risk score also improved prediction, reclassifying 42% of patients versus the simplest clinical model (age + sex), with a net reclassification index (NRI) (95% CI) of 0.19 (0.10-0.27); and 28% of patients versus the most comprehensive clinical model (age + sex + diabetes + hypertension + tobacco use + history of CVD + CRP), with an NRI of 0.07 (0.001-0.13). C-index was 0.715 versus 0.661 to 0.696 for the four clinical models. CONCLUSION: A prognostic score has been developed to predict 3-year CVD risk for RA patients by using clinical data, three serum biomarkers and the MBDA score. In internal validation, it had good accuracy and outperformed clinical models with and without CRP. The MBDA-based CVD risk prediction score may improve RA patient care by offering a risk stratification tool that incorporates the effect of RA inflammation.

Plasma glial fibrillary acidic protein and neurofilament light chain, but not tau, are biomarkers of sports-related mild traumatic brain injury.

Mild traumatic brain injury is a relatively common event in contact sports and there is increasing interest in the long-term neurocognitive effects. The diagnosis largely relies on symptom reporting and there is a need for objective tools to aid diagnosis and prognosis. There are recent reports that blood biomarkers could potentially help triage patients with suspected injury and normal CT findings. We have measured plasma concentrations of glial and neuronal proteins and explored their potential in the assessment of mild traumatic brain injury in contact sport. We recruited a prospective cohort of active male rugby players, who had pre-season baseline plasma sampling. From this prospective cohort, we recruited 25 players diagnosed with mild traumatic brain injury. We sampled post-match rugby players without head injuries as post-match controls. We measured plasma neurofilament light chain, tau and glial fibrillary acidic protein levels using ultrasensitive single molecule array technology. The data were analysed at the group and individual player level. Plasma glial fibrillary acidic protein concentration was significantly increased 1-h post-injury in mild traumatic brain injury cases compared to the non-injured group (P = 0.017). Pairwise comparison also showed that glial fibrillary acidic protein levels were higher in players after a head injury in comparison to their pre-season levels at both 1-h and 3- to 10-day post-injury time points (P = 0.039 and 0.040, respectively). There was also an increase in neurofilament light chain concentration in brain injury cases compared to the pre-season levels within the same individual at both time points (P = 0.023 and 0.002, respectively). Tau was elevated in both the non-injured control group and the 1-h post-injury group compared to pre-season levels (P = 0.007 and 0.015, respectively). Furthermore, receiver operating characteristic analysis showed that glial fibrillary acidic protein and neurofilament light chain can separate head injury cases from control players. The highest diagnostic power was detected when biomarkers were combined in differentiating 1-h post-match control players from 1-h post-head injury players (area under curve 0.90, 95% confidence interval 0.79-1.00, P < 0.0002). The brain astrocytic marker glial fibrillary acidic protein is elevated in blood 1 h after mild traumatic brain injury and in combination with neurofilament light chain displayed the potential as a reliable biomarker for brain injury evaluation. Plasma total tau is elevated following competitive rugby with and without a head injury, perhaps related to peripheral nerve trauma and therefore total tau does not appear to be suitable as a blood biomarker.

IL-15 enhanced antibody-dependent cellular cytotoxicity mediated by NK cells and macrophages.

The goal of cancer immunotherapy is to stimulate the host immune system to attack malignant cells. Antibody-dependent cellular cytotoxicity (ADCC) is a pivotal mechanism of antitumor action of clinically employed antitumor antibodies. IL-15 administered to patients with metastatic malignancy by continuous i.v. infusion at 2 µg/kg/d for 10 days was associated with a 38-fold increase in the number and activation status of circulating natural killer (NK) cells and activation of macrophages which together are ADCC effectors. We investigated combination therapy of IL-15 with rituximab in a syngeneic mouse model of lymphoma transfected with human CD20 and with alemtuzumab (Campath-1H) in a xenograft model of human adult T cell leukemia (ATL). IL-15 greatly enhanced the therapeutic efficacy of both rituximab and alemtuzumab in tumor models. The additivity/synergy was shown to be associated with augmented ADCC. Both NK cells and macrophages were critical elements in the chain of interacting effectors involved in optimal therapeutic responses mediated by rituximab with IL-15. We provide evidence supporting the hypothesis that NK cells interact with macrophages to augment the NK-cell activation and expression of FcγRIV and the capacity of these cells to become effectors of ADCC. The present study supports clinical trials of IL-15 combined with tumor-directed monoclonal antibodies.

Development of a single, practical measure of surgical site infection (SSI) for patient report or observer completion.

BACKGROUND: Surgical site infections (SSIs) are the third most common hospital-associated infection and can lead to significant patient morbidity and healthcare costs. Identification of SSIs is key to surveillance and research but reliable assessment is challenging, particularly after hospital discharge when most SSIs present. Existing SSI measurement tools have limitations and their suitability for post-discharge surveillance is uncertain. AIMS: This study aimed to develop a single measure to identify SSI after hospital discharge, suitable for patient or observer completion. METHODS: A three-phase mixed methods study was undertaken: Phase 1, an analysis of existing tools and semi-structured interviews with patients and professionals to establish the content of the measure; Phase 2, development of questionnaire items suitable for patients and professionals; Phase 3, pre-testing the single measure to assess acceptability and understanding to both stakeholder groups. Interviews and pre-testing took place over 12 months in 2014-2015 with patients and professionals from five specialties recruited from two UK hospital Trusts. FINDINGS: Analyses of existing tools and interviews identified 19 important domains for assessing SSIs. Domains were developed into provisional questionnaire items. Pre-testing and iterative revision resulted in a final version with 16 items that were understood and easily completed by patients and observers (healthcare professionals). CONCLUSION: A single patient and observer measure for post-discharge SSI assessment has been developed. Further testing of the validity, reliability and accuracy of the measure is underway.

Intraoperative ultrasound for the colorectal surgeon: current trends and barriers.

Up to two thirds of patients diagnosed with colorectal cancer (CRC) develop colorectal liver metastases (CRLMs) and one quarter of patients present with synchronous metastases. Early detection of CRLM widens the scope of potential treatment. Surgery for CRLM offers the best chance of a cure. Current preoperative staging of CRC relies on computerized tomography and magnetic resonance imaging. Intraoperative ultrasound (IOUS) scans and contrast-enhanced IOUS (CE-IOUS) have been demonstrated to detect additional metastases not seen on routine preoperative imaging. IOUS is not widely used by colorectal surgeons during primary resection for CRC. Confident use of IOUS/CE-IOUS during primary resection of CRC may improve decision-making by providing the most sensitive form of liver staging even when compared with magnetic resonance imaging. This may be particularly important in the era of laparoscopic resections, where the colorectal surgeon loses the opportunity to palpate the liver. There are several implied barriers to the routine use of IOUS/CE-IOUS by colorectal surgeons. These include time pressure, familiarity with techniques, a perceived learning curve, cost implications and limitation of the modality due to operator variations. Inclusion of IOUS in the training of colorectal surgeons and further investigation of potential benefits of IOUS/CE-IOUS could potentially reduce these barriers, enabling usage during primary resection for CRC to become more widespread.

Cytokine receptor signaling is required for the survival of ALK- anaplastic large cell lymphoma, even in the presence of JAK1/STAT3 mutations.

Activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) mutations have been discovered in many T-cell malignancies, including anaplastic lymphoma kinase (ALK)- anaplastic large cell lymphomas (ALCLs). However, such mutations occur in a minority of patients. To investigate the clinical application of targeting JAK for ALK- ALCL, we treated ALK- cell lines of various histological origins with JAK inhibitors. Interestingly, most exogenous cytokine-independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with the STAT3 phosphorylation status of tumor cells. Using retroviral shRNA knockdown, we have demonstrated that these JAK inhibitor-sensitive cells are dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some, but not all, JAK inhibitor-sensitive cells. Moreover, the mutations alone cannot explain the JAK1/STAT3 dependency, given that wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in selected JAK inhibitor-sensitive cells. High expression levels of cytokines, including IL-6, were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest that cytokine receptor signaling is required for tumor cell survival in diverse forms of ALK- ALCL, even in the presence of JAK1/STAT3 mutations. Therefore, JAK inhibitor therapy might benefit patients with ALK- ALCL who are phosphorylated STAT3^.

Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or Navitoclax in a murine model of human Hodgkin's lymphoma.

Despite relative success of therapy for Hodgkin's lymphoma (HL), novel therapeutic agents are needed for patients with refractory or relapsed disease. Recently, anti-PD1 immunotherapy or treatment with the anti-CD30 toxin conjugate brentuximab vedotin (BV) have been associated with remissions; however, the median responses of complete responses (CRs) with the latter were only 6.7 mo. To obtain curative therapy, other effective agents, based on HL biology, would have to be given in combination with BV. Hodgkin's Reed-Sternberg (HRS) cells secrete cytokines including IL-6 and -13, leading to constitutive activation of JAK/STAT signaling. In the present study the JAK1/2 inhibitor ruxolitinib reduced phosphorylation of STAT3 and STAT6 and expression of c-Myc in the HL cell line HDLM-2. These changes were enhanced when, on the basis of a matrix screen of drug combinations, ruxolitinib was combined with the Bcl-2/Bcl-xL inhibitor Navitoclax. The combination augmented expression of Bik, Puma, and Bax, and attenuated Bcl-xL expression and the phosphorylation of Bad. The use of the two-agent combination of either ruxolitinib or Navitoclax with BV or the three-agent combination strongly activated Bax and increased activities of cytochrome c and caspase-9 and -3 that, in turn, led to cleavage of poly(ADP ribose) polymerase and Mcl-1. Either ruxolitinib combined with Navitoclax or BV alone prolonged survival but did not cure HDLM-2 tumor-bearing mice, whereas BV combined with ruxolitinib and/or with Navitoclax resulted in a sustained, complete elimination of the HDLM-2 HL. These studies provide scientific support for a clinical trial to evaluate BV combined with ruxolitinib in select patients with HL.

Stable Versus Unstable Grade II High Ankle Sprains: A Prospective Study Predicting the Need for Surgical Stabilization and Time to Return to Sports.

PURPOSE: To investigate grade II syndesmosis injuries in athletes and identify factors important in differentiating stable from dynamically unstable ankle sprains and those associated with a longer time to return to sports. METHODS: Sixty-four athletes with an isolated syndesmosis injury (without fracture) were prospectively assessed, with a mean follow-up period of 37 months (range, 24 to 66 months). Those with an associated deltoid ligament injury or osteochondral lesion were included. Those whose injuries were considered stable (grade IIa) were treated conservatively with a boot and rehabilitation. Those whose injuries were clinically unstable underwent arthroscopy, and if instability was confirmed (grade IIb), the syndesmosis was stabilized. Clinical and magnetic resonance imaging assessments of injury to individual ligaments were recorded, along with time to return to play. A power analysis estimated that each group would need 28 patients. RESULTS: All athletes returned to the same level of professional sport. The 28 patients with grade IIa injuries returned at a mean of 45 days (range, 23 to 63 days) compared with 64 days (range, 27 to 104 days) for those with grade IIb injuries (P < .0001). There was a highly significant relationship between clinical and magnetic resonance imaging assessments of ligament injury (anterior tibiofibular ligament [ATFL], anterior-inferior tibiofibular ligament [AITFL], and deltoid ligament, P < .0001). Instability was 9.5 times as likely with a positive squeeze test and 11 times as likely with a deltoid injury. Combined injury to the anterior-inferior tibiofibular ligament and deltoid ligament was associated with a delay in return to sports. Concomitant injury to the ATFL indicated a different mechanism of injury-the syndesmosis is less likely to be unstable and is associated with an earlier return to sports. CONCLUSIONS: A positive squeeze test and injury to the ATFL and deltoid ligament are important factors in differentiating stable from dynamically unstable grade II injuries and may be used to identify which athletes may benefit from early arthroscopic assessment and stabilization. They may also be important in predicting the time frame for athletes' expected return to play. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2-dependent adult T-cell leukemia.

Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokine-dependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients' PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL.

Laparoscopic retrieval of an intra-abdominal air gun pellet.

A 19-year-old man presented to the emergency department following an air gun pellet injury to the abdomen. He was clinically stable and underwent laparoscopic retrieval of the pellet, which was found embedded in the small bowel mesentery. He recovered fully and was discharged after 2 days. We further discuss air gun-related injuries.

Therapeutic mammoplasty allows for clear surgical margins in large and multifocal tumours without delaying adjuvant therapy.

INTRODUCTION: Therapeutic mammoplasty (TM) is suggested to have a number of advantages by comparison to standard breast conservation surgery in selected patients, however, data to support such assertions are sparse and outcomes remain uncertain. We assess the ability of TM to achieve some of its suggested benefits, specifically obtaining clear surgical margins (CSM) around large or multifocal tumours, and examine whether TM is associated with delay in administering adjuvant therapies. METHOD: Data were extracted from a prospectively maintained database on all patients undergoing TM over 8 years. Key oncological outcomes and time to initiation of adjuvant therapies were recorded. RESULTS: Sixty eight patients underwent TM, sixty two for invasive disease and six for in-situ disease only. Tumour size ranged from 3 mm to 85 mm. Twenty-one (30.8%) patients received neo-adjuvant therapy, with 15 (22.0%) receiving chemotherapy and six (8.8%) receiving endocrine therapy prior to surgery. CSM were obtained in 65 patients (95.6%). Where margins were involved, two were due to Ductal Carcinoma in situ and one from undiagnosed invasive lobular cancer, resulting in one wider excision and two completion mastectomies. Radiotherapy was delayed in one patient with delayed wound healing. No local recurrence has been recorded. CONCLUSION: These data support the ability of TM to consistently achieve CSM around large and multifocal tumours in selected patients, with acceptable local control and minimal morbidity and delay in adjuvant therapies.

Resection leads to less recurrence than strictureplasty in a paediatric population with obstructive Crohn's disease.

Introduction. Resection and strictureplasty are used to treat patients with obstructive Crohn's disease. Strictureplasty is preferable in adults as it retains bowel length. This study aims to identify differences in outcomes of children undergoing strictureplasty and resection for obstructive Crohn's disease. Method. Patients under 20 years undergoing surgery over a nine-year period were included. Data was collected on procedures for stenotic Crohn's disease. Patients were divided into 2 groups: Group 1 treated with strictureplasties and Group 2 resections. Postoperative complications and recurrence rates were recorded. Kaplan-Meier method was used to analyze the data. Results. Twenty-six patients and 40 operations were identified. Mean age was 15.6 years (7.2-19.4) with equal numbers of males and females. Mean follow-up was 45.9 months (0.1-149.9). 20/40 procedures involved the terminal ileum; 9/40, the ileocolic junction; 8/40, the upper GI tract; and 3/40, the colon. Group 1 consisted of 19 strictureplasties and Group 2 consisted of 13 resections and 8 combined procedures. Significantly more patients in Group 1 required further surgery (11/19 versus 3/21; P = 0.008). Conclusion. Allowing for variations in disease duration, severity, and previous medical management, these data suggest that resection is preferable to strictureplasty in treating obstructive Crohn's disease in children and adolescents.

IL-15-dependent CD8+ CD122+ T cells ameliorate experimental autoimmune encephalomyelitis by modulating IL-17 production by CD4+ T cells.

Interleukin-15 (IL-15) is an inflammatory cytokine whose role in autoimmune diseases has not been fully elucidated. Th17 cells have been shown to play critical roles in experimental autoimmune encephalomyelitis (EAE) models. In this study, we demonstrate that blockade of IL-15 signaling by TMß-1 mAb treatment aggravated EAE severity. The key mechanism was not NK-cell depletion but depletion of CD8+ CD122+ T cells. Adoptive transfer of exogenous CD8+ CD122+ T cells to TMß-1-treated mice rescued animals from severe disease. Moreover, transfer of preactivated CD8+ CD122+ T cells prevented EAE development and significantly reduced IL-17 secretion. Naïve effector CD4+ CD25- T cells cultured with either CD8+ CD122+ T cells from wild-type mice or IL-15 transgenic mice displayed lower frequencies of IL-17A production with lower amounts of IL-17 in the supernatants when compared with production by effector CD4+ CD25- T cells cultured alone. Addition of a neutralizing antibody to IL-10 led to recovery of IL-17A production in Th17 cultures. Furthermore, coculture of CD8+ CD122+ T cells with effector CD4+ T cells inhibited their proliferation significantly, suggesting a regulatory function for IL-15 dependent CD8+ CD122+ T cells. Taken together, these observations suggest that IL-15, acting through CD8+ CD122+ T cells, has a negative regulatory role in reducing IL-17 production and Th17-mediated EAE inflammation.

A new domain in the Toll/IL-1R domain-containing adaptor inducing interferon-ß factor protein amino terminus is important for tumor necrosis factor-α receptor-associated factor 3 association, protein stabilization and interferon signaling.

Toll/IL-1R domain-containing adaptor inducing interferon-ß (IFN-ß) factor (TRIF) is a key adaptor for Toll-like receptor (TLR) 3 and TLR4 signaling. Using a novel cDNA isolate encoding a TRIF protein with a 21-residue deletion (Δ160-181) from its amino-terminal half, we investigated the impact of this deletion on TRIF functions. Transfection studies consistently showed higher expression levels of the (Δ160-181) TRIF compared to wild-type (wt) TRIF, an effect unrelated to apoptosis, cell lines or plasmid amplification. Colocalization of wt and (Δ160-181) TRIF proteins led to a dramatic reduction of their respective expressions, suggesting that wt/(Δ160-181) TRIF heterocomplexes are targeted for degradation. We demonstrated that wt TRIF associates with tumor necrosis factor-α receptor-associated factor 3 (TRAF3) better than (Δ160-181) TRIF, culminating in its greater ubiquitination and proteolysis. This explains, in part, the differential expression levels of the two TRIF proteins. Despite higher expression levels in transfected cells, (Δ160-181) TRIF inefficiently transactivated the IFN pathway, whereas the nuclear factor-κB (NF-κB) pathway activation remained similar to that by wt TRIF. In coexpression studies, (Δ160-181) TRIF marginally contributed to the IFN pathway activation, but still enhanced NF-κB signaling with wt TRIF. Therefore, this 21 amino acid sequence is crucial for TRAF3 association, modulation of TRIF stability and activation of the IFN pathway.

Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Rα.

Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15Rα levels in human T1D. To investigate the role of IL-15/IL-15Rα in the pathogenesis of T1D, we generated double transgenic mice with pancreatic ß-cell expression of IL-15 and IL-15Rα. The mice developed hyperglycemia, marked mononuclear cell infiltration, ß-cell destruction, and anti-insulin autoantibodies that mimic early human T1D. The diabetes in this model was reversed by inhibiting IL-15 signaling with anti-IL2/IL15Rß (anti-CD122), which blocks IL-15 transpresentation. Furthermore, the diabetes could be reversed by administration of the Janus kinase 2/3 inhibitor tofacitinib, which blocks IL-15 signaling. In an alternative diabetes model, nonobese diabetic mice, IL15/IL-15Rα expression was increased in islet cells in the prediabetic stage, and inhibition of IL-15 signaling with anti-CD122 at the prediabetic stage delayed diabetes development. In support of the view that these observations reflect the conditions in humans, we demonstrated pancreatic islet expression of both IL-15 and IL-15Rα in human T1D. Taken together our data suggest that disordered IL-15 and IL-15Rα may be involved in T1D pathogenesis and the IL-15/IL15Rα system and its signaling pathway may be rational therapeutic targets for early T1D.

Modernizing the treatment of venous thoracic outlet syndrome.

This study aims to quantify the management and outcomes of patients treated for venous thoracic outlet syndrome (vTOS) over a seven-year period. A retrospective case-note review of all patients undergoing first rib resection at a regional vascular unit between January 1, 2002 and December 31, 2009 was performed. Treatment pathways and outcomes recorded as freedom from symptoms and venous patency were analyzed. Thirty-five patients were identified with vTOS. Ninety-one percent of patients had patent veins at discharge from clinical follow-up and were symptom-free at a median of 44 months. Patients treated within seven days of symptoms (94.7 versus 85.7, P = 0.060), with catheter-directed thrombolysis (94 versus 87.5% P = 0.702) and excision of first rib in less than 30 days (100 versus 85.7%, P = 0.002), had improved symptom-free rates. In conclusion, early referral, immediate catheter-directed thrombolysis, perioperative balloon venoplasty and early thoracic outlet decompression may provide a suitable model for improving outcomes in vTOS.