Integrins in T Cell Physiology

From the thymus to the peripheral lymph nodes, integrin-mediated interactions with neighbor cells and the extracellular matrix tune T cell behavior by organizing cytoskeletal remodeling and modulating receptor signaling. LFA-1 (\u3b1L\u3b22 integrin) and VLA-4 (\u3b14\u3b21 integrin) play a key role throughout the T cell lifecycle from thymocyte differentiation to lymphocyte extravasation and finally play a fundamental role in organizing immune synapse, providing an essential costimulatory signal for the T cell receptor. Apart from tuning T cell signaling, integrins also contribute to homing to specific target organs as exemplified by the importance of \u3b14\u3b27 in maintaining the gut immune system. However, apart from those well-characterized examples, the physiological significance of the other integrin dimers expressed by T cells is far less understood. Thus, integrin-mediated cell-to-cell and cell-to-matrix interactions during the T cell lifespan still represent an open field of research

In vivo migration of labeled autologous natural killer cells to liver metastases in patients with colon carcinoma

BACKGROUND: Besides being the effectors of native anti-tumor cytotoxicity, NK cells participate in T-lymphocyte responses by promoting the maturation of dendritic cells (DC). Adherent NK (A-NK) cells constitute a subset of IL-2-stimulated NK cells which show increased expression of integrins and the ability to adhere to solid surface and to migrate, infiltrate, and destroy cancer. A critical issue in therapy of metastatic disease is the optimization of NK cell migration to tumor tissues and their persistence therein. This study compares localization to liver metastases of autologous A-NK cells administered via the systemic (intravenous, i.v.) versus locoregional (intraarterial, i.a.) routes. PATIENTS AND METHODS: A-NK cells expanded ex-vivo with IL-2 and labeled with (111)In-oxine were injected i.a. in the liver of three colon carcinoma patients. After 30 days, each patient had a new preparation of (111)In-A-NK cells injected i.v. Migration of these cells to various organs was evaluated by SPET and their differential localization to normal and neoplastic liver was demonstrated after i.v. injection of (99m)Tc-phytate. RESULTS: A-NK cells expressed a donor-dependent CD56(+)CD16(+)CD3(- )(NK) or CD56(+)CD16(+)CD3(+ )(NKT) phenotype. When injected i.v., these cells localized to the lung before being visible in the spleen and liver. By contrast, localization of i.a. injected A-NK cells was virtually confined to the spleen and liver. Binding of A-NK cells to liver neoplastic tissues was observed only after i.a. injections. CONCLUSION: This unique study design demonstrates that A-NK cells adoptively transferred to the liver via the intraarterial route have preferential access and substantial accumulation to the tumor site

Venous thromboembolism in non-small cell lung cancer patients: retrospective analysis of cases treated at the Oncology Day Hospital of Novara, Italy

Venous thromboembolism (VTE) is the leading cause of mortality and morbidity in patients with cancer. The estimated risk of VTE in cancer patients is 0.5% per year and 0.04% per month. In small cell lung cancer and non-small cell lung cancer (NSCLC) the cumulative incidence is 3% per year and it seems to be associated with advanced stage and histotype. We performed a retrospective analysis on data from all NSCLC treated at the Oncology Day Hospital in Novara, Italy, northern Italy, to assess the incidence of thromboembolic events in patients undergoing systemic cancer treatments. All patients diagnosed with NSCLC who were treated at the Oncology Day Hospital in Novara from January 2008 to May 2011 have been assessed. Many variables related to VTE were analyzed: age, gender, different NSCLC histotype, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index, stage of disease, treatment and chemotherapy regimen, development of a VTE event and its temporal correlation with chemotherapy, central venous catheter presence, use of erythropoietin, use of low molecular weight heparin at baseline, use of acetyl salicylic acid. A total of 355 patients were evaluated, 307 of whom were considered to be eligible for analysis. Median age was 68 years. Histology was as follows: 7% not otherwise specified, 60% adenocarcinoma, 31% squamous cell carcinoma and 2% large cell carcinoma. Thirty-six cases of deep vein thrombosis (DVT) have been reported (incidence 12%). Thirty-one DVT were recorded in patients who were candidates for or undergoing chemotherapy: 14 during treatment, 7 at the end of chemotherapy, and 10 before treatment. The incidence was significantly higher for patients treated with cisplatin (CDDP), both during chemotherapy and after chemotherapy. A correlation with disease stage was documented: 26.5% of total VTE occurred in locally advanced and metastatic stages (IIIB and IV); 18.8% in stage IIIA (N2). A significant correlation between non-squamous histology was also highlighted (P=0.015) and ECOG 0-1 (P=0.010). According to the high incidence of VTE in patients with NSCLC, especially adenocarcinoma, and the correlation highlighted in this study with ECOG performance status 0-1 and CDDP-based treatment, we believe that outpatients undergoing chemotherapy for advanced stage (IIIB-IV) lung cancer should receive thromboembolic prophylaxis at least for the duration of chemotherapy. It is, therefore, essential to propose a thrombo-prophylaxis clinical trial that recruits only lung cancer patients to evaluate the benefit of prophylaxis in this population and to assess the real risk of bleeding during antithrombotic treatment

Port in oncology practice: 3-monthly locking with normal saline for catheter maintenance, a preliminary report

Introduction Patients with cancer need stable venous access using central vascular devices like central venous ports and peripherally inserted central catheters that can be used for a wide range of indications. Numerous flushing protocols exist including different frequencies for catheter locking to maintain catheter patency. The aim of this retrospective study was to evaluate the incidence of lumen occlusion of central venous ports in a group of adult cancer patients, adopting a policy of locking with normal saline every three months. Methods This is a single-center retrospective observational study. During follow-up, we analyzed adult cancer patients who had undergone port insertion from January 1st, 2007 to August 31st, 2014. Flushing and locking were performed every three months with a syringe containing normal saline. Results We collected data from 381 patients with ports inserted in subclavian vein (379 patients) and in the right jugular vein (2 patients). Locking was performed during 3-monthly follow-up visits. Median follow-up was 810 days (90-2700 days). Among 381 ports, 59 were removed; the reasons for removal were: end of use (45 cases), catheter rupture (9 cases), dislocation (3 cases) and catheter-related bloodstream infection (2 cases). We had no reports of lumen occlusion. Conclusions Our data suggest that locking ports with normal saline every three months is not associated with an increased risk of lumen occlusion. </jats:sec

Epigenetic control of autophagy in women’s tumors: role of non-coding RNAs

Cancer remains the second leading cause of death worldwide and a major public health and economic issue. To reduce the burden, new approaches are necessary to diagnose the disease at early stages and improve clinical outcomes of cancer patients, for which understanding the molecular mechanisms of carcinogenesis is crucial. Autophagy is a pro-survival pathway that ensures the removal and renewal of cellular macromolecular structures, thus playing a crucial role in the maintenance of cellular homeostasis. Dysregulation of autophagy can favor chemoresistance and survival of dormant cancer cells, thus favoring cancer progression and relapse. Several studies report dysregulated expression of long non-coding RNAs and micro-RNAs acting as tumor suppressors or tumor promoters by targeting genes involved in the autophagy pathway. Here, we focus on the role played by non-coding RNAs-mediated regulation of autophagy in development and progression of cancers in women. Understanding how epigenetics can impact autophagy might open novel therapeutic strategies in the fight against cancers in women

Autophagy and thyroid carcinogenesis: genetic and epigenetic links

Thyroid cancer is the most common cancer of the endocrine system and is responsible for the majority of deaths from endocrine malignancies. Although a large proportion of thyroid cancers belong to well differentiated histologic subtypes, which in general show a good prognosis after surgery and radioiodine ablation, the treatment of radio-resistant papillary-type, of undifferentiated anaplastic, and of medullary-type thyroid cancers remains unsatisfactory. Autophagy is a vesicular process for the lysosomal degradation of protein aggregates and of damaged or redundant organelles. Autophagy plays an important role in cell homeostasis, and there is evidence that this process is dysregulated in cancer cells. Recent in vitro preclinical studies have indicated that autophagy is involved in the cytotoxic response to chemotherapeutics in thyroid cancer cells. Indeed, several oncogenes and oncosuppressor genes implicated in thyroid carcinogenesis also play a role in the regulation of autophagy. In addition, some epigenetic modulators involved in thyroid carcinogenesis also influence autophagy. In this review,we highlight the genetic and epigenetic factors that mechanistically link thyroid carcinogenesis and autophagy, thus substantiating the rationale for an autophagy-targeted therapy of aggressive and radio-chemo-resistant thyroid cancer