Novel strategies of adoptive immunotherapy: How natural killer cells may change the treatment of elderly patients with acute myeloblastic leukemia

Although many attempts have been made to identify novel molecular-targeted therapies for patients with acute myeloid leukemia, their translation into the clinic have had limited impact. In particular, the question of effective and curative treatments for elderly patients, who are not eligible for stem cell transplantation, remains an unmet medical need. To answer this question, a wide range of immunologic therapeutic strategies, mostly T cell based, have been proposed and investigated. At present, however, the clinical results have been largely unsatisfactory. Natural killer cells have recently been used as a means of adoptive immunotherapy with promising clinical results. On the basis of recent clinical reports and moving from the basic immunobiology of natural killer cells, here we discuss some open issues in the clinical translation of natural killer-based adoptive immunotherapy for the management of elderly patients with acute myeloid leukemia

Dendritic Cell Differentiation

Dauer et al. ([1][1]) presented a method to differentiate CD14+ cells into mature dendritic cells (DC) within 48 h (FastDC). FastDC displayed a DC-like morphology, down-regulated CD14, and induced proliferation of autologous T cells against soluble Ags as efficiently as standard monocyte-derived D

Knee osteoarthritis in a chestnut farmer – Case Report

Introduction Several studies have dealt with the issue of professional risk factors and onset of knee osteoarthritis (OA). In particular, occupational epidemiological studies have provided evidence that activities resulting in biomechanical overload may be linked with an increased risk of knee OA – also among farmers. To our knowledge, no cases of knee OA among chestnut farmers have been reported in the literature. Case report We report the case of a 70-year-old Caucasian male who has worked for more than 50 years on a chestnut farm. In 2007, an X-ray and a MRI, performed after a workplace accident to his left knee, showed the presence of knee OA. His job required a range of repetitive tasks, such as squatting, kneeling, climbing, walking on sloping terrain, assuming uncomfortable postures, and lifting and carrying heavy loads for the great majority of the working day. All the aforementioned tasks are known occupational risk factors for knee OA. Regarding individual risk factors, at the time of the first diagnosis of knee OA, the worker was 64-years-old with a body mass index of 26.5 kg/m2. He reported no cases of arthritis among his relatives and no sports playing on his part. In addition, his medical history revealed the presence of two minor lumbar disc herniations and tendinitis of the long head of the biceps. Conclusions Considering the lack of major individual risk factors for knee OA, it is reasonable to suppose that five decades of exposure to biomechanical overload as a chestnut farmer was a relevant risk factor for the onset of the disease

The Yin and Yang of the Bone Marrow Microenvironment: Pros and Cons of Mesenchymal Stromal Cells in Acute Myeloid Leukemia

Mesenchymal stromal cells (MSCs) have, for a long time, been recognized as pivotal contributors in the set up and maintenance of the hematopoietic stem cell (HSC) niche, as well as in the development and differentiation of the lympho-hematopoietic system. MSCs also have a unique immunomodulatory capacity, which makes them able to affect, both in vitro and in vivo, the function of immune cells. These features, namely the facilitation of stem cell engraftment and the inhibition of lymphocyte responses, have both proven essential for successful allogeneic stem cell transplantation (allo-SCT), which remains the only curative option for several hematologic malignancies. For example, in steroid-refractory acute graft-vs. host disease developing after allo-SCT, MSCs have produced significant results and are now considered a treatment option. However, more recently, the other side of the MSC coin has been unveiled, because of their emerging role in creating a protective and immune-tolerant microenvironment able to support the survival of leukemic cells and affect the response to therapies. In this light, it has been proposed that the failure of current treatments to efficiently override the stroma-mediated protection of leukemic cells accounts for the high rate of relapse in acute myeloid leukemia, at least in part. In this review, we will focus on emerging microenvironment-driven mechanisms conferring a survival advantage to leukemic cells overt physiological HSCs. This body of evidence increasingly highlights the opportunity to consider tumor-microenvironment interactions when designing new therapeutic strategies

Chemotherapy-Induced Tumor Cell Death at the Crossroads Between Immunogenicity and Immunotolerance: Focus on Acute Myeloid Leukemia

In solid tumors and hematological malignancies, including acute myeloid leukemia, some chemotherapeutic agents, such as anthracyclines, have proven to activate an immune response via dendritic cell-based cross-priming of anti-tumor T lymphocytes. This process, known as immunogenic cell death, is characterized by a variety of tumor cell modifications, i.e., cell surface translocation of calreticulin, extracellular release of adenosine triphosphate and pro-inflammatory factors, such as high mobility group box 1 proteins. However, in addition to with immunogenic cell death, chemotherapy is known to induce inflammatory modifications within the tumor microenvironment, which may also elicit immunosuppressive pathways. In particular, DCs may be driven to acquire tolerogenic features, such as the overexpression of indoleamine 2,3-dioxygensase 1, which may ultimately hamper anti-tumor T-cells via the induction of T regulatory cells. The aim of this review is to summarize the current knowledge about the mechanisms and effects by which chemotherapy results in both activation and suppression of anti-tumor immune response. Indeed, a better understanding of the whole process underlying chemotherapy-induced alterations of the immunological tumor microenvironment has important clinical implications to fully exploit the immunogenic potential of anti-leukemia agents and tune their application

The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling

We and others have shown that the Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), a member of the inflammatory network exerting pleiotropic effects in the bone marrow (BM) microenvironment, regulates the survival and proliferation of different cell types, including normal hematopoietic progenitor cells. Moreover, TIMP-1 has been shown to be involved in cancer progression. However, its role in leukemic microenvironment has not been addressed. Here, we investigated the activity of TIMP-1 on Acute Myelogenous Leukemia (AML) cell functions. First, we found that TIMP-1 levels were increased in the BM plasma of AML patients at diagnosis. In vitro, recombinant human (rh)TIMP-1 promoted the survival and cell cycle S-phase entry of AML cells. These kinetic effects were related to the downregulation of cyclindependent kinase inhibitor p21. rhTIMP-1 increases CXCL12-driven migration of leukemic cells through PI3K signaling. Interestingly, activation of CD63 receptor was required for TIMP-1's cytokine/chemokine activity. Of note, rhTIMP-1 stimulation modulated mRNA expression of Hypoxia Inducible Factor (HIF)-1a, downstream of PI3K/Akt activation. We then co-cultured AML cells with normal or leukemic mesenchymal stromal cells (MSCs) to investigate the interaction of TIMP-1 with cellular component(s) of BM microenvironment. Our results showed that the proliferation and migration of leukemic cells were greatly enhanced by rhTIMP-1 in presence of AML-MSCs as compared to normal MSCs. Thus, we demonstrated that TIMP-1 modulates leukemic blasts survival, migration and function via CD63/PI3K/ Akt/p21 signaling. As a "bad actor" in a "bad soil", we propose TIMP-1 as a potential novel therapeutic target in leukemic BM microenvironment

O8D.8 Severity of carpal tunnel syndrome and manual work: findings from a case-control study

ObjectiveCarpal tunnel syndrome (CTS) is a socially relevant condition. This case-control study aims to investigate the association between CTS severity and manual work considering personal anthropometric risk factors as well.MethodsWe consecutively enrolled one CTS case for two controls (subjects without clinical and electrophysiological CTS signs) regardless of age and gender who were admitted to the same three outpatient electromyography labs.CTS cases were grouped in three classes of progressive clinical and electrophysiological severity according to two validated five-stage scales. Anthropometric measures and occupational history were collected. Job titles were coded according to the International Standard Classification of Occupations (ISCO 88) by two occupational physicians who were blind to case/control status. Job titles were grouped in two main occupational categories: manual workers and non-manual workers.To assess the association between CTS severity and manual work, ordered logistic regression models (adjusted for age, sex, wrist-palm ratio and waist-stature ratio) were performed. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated.ResultsThis case-control study enrolled 370 cases and 747 controls. After the exclusion of retired subjects, subjects older than 65 years and subjects with no information about occupational history, we included 183 cases and 445 controls in the main analysis.For manual workers with respect to non-manual workers, the OR for the electrophysiological severity scale was 2.4 (95%CI 1.5–3.7). Regarding the clinical severity scale, the OR for manual workers compared to non-manual workers were 2.3 (95%CI 1.5–3.7).ConclusionThis study confirms that manual work is an important risk factor for CTS. The association between manual work and CTS severity tends to increase from mild to severe stage of both electrophysiological and clinical scale