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PDF - 152K, Supplementary Figure 1: CD4+ and CD8+ T cells infiltrate the stroma and the transformed epithelium following transplantation and vaccination.) Supplementary Figure 2: Tumor-directed vaccination and alloreactive DLI synergize in evoking intratumoral infiltration.

Introduction:Avascular necrosis of femoral head (AVN) is 1 of the main factors causing disability in young adults. Hip prosthesis can be considered an effective treatment of the painful symptoms but it is a major surgical intervention for this type of population. Thus, a large space should be left to therapeutic alternatives such as regenerative medicine. This retrospective study evaluates 52 AVN treated by core decompression, bone chips allograft, fibrin platelet-rich plasma (PRF) and concentrated autologous mesenchymal stromal cells (MSCs).Methods:The AVN was diagnosed using magnetic resonance imaging (MRI) and graded according to ARCO classification: a patient was classified stage 1 (21 patients), stage 3 (26 patients), and 4 patients were classified as stage 4. We evaluated patients with functional scores (Harris Hip Score) and radiological analysis at 3, 6, 12 and 24 months after the procedure. Patients requiring prosthetic replacement of the joint were included; in these cases, follow-up was interrupted at the time of the joint replacement procedure.Results:Our statistical analysis showed differences between survived and failed treatments, in terms of patient profile and ARCO radiological classification. The best result occurred in patients with ARCO grades 1 and 2, while the more advanced grades showed a high failure rate. It is interesting to note that ARCO quantification, conceived as the joint surface involved in the necrosis, has a negative influence on the outcome of the procedure. Indeed, patients affected by ARCO 3a, where necrosis involved a small portion of the femoral epiphysis and the collapse of the articular surface was limited to 2 mm, showed results similar to those obtained in patients with ARCO 1 and 2.Conclusions:In conclusion, compared with the alternative technique of decompression, our data suggest that post-collapse cases with a small area of necrosis and the use of bone grafts may show better results compared to those of the literature.

The optimization of advanced in vitro models is essential for the development of alternative methods. The in vitro study of osteochondral regeneration still has numerous limitations and wide scope for exploration.

BackgroundA first-year interim analysis of this two-year study suggested that intra-articular injections of highly purified, natural-origin polynucleotides and hyaluronic acid (HA) as a fixed combination (PNHA) might improve knee function and joint pain more effectively than HA alone in patients with knee osteoarthritis (OA). The purpose of the second-year analysis herein described was to verify whether the first-year interim outcomes persist over the whole two-year period.MethodsRandomised, double-blind, HA-controlled clinical trial in 100 knee OA patients (98 randomised, 79 completing the study) in a high-specialisation tertiary care setting. The hypothesised difference of efficacy between PNHA and HA for the original sample size estimate is 20%. Treatment cycle: three intra-articular knee injections of either PNHA or HA, at baseline and weekly for two weeks. Evaluations: Western Ontario and McMaster Universities (WOMAC) score and Knee Society Score (KSS) as, respectively, primary and secondary endpoints, evaluated at baseline and after 2, 6, 12, and 24 months; synovial fluid levels of mediators (at baseline and the end of the treatment cycle). Adverse effects investigated at each control visit. Statistical analysis: Kruskal-Wallis test for independent samples (nonparametric one-way analysis of variance) after correction of means for age, Body Mass Index and Kellgren-Lawrence grade. If significant, pairwise post-hoc Sidak multiple comparisons.ResultsKSS total score and KSS pain item: significant improvement in both groups, with significantly more pain improvement in patients treated with PNHA (2-point reduction) than HA (1-point reduction). Both groups experienced significant long-term reductions in WOMAC total scores: significantly stronger in PNHA-treated patients after 24 months with a steady difference of 16% favouring PNHA in WOMAC pain subscore. No clinically significant adverse events in either group.ConclusionsThe outcomes of the 2-year study confirmed that a short cycle of intra-articular treatment (3 weekly double-blind injections) with polynucleotides (long-acting viscosupplementation properties, chondrocyte activation, pain-relieving properties) in fixed combination with high molecular weight hyaluronic acid is more effective in improving knee function and pain in knee OA patients than HA alone. PNHA may be elective for viscosupplementation in knee OA patients with fastidious and resistant pain and worsening disease.Trial registrationNCT02417610.Registration, 15/04/2015.ClinicalTrials.govdatabase link

Introduction Nonunions remain a significant burden in orthopedics, often afflicting young males of working age. Positive findings have been published using bone marrow aspirate concentrate (BMAC) and platelet-rich fibrin (PRF) for the treatment augmentation of lower limb nonunions. The aim of this study was to investigate if the treatment augmentation with BMAC and PRF can also accelerate the healing of nonunions of the upper limb. Materials and methods Sixty-eight patients (45 men, 23 women) affected by 75 nonunions of long bones of the upper limb were treated and divided into two groups. The first series was treated with standard surgery alone (group A); afterwards, the second series benefited from standard surgery with the addition of BMAC and PRF applied on lyophilized bone chips. Nonunions were classified radiographically according to the Weber–Cech method and prognostically using the Calori and Moghaddam scores. All patients were radiographically assessed at 1.5, 3, 6, 12, and 24 months of follow-up. Results Baseline demographic characteristics did not present differences between groups. No differences were documented in terms of complications (two in group A and three in group B). Significant differences were instead documented in terms of healing time. The first healing signs were observed 1.5 months after surgery in 90.7% of patients in group B and 34.4% of group A (p p p = 0.001). Conclusion This study showed the benefits of restoring both mechanical and biological aspects when addressing nonunions of the long bones of the upper limb. In particular, the association of BMAC and PRF to lyophilized bone chips was safe and able to accelerate healing time. These good results were confirmed for humerus, radius, and ulna sites, as well as for challenging atrophic nonunions of the upper limb.

Significance Functional loss of gut barrier integrity with subsequent increased antigen trafficking and occurrence of low-grade intestinal inflammation precede the onset of type 1 diabetes (T1D) in patients and preclinical models, thus suggesting that these events are mechanistically linked to the autoimmune pathogenesis of the disease. However, a causal relationship between increased intestinal permeability and autoimmune diabetes was never demonstrated. Our data show that breakage of gut barrier continuity leads to activation of islet-reactive T cells in the intestine, thus triggering autoimmune diabetes. An important implication of our findings is that restoration of a healthy gut barrier through microbiota and diet modulation in diabetes-prone individuals could reduce intestinal activation of islet-reactive T cells and prevent T1D occurrence., Low-grade intestinal inflammation and alterations of gut barrier integrity are found in patients affected by extraintestinal autoimmune diseases such as type 1 diabetes (T1D), but a direct causal link between enteropathy and triggering of autoimmunity is yet to be established. Here, we found that onset of autoimmunity in preclinical models of T1D is associated with alterations of the mucus layer structure and loss of gut barrier integrity. Importantly, we showed that breakage of the gut barrier integrity in BDC2.5XNOD mice carrying a transgenic T cell receptor (TCR) specific for a beta cell autoantigen leads to activation of islet-reactive T cells within the gut mucosa and onset of T1D. The intestinal activation of islet-reactive T cells requires the presence of gut microbiota and is abolished when mice are depleted of endogenous commensal microbiota by antibiotic treatment. Our results indicate that loss of gut barrier continuity can lead to activation of islet-specific T cells within the intestinal mucosa and to autoimmune diabetes and provide a strong rationale to design innovative therapeutic interventions in “at-risk” individuals aimed at restoring gut barrier integrity to prevent T1D occurrence.

Background To date, hip arthroplasty is one of the most commonly performed surgical procedures, with growing worldwide demand. In recent decades, major progress made in terms of surgical technique, biomechanics, and tribology knowledge has contributed to improve the medical and functional management of the patient. This study aims to assess if the application of a fast track protocol, consisting of a preoperative educational intervention, adequate postoperative pain control, and intensive rehabilitation intervention, reduces the length of stay (LOS) and allows the early functional recovery compared to standard clinical practice for patients undergoing hip arthroplasty. Methods The study population consists of 90 patients with primary arthrosis of the hip with an anterior indication of hip arthroplasty. The exclusion criteria are older than 70 years, a contraindication to performing spinal anesthesia, and bone mass index (BMI) greater than 32. Participants, 45 for each group, are randomly allocated to one of two arms: fast track clinical pathway or standard care protocol. During allocation, baseline parameters such as Harris Hip Score (HHS) and Western Ontario and McMaster Universities (WOMAC) index are collected. On the third postoperative day, the functional autonomy for each patient is assessed by the Iowa Level of Assistance (ILOA) scale, and it is expected the discharge for patients in the fast track group (primary outcome). On the other hand, standard care patient discharge is expected after 5–7 days after surgery. During follow-up fixed at 6 weeks and 3, 6, and 12 months, HHS and WOMAC scores are collected for each patient (secondary outcomes). Discussion Although total hip replacement has become a widespread standardized procedure, to the authors’ knowledge, only few randomized controlled trials were performed to evaluate the effectiveness of fast track pathway vs. standard care procedure in the reduction of the LOS after hip arthroplasty. It is expected that our results collected by the application of minimally invasive surgical interventions with concomitant management of perioperative pain and bleeding and early functional rehabilitation will contribute to enriching the understanding of clinical and organizational aspects linked to fast track arthroplasty. Trial registration ClinicalTrials.gov NCT03875976. Registered on 15 March 2019—“retrospectively registered”.

Osteoarthritis (OA) is a very common disease, its prevalence increases with age and is a frequent cause of disability. Osteoarthritis is characterised by joint pain, stiffness and loss of range of motion. Overall, as many as 40% of those aged over 65 years in the community may have symptomatic OA of the knee or hip ( 1 ). OA results from a complex interaction of biomechanical and biochemical factors and is characterised by cartilage disruption and hypertrophy of bone. Intraarticular proinflammatory cytokines and proteinases in OA interfere with the synthesis of hyaluronic acid (HA), a complex glycosaminoglycan composed of repeated disaccharide units to form a linear polymer, resulting in an HA with a significantly reduced molecular weight and a reduction in synovial fluid viscoelasticity ( 2 - 3 ). Loss of normal characteristics of HA leads to the degradation of the articular cartilage and the disruption of the mechanical and homeostasis of the joint. Several pharmaceutical approaches, such as analgesics, non steroidal antiinflammatory drugs, COX-2 inhibitors and steroids, have been proposed ( 4 ), with the aim of reducing pain and maintaining and/or improving joint function. However, none of these options has shown to delay the progression of osteoarthritis or reverse joint damage. Infiltrative hip therapy involves injecting into the joint the drugs or medicinal substances that are used primarily to control the symptoms of the disease, such as pain and functional limitation. The aim of this review is to analyse existing infiltrative alternatives for hip osteoarthritis, and describe our experience.

The autologous bone substitutes are the gold standard of orthopedic surgery for the treatment of severe losses of substance. Nevertheless there are different issues, from co-morbidity of the donor site, the limited quantity and poor osteogenic properties. To overcome these limits the bank of the skeletal muscle tissue of the Rizzoli Institutes in cooperation with FIN-ceramic Faenza SpA have developed DBSint: a new synthetic bone composite, equipped with biomimetic and osteoinductive properties, consisting of demineralized bone matrix conveyed by nanostructured hydroxyapatite enriched with magnesium. The DBSint has recently been evaluated with a clinical preliminary study with the purpose to analyze the ability to form new bone tissue and the time necessary to determine bone repair. We enrolled 36 patients with indication to perform a valgus osteotomy of the tibia, divided into 3 groups, respectively, treated with nano hydroxyapatite structured in the form of paste (SINTlife) currently on the market, the cortico-cancellous bone chips provided by the BTM-IOR, and finally DBSint. There were no adverse effects, we performed biopsies and histological exam, and radiographic assessment, respectively, at 40 days and 6 months after treatment, showing that the DBSint is able to promote a fast bone regeneration, higher than in the two groups treated with Sintlife and homologous bone.

The role of monocytes/macrophages in the development and progression of chronic lymphocytic leukemia (CLL) is poorly understood. Transcriptomic analyses show that monocytes/macrophages and leukemic cells cross talk during CLL progression. Macrophage depletion impairs CLL engraftment, drastically reduces leukemic growth, and favorably impacts mouse survival. Targeting of macrophages by either CSF1R signaling blockade or clodrolip-mediated cell killing has marked inhibitory effects on established leukemia also. Macrophage killing induces leukemic cell death mainly via the TNF pathway and reprograms the tumor microenvironment toward an antitumoral phenotype. CSF1R inhibition reduces leukemic cell load, especially in the bone marrow, and increases circulating CD20(+) leukemic cells. Accordingly, co-targeting TAMs and CD20-expressing leukemic cells provides a survivalbenefit in the mice. These results establish the important role of macrophages in CLL and suggest therapeutic strategies based on interfering with leukemia-macrophage interactions.

Background The treatment of comminuted radial head fractures can include prosthetic replacement or open reduction and internal fixation. The purpose of this study is to evaluate the results of two different internal fixation systems for Mason type II-III radial head fractures. Methods Between 2005 and 2015, 82 patients were treated using pins and 65 patients by mini-screws. The follow-up protocol included: a clinical evaluation 15 days after surgery, and clinical and radiographic evaluations performed at 30 and 60 day intervals, unless any complications were reported by the patient. Over a period of at least 12-months of follow-up, patients were checked and interviewed. Clinical examinations included elbow range of motion (ROM), arm, shoulder and hand Disabilities, (DASH), and the Mayo Elbow Performance Score (MEPS). Results Sixty-one subjects who had been treated with mini-screws were clinically reviewed at a mean 47.3 ± 35.8 month of follow-up; all patients who had been treated using absorbable pins were evaluated at a mean 82.5 ± 20.6 month of follow-up. No significant statistically differences were observed between the two groups in the mean ROM, DASH, and MEPS scores. Residual pain was reported in 15.8%of the patients treated by pins and 9.2% patients treated by mini-screws. Secondary displacement of fracture fragments was observed in 8.5% patients treated by pins and 1.6% using mini-screws. Conclusions Both absorbable pins and mini-screws provided adequate strength and rigidity, allowing good clinical and functional scores at a mid-term follow-up. However, a higher rate of secondary displacement of the fracture fragments was reported among subjects who had been treated using absorbable pins.

Background Radial head fractures make up approximately 3% of all fractures and they are the most common elbow fracture in adults. Replacement through arthroplasty is the recommended treatment in the context of unstable elbow injury and comminuted radial head fracture. The midterm clinical, functional, and radiographic results in patients treated with anatomic radial head arthroplasty for a Mason type III radial head fracture are presented. Material and methods We performed a retrospective search of our facility's prospective trauma database to identify all skeletally mature patients who were treated by primary radial head replacement or open reduction and internal fixation following an acute radial head fracture. Inclusion criteria were Mason type III fractures and anatomic radial head arthroplasty (RHA). All the patients included were evaluated using a standard postoperative protocol including clinical and radiographic evaluation at 1, 3 and 12 months of follow-up. All the patients were reviewed clinically at an average of 30 months’ follow-up. Results Forty-one subjects (32 Mason type III and 9 Mason IV fractures) were treated with anatomic RHA (Acumed, Hillsboro, OR, USA). Of these, two patients (1 Mason type III and 1 Mason type IV) were excluded from the analysis because severe cognitive impairment. Moreover, we decided to exclude the subjects with a Mason type IV fracture to obtain a more homogeneous sample. Therefore, 31 patients with a Mason type III fracture were included in this study. Based on the Mayo Elbow Performance Score, excellent results were obtained in 24 (77%) patients, good in 3 (10%) and fair in 4 (13%) patients. Heterotopic ossification was reported in 8 patients (26% of cases). The final elbow flexion-extension range of motion was of 112°, with a mean flexion of 125°. The final forearm rotational range of motion was 134° with a mean pronation of 68° and a mean supination of 66°. Discussion Anatomic radial head replacement leads to a good functional recovery, even in the presence of severe instability, such as coronoid fractures and LUCL injury. However, patients should be informed of the high number of adverse events (mainly heterotopic ossification) following this treatment. Level of evidence Therapeutic IV.

Fractures of the humerus shaft often are complicated by radial nerve palsy. Controversy still exists in the treatment that includes clinical observation and eventually late surgical exploration or early surgical exploration. Algorithms have been proposed to provide recommendations with regard to management of the injuries. However, advantages and disadvantages are associated with each of these algorithms. The aim of this study was to analyze the indications of each treatment options and facilitate the surgeon in choosing the conduct for each lesion, proposing our own algorithm.

Distal humeral malunions are uncommon injuries, often associated with limited elbow motion, pain, instability, weakness, and sometimes ulnar neuritis. The complex anatomy of the elbow joint makes this condition one of the most complex elbow injuries to treat. Four patients were treated by the same surgeon between 2011 and 2013 using a double-locking precontoured plating system for malunited intra-articular or extra-articular fractures of the distal end of the humerus. At a mean 3 years of follow-up, a significant improvement in the elbow motion and functional outcome, evaluated with the Mayo Elbow Performance Index and the Disability of the Arm, Shoulder, and Hand, were observed. Articular reduction obtained after the surgery was maintained in all patients without evidence of avascular necrosis. No other complications (i.e., infection, nervous iatrogenic lesions) were reported. Corrective osteotomy using double-locking precontoured plating system preceded by preoperative planning using a CT scan allowed an improvement in the functional outcome and elbow motion, without complications.

Background Radial head fractures make up approximately 3% of all fractures and they are the most common elbow fracture in adults. Replacement through arthroplasty is the recommended treatment in the context of unstable elbow injury and comminuted radial head fracture. The midterm clinical, functional, and radiographic results in patients treated with anatomic radial head arthroplasty for a Mason type III radial head fracture are presented. Material and methods We performed a retrospective search of our facility's prospective trauma database to identify all skeletally mature patients who were treated by primary radial head replacement or open reduction and internal fixation following an acute radial head fracture. Inclusion criteria were Mason type III fractures and anatomic radial head arthroplasty (RHA). All the patients included were evaluated using a standard postoperative protocol including clinical and radiographic evaluation at 1, 3 and 12 months of follow-up. All the patients were reviewed clinically at an average of 30 months’ follow-up. Results Forty-one subjects (32 Mason type III and 9 Mason IV fractures) were treated with anatomic RHA (Acumed, Hillsboro, OR, USA). Of these, two patients (1 Mason type III and 1 Mason type IV) were excluded from the analysis because severe cognitive impairment. Moreover, we decided to exclude the subjects with a Mason type IV fracture to obtain a more homogeneous sample. Therefore, 31 patients with a Mason type III fracture were included in this study. Based on the Mayo Elbow Performance Score, excellent results were obtained in 24 (77%) patients, good in 3 (10%) and fair in 4 (13%) patients. Heterotopic ossification was reported in 8 patients (26% of cases). The final elbow flexion-extension range of motion was of 112°, with a mean flexion of 125°. The final forearm rotational range of motion was 134° with a mean pronation of 68° and a mean supination of 66°. Discussion Anatomic radial head replacement leads to a good functional recovery, even in the presence of severe instability such as coronoid fractures and LUCL injury. However, patients should be informed of the high number of adverse events (mainly heterotopic ossification) following this treatment. Level of evidence Therapeutic IV.

Vaccination can synergize with transplantation of allogeneic hematopoietic stem cells to cure hematologic malignancies, but the basis for this synergy is not understood to the degree where such approaches could be effective for treating solid tumors. We investigated this issue in a transgenic mouse model of prostate cancer treated by transplantation of a nonmyeloablative MHC-matched, single Y chromosome–encoded, or multiple minor histocompatibility antigen-mismatched hematopoietic cell preparation. Here, we report that tumor-directed vaccination after allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion is essential for acute graft versus tumor responses, tumor regression, and prolonged survival. Vaccination proved essential for generation of CD8+ IFN-γ+ tumor-directed effector cells in secondary lymphoid organs and also for IFN-γ+ upregulation at the tumor site, which in turn instructed local expression of proinflammatory chemokines and intratumoral recruitment of donor-derived T cells for disease regression. Omitting vaccination, transplanting IFN-γ–deficient donor T cells, or depleting alloreactive T cells all compromised intratumoral IFN-γ–driven inflammation and lymphocyte infiltration, abolishing antitumor responses and therapeutic efficacy of the combined approach. Our findings argue that posttransplant tumor-directed vaccination is critical to effectively direct donor T cells to the tumor site in cooperation with allogeneic hematopoietic cell transplantation. Cancer Res; 73(00); 4641–52. ©2013 AACR.

Inflammation is involved in the initiation and progression of several chronic lymphoid malignancies of B-cell type. Toll-like receptors (TLR) are transmembrane inflammatory receptors that on recognition of pathogen-associated molecular patterns trigger an innate immune response and bridge the innate and adaptive immune response by acting as costimulatory signals for B cells. Fine tuning of TLR and IL-1R-like (ILR) activity is regulated by TIR8 (SIGIRR), a transmembrane receptor of the TLR/ILR family which inhibits other family members. To test the hypothesis that TLR and/or ILR may play a role in the natural history of chronic B-cell tumors, we crossed E mu-TCL1 transgenic mice, a well established model of chronic lymphocytic leukemia (CLL), with mice lacking the inhibitory receptor TIR8 that allow an unabated TLR-mediated stimulation. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened. The morphology and phenotype of the mouse leukemic expansions reproduce the progression of human CLL into an aggressive and frequently terminal phase characterized by the appearance of prolymphocytes. This study reveals an important pathogenetic implication of TLR in CLL development and progression. (Blood. 2011;118(3):660-669) "Inflammation is involved in the initiation and progression of several chronic lymphoid malignancies of B-cell type. Toll-like receptors (TLR) are transmembrane inflammatory receptors that on recognition of pathogen-associated molecular patterns trigger an innate immune response and bridge the innate and adaptive immune response by acting as costimulatory signals for B cells. Fine tuning of TLR and IL-1R-like (ILR) activity is regulated by TIR8 (SIGIRR), a transmembrane receptor of the TLR\/ILR family which inhibits other family members. To test the hypothesis that TLR and\/or ILR may play a role in the natural history of chronic B-cell tumors, we crossed E mu-TCL1 transgenic mice, a well established model of chronic lymphocytic leukemia (CLL), with mice lacking the inhibitory receptor TIR8 that allow an unabated TLR-mediated stimulation. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened. The morphology and phenotype of the mouse leukemic expansions reproduce the progression of human CLL into an aggressive and frequently terminal phase characterized by the appearance of prolymphocytes. This study reveals an important pathogenetic implication of TLR in CLL development and progression. (Blood. 2011;118(3):660-669)"

The function of the intracellular protein hematopoietic cell-specific Lyn substrate-1 (HS1) in B lymphocytes is poorly defined. To investigate its role in migration, trafficking, and homing of leukemic B lymphocytes we have used B cells from HS1(-/-) mice, the HS1-silenced human chronic lymphocytic leukemia (CLL) MEC1 cell line and primary leukemic B cells from patients with CLL. We have used both in vitro and in vivo models and found that the lack of expression of HS1 causes several important functional effects. In vitro, we observed an impaired cytoskeletal remodeling that resulted in diminished cell migration, abnormal cell adhesion, and increased homotypic aggregation. In vivo, immunodeficient Rag2(-/-)gamma(-/-)(c) mice injected with HS1-silenced CLL B cells showed a decreased organ infiltration with the notable exception of the bone marrow (BM). The leukemic-prone E mu-TCL1 transgenic mice crossed with HS1-deficient mice were compared with E mu-TCL1 mice and showed an earlier disease onset and a reduced survival. These findings show that HS1 is a central regulator of cytoskeleton remodeling that controls lymphocyte trafficking and homing and significantly influences the tissue invasion and infiltration in CLL. (Blood. 2010;116(18):3537-3546) The function of the intracellular protein hematopoietic cell-specific Lyn substrate-1 (HS1) in B lymphocytes is poorly defined. To investigate its role in migration, trafficking, and homing of leukemic B lymphocytes we have used B cells from HS1(-/-) mice, the HS1-silenced human chronic lymphocytic leukemia (CLL) MEC1 cell line and primary leukemic B cells from patients with CLL. We have used both in vitro and in vivo models and found that the lack of expression of HS1 causes several important functional effects. In vitro, we observed an impaired cytoskeletal remodeling that resulted in diminished cell migration, abnormal cell adhesion, and increased homotypic aggregation. In vivo, immunodeficient Rag2(-/-)gamma(-/-)(c) mice injected with HS1-silenced CLL B cells showed a decreased organ infiltration with the notable exception of the bone marrow (BM). The leukemic-prone E mu-TCL1 transgenic mice crossed with HS1-deficient mice were compared with E mu-TCL1 mice and showed an earlier disease onset and a reduced survival. These findings show that HS1 is a central regulator of cytoskeleton remodeling that controls lymphocyte trafficking and homing and significantly influences the tissue invasion and infiltration in CLL. (Blood. 2010;116(18):3537-3546)

Easily reproducible animal models that allow for study of the biology of chronic lymphocytic leukemia (CLL) and to test new therapeutic agents have been very difficult to establish. We have developed a novel transplantable xenograft murine model of CLL by engrafting the CLL cell line MEC1 into Rag2(-/-)gamma(-/-)(c) mice. These mice lack B, T, and natural killer (NK) cells, and, in contrast to nude mice that retain NK cells, appear to be optimal recipient for MEC1 cells, which were successfully transplanted through either subcutaneous or intravenous routes. The result is a novel in vivo model that has systemic involvement, develops very rapidly, allows the measurement of tumor burden, and has 100% engraftment efficiency. This model closely resembles aggressive human CLL and could be very useful for evaluating both the biologic basis of CLL growth and dissemination as well as the efficacy of new therapeutic agents. (Blood. 2010;115:1605-1609) Easily reproducible animal models that allow for study of the biology of chronic lymphocytic leukemia (CLL) and to test new therapeutic agents have been very difficult to establish. We have developed a novel transplantable xenograft murine model of CLL by engrafting the CLL cell line MEC1 into Rag2(-/-)gamma(-/-)(c) mice. These mice lack B, T, and natural killer (NK) cells, and, in contrast to nude mice that retain NK cells, appear to be optimal recipient for MEC1 cells, which were successfully transplanted through either subcutaneous or intravenous routes. The result is a novel in vivo model that has systemic involvement, develops very rapidly, allows the measurement of tumor burden, and has 100% engraftment efficiency. This model closely resembles aggressive human CLL and could be very useful for evaluating both the biologic basis of CLL growth and dissemination as well as the efficacy of new therapeutic agents. (Blood. 2010;115:1605-1609)

On page 660 of the 21 July 2011 issue, there are 3 authors whose affiliations are partially incorrect. Cecilia Garlanda should be affiliated only with Laboratory of Immunology and Inflammation, Istituto Clinico Humanitas, IRCCS, Rozzano, Milano, Italy. In addition, the correct spelling of the