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Capillary hemangioma is a congenital malformation of the capillary. It commonly affects the face, eyelids, lips and skin. Adult capillary hemangioma involving the nasal cavity is rare and may be misdiagnosed as polyps or another tumor. This case report illustrated a middle-age adult patient in Malaysia who presents with unilateral nasal obstruction and intermittent epistaxis who later confirmed capillary hemangioma involving the right nasal septum. Endoscopic surgery excision of the hemangioma was successfully performed. There were no known risk factors present in him. A treating doctor in the outpatient clinic seeing symptoms such as unilateral nasal obstruction must consider alternative diagnosis such as hemangioma besides usual diagnosis of polyps.

Half of the women who sustain a hip fracture would not qualify for osteoporosis treatment based on current DXA-estimated bone mineral density criteria. Therefore, a better approach is needed to determine if an individual is at risk of hip fracture from a fall. The objective of this study was to determine the association between radiation-free MRI-derived bone strength and strain simulations compared to results from direct mechanical testing of cadaveric femora. Imaging was conducted on a 3-Tesla MRI scanner using two sequences: one balanced steady-state free precession sequence with 300 μm isotropic voxel size and one spoiled gradient echo with anisotropic voxel size of 234 × 234 × 1500 μm. Femora were dissected free of soft-tissue and 4350-ohm strain-gauges were securely applied to surfaces at the femoral shaft, inferior neck, greater trochanter, and superior neck. Cadavers were mechanically tested with a hydraulic universal test frame to simulate loading in a sideways fall orientation. Sideways fall forces were simulated on MRI-based finite element meshes and bone stiffness, failure force, and force for plastic deformation were computed. Simulated bone strength metrics from the 300 μm isotropic sequence showed strong agreement with experimentally obtained values of bone strength, with stiffness (r = 0.88, p = 0.0002), plastic deformation point (r = 0.89, p 0.0001), and failure force (r = 0.92, p 0.0001). The anisotropic sequence showed similar trends for stiffness, plastic deformation point, and failure force (r = 0.68, 0.70, 0.84; p = 0.02, 0.01, 0.0006, respectively). Surface strain-gauge measurements showed moderate to strong agreement with simulated magnitude strain values at the greater trochanter, superior neck, and inferior neck (r = -0.97, -0.86, 0.80; p ≤0.0001, 0.003, 0.03, respectively). The findings from this study support the use of MRI-based FE analysis of the hip to reliably predict the mechanical competence of the human femur in clinical settings.

Ongoing research is being conducted in the field of transplantation to discover novel, noninvasive biomarkers for assessment of graft quality before transplantation and monitoring of graft injury after transplantation. MicroRNAs (miRNAs) are among the most promising in this field. MiRNAs are small noncoding RNAs that function as important regulators of gene expression in response to cellular stress and disease. An advantage that makes miRNAs attractive candidates for biomarker research is their fast release from cells in response to stress and injury, which can occur via different routes. In the context of liver transplantation (LT), noninvasive measurement and stability of extracellular miRNAs in blood, bile, and graft perfusates has been linked to cell-type specific injury and early graft outcome following LT. Furthermore, specific intrahepatic miRNA expression patterns have been associated with graft survival and recurrent disease, like hepatitis C virus-related fibrosis and hepatocellular carcinoma. Therefore, miRNAs with strong predictive value and high sensitivity and specificity might be successfully applied to assess hepatic injury and to diagnose (recurrent) liver disease before, during and after LT. In this review, the current features and future prospects of miRNAs as biomarkers in and out of the liver are discussed.

Treatment options for arthrofibrosis following total knee arthroplasty include manipulation under anesthesia, open or arthroscopic arthrolysis, and revision surgery to correct identifiable problems. We propose preoperative low-dose irradiation and Constrained Condylar or Rotating-hinge revision for severe, idiopathic arthrofibrosis. Irradiation may decrease fibro-osseous proliferation while constrained implants allow femoral shortening and release of contracted collateral ligaments. Fourteen patients underwent fifteen procedures for a mean overall motion of 46° and flexion contracture of 30°. One patient had worsening range of motion while thirteen patients had 57° mean gain in range of motion (range 5°-90°). Flexion contractures decreased by a mean of 28°. There were no significant complications at a mean follow up of 34 months (range 24 to 74 months).

Ischemic-type biliary lesions (ITBLs) are a major cause of morbidity after liver transplantation (LT). Their assumed underlying pathophysiological mechanism is ischemia/reperfusion injury of the biliary tree, in which the portal circulation has been proposed recently to have a role. The aim of this study was to investigate whether early histological changes, particularly in the portal vein, predispose patients to ITBLs. A case-control study of 22 LT recipients was performed through a retrospective assessment of more than 30 histological parameters in 44 intraoperative liver biopsy samples taken after cold ischemia (time 0) and portal reperfusion (time 1). Eleven grafts developed ITBLs requiring retransplantation (the ITBL group), and 11 matched controls had normally functioning grafts 11 years after LT on average (the non-ITBL group). Additionally, 11 liver biopsy samples from hemihepatectomies performed for metastases of colorectal cancer (CRC) were assessed similarly. Analyses showed no significant histological differences at time 0 between the ITBL and non-ITBL groups. However, the time 1 biopsy samples from the ITBL group showed smaller portal vein branches (PVBs) significantly more often than the samples from the non-ITBL group, which also showed persisting paraportal collateral vessels. Larger PVBs and paraportal collateral vessels were also found in the CRC group. A morphometric analysis confirmed these findings and showed that PVB measurements were significantly lower for the ITBL group at time 1 versus the ITBL group at time 0 and the non-ITBL and CRC groups (they were largest in the CRC group). Thus, the PVB dimensions decreased in the ITBL group in comparison with the time 0 biopsy samples, and they were significantly smaller at time 1 in comparison with the dimensions for the non-ITBL and CRC groups. In conclusion, a smaller PVB lumen size in postreperfusion biopsy samples from liver grafts, suggesting a relatively decreased portal blood flow, is associated with a higher incidence of ITBLs. These findings support recent clinical studies suggesting a possible pathophysiological role of portal blood flow in the oxygenation of the biliary tree after LT.

As chronic hepatitis C patients with progressive disease can present themselves with normal ALT levels, more sensitive biomarkers are needed. MicroRNAs are newly discovered small noncoding RNAs that are stable and detectable in the circulation. We aimed to investigate the association between hepatocyte-derived microRNAs in serum and liver injury in patients with chronic hepatitis C. The hepatocyte-derived miR-122 and miR-192 were analysed in sera of 102 chronic HCV-infected patients and 24 healthy controls. Serum levels of miR-122 and miR-192 correlated strongly with ALT (R = 0.67 and R = 0.65, respectively, P < 0.001 for both). Median levels of miR-122 and miR-192 in HCV-infected patients were 23 times and 8 times higher as in healthy controls (P < 0.001 for both). Even within the HCV-infected patients with a normal ALT (n = 38), the levels of miR-122 and miR-192 were 12 times and 4 times higher compared with healthy controls (P < 0.001 for both). Multivariate logistic regression analyses showed that only miR-122 was a significant predictor of the presence of chronic HCV infection (P = 0.026). Importantly, miR-122 was also superior in discriminating chronic HCV-infected patients with a normal ALT from healthy controls compared with the ALT level (AUC = 0.97 vs AUC = 0.78, P = 0.007). In conclusion, our study confirmed that liver injury is associated with high levels of hepatocyte-derived microRNAs in circulation and demonstrated that in particular miR-122 is a sensitive marker to distinguish chronic hepatitis C patients from healthy controls. More sensitive blood markers would benefit especially those patients with minor levels of hepatocellular injury, who are not identified by current screening with ALT testing.

Background & Aims: Extracellular microRNAs (miRNAs) in serum and bile are currently under intense investigation for biomarker purposes in liver disease. However, the directions and pathways by which miRNAs are released from hepatic cells remains largely unknown. Here, we investigated the release of hepatocyte and cholangiocyte-derived miRNAs (HDmiRs and CDmiRs) into blood and bile during various (patho)physiological hepatic conditions. Methods: MiRNA release was analysed using longitudinally collected tissue and paired bile and serum samples (n = 124) that were obtained from liver transplant recipients during follow-up. Results: Cell-type specificity of HDmiRs and CDmiRs was confirmed in liver and common bile duct biopsies (P < 0.001). Analysis of paired bile and serum samples showed up to 20-times higher miRNA-levels in bile compared to serum (P < 0.0001). Fractionation of bile showed the majority of miRNAs being present in the unpelletable supernatant, where protein conjunctions protect miRNAs against degradation (P < 0.0001). During episodes of liver injury and histologically proven rejection in liver transplant recipients, relative HDmiR-levels in bile decreased while its levels in serum increased (P

Recent animal and human studies have highlighted the potential of hepatocyte-derived microRNAs (HDmiRs) in serum as early, stable, sensitive, and specific biomarkers of liver injury. Their usefulness in human liver transplantation, however, has not been addressed. The aim of this study was to investigate serum HDmiRs as markers of hepatic injury and rejection in liver transplantation. Serum samples from healthy controls and liver transplant recipients (n = 107) and peritransplant liver allograft biopsy samples (n = 45) were analyzed via the real-time polymerase chain reaction quantification of HDmiRs (miR-122, miR-148a, and miR-194). The expression of miR-122 and miR-148a in liver tissue was significantly reduced with prolonged graft warm ischemia times. Conversely, the serum levels of these HDmiRs were elevated in patients with liver injury and positively correlated with aminotransferase levels. HDmiRs appear to be very sensitive because patients with normal aminotransferase values (

Ischemic-type biliary lesions (ITBL) are the most frequent cause of nonanastomotic biliary strictures after liver transplantation. This complication develops in up to 25% of patients, with a 50% retransplantation rate in affected patients. Traditionally, ischemia-reperfusion injury to the biliary system is considered to be the major risk factor for ITBL. Several other risk factors for ITBL have been identified, including the use of liver grafts donated after cardiac death, prolonged cold and warm ischemic times and use of University of Wisconsin preservation solution. In recent years however, impaired microcirculation of the peribiliary plexus (PBP) has been implicated as a possible risk factor. It is widely accepted that the PBP is exclusively provided by blood from the hepatic artery, and therefore, the role of the portal venous blood supply has not been considered as a possible cause for the development of ITBL. In this short report, we present three patients with segmental portal vein thrombosis and subsequent development of ITBL in the affected segments in the presence of normal arterial blood flow. This suggests that portal blood flow may have an important contribution to the biliary microcirculation and that a compromised portal venous blood supply can predispose to the development of ITBL.

Acetabular fractures with complete or incomplete quadrilateral plate separation frequently present with central displacement of the femoral head. Failure of stable fixation of medial wall fractures leaves residual subluxation despite reduction of other fracture components. Several fixation techniques may be either technically demanding or insufficient for stable fixation in conditions of comminution, osteoporosis, or neglected injuries. The proposed wire-plate composite uses a reconstruction spring plate over the pelvic brim for medial wall buttressing. One hole on its true pelvic limb provides a pulley to deviate a cerclage wire or cable passed through the greater sciatic notch into the true pelvis. This enhances buttressing against medial protrusion. Application through anterior approaches is simple and fixation is reliable in difficult fractures without the risk of joint penetration because all quadrilateral plate buttressing implants remain extraosseous.

En bloc resection of iliosacral sarcomas is a surgical challenge. There are substantial risks of inadequate margins, local recurrence, and nerve root loss when pelvic sarcomas involve sacral root canals and foramina. The decancellation technique uses principles similar to transpedicle decancellation in spinal deformity correction to perform the sacral osteotomy in iliosacral tumor resection. The technique aims at improving sacral margins and minimizing loss of neural function. We performed a decancellation osteotomy in five patients with sarcomas requiring difficult oblique or sagittal sacral osteotomies and selective root sacrifice. Through laminectomy and without anterior exposure, a precise full-thickness osteotomy of the sacrum was performed without major technique-related morbidities or complications. This was followed by formal pelvic resection and reconstruction. Surgical margins were adequate in all patients and all tumor-free nerve roots were preserved.

We found HLA-DR5 to be present among 53% of 40 patients with goitrous autoimmune (Hashimoto's ) thyroiditis compared to 26% of 80 controls. No deviations from those expected in the incidences of HLA-A, B, C antigens were seen. In contrast HLA-DR3 was increased among 50 patients with atrophic thyroiditis (65%) compared to controls (24%). These findings stress the immunogenetic heterogeneity between the goitrous and atrophic varieties of thyroiditis.

One-hundred-and-forty-seven patients with autoimmune thyroiditis were studied with respect to HLA antigens as they related to various clinical features. HLA--B8 was found to be significantly increased among 59 patients with atrophic thyroiditis (57% vs. 26% for controls) but was identical to controls in 88 patients with goitrous thyroiditis (26%). No relation was found in either group between B8 and thyroid autoantibody titer or, in the case of goitrous thyroiditis, the rate of progression of the disease. Thus a link seems to be established between Graves' disease and atrophic thyroiditis in that both are significantly associated with HLA-B8. This study stresses the need to take clinical features into consideration when examining for HLA/disease associations.

In order to further elucidate the genetics of Graves' disease, we studied two families with several affected members, as well as tested the degree to which HLA haplotypes were shared in affected sibpairs. Further, we sought to identify the disease related haplotypes by determining the haplotypes shared among affected parent-child combinations. In one family, two affected sibs differed at four possible parental HLA haplotypes; no evidence of recombination was observed which could account for the result. In the other family, five siblings were affected. Four out of the five affected sibs shared the maternal haplotype HLA-A11, Bw51, Cw5, Cw-, DRw5, Bfs, GLO1, whereas three shared the paternal haplotype HLA-A1, B8, Cw-, DRw3, BfS and GLO1. Looking at haplotype sharing, two pairs of sibs were found to be HLA identical, whereas the fifth sib shared one haplotype with one of these pairs but not with the other. Out of 14 (eight of our own and six from the literature) affected sibpairs examined, nine were found to be HLA identical and four shared one haplotype, suggesting that the contribution of both paternal haplotypes may be necessary for the susceptibility to the disease. Fourteen parent-child combinations were studied; in only three out of 13 in which the shared haplotype could be ascertained was the haplotype B8 positive; this distribution is similar to controls. However, of the remaining 10 combinations which did not share a B8 positive haplotype, five were B8 positive at one or the other of the non-shared haplotypes.

The prospective controlled study was designed for comparing the influence of methimazole (MMI + placebo)(control group) and MMI + pentoxiphylline (PTX) with respect to grades of Thyroid Associated Ophthalmopathy (TAO). The control group consisted of 112 patients with hyperthyroidism (mean age 44.0 ± 12.4 yr, 83 females and 29 males). PTX treated group of 112 (mean age 47.7 ± 10.2 yr, 83 female and 29 male) hyperthyroid patients were treated with MMI + PTX. At the onset of the study there were no remarkable differences between the two treated groups. After six- and twelve-month observation periods the manifestations of TAO with moderate and severe forms were significantly lower in the PTX treated patients. Various risk factors were analyzed in both groups. Smoking by itself without genetic factors greatly increased the risk of TAO (OR: 7.1, CI 95% 9.3–5.4). If the smoking habit was associated with a genetic background, the manifestation of TAO significantly increased (OR: 9.2 CI 95%, 12.1–6.9, p < 0.0001)....

Activating BRAF mutations have recently been reported in 28-83% of papillary thyroid carcinomas (PTCs). However, it is not known whether aberrant BRAF splicing occurs in thyroid carcinoma. To investigate aberrant BRAF splicing and its association with BRAF mutation in thyroid tumours, we studied aberrant BRAF splicing and BRAF mutation from 68 thyroid tumours. BRAF(V600E) mutation was detected in 20 of 43 PTCs and all three anaplastic thyroid carcinomas (ATCs). There is a higher frequency of BRAF mutation in PTC patients with stage III and IV tumours compared with stage I and II. Novel BRAF splicing variants were detected in 12 PTCs, three follicular variants of PTC (FVPTCs), and one ATC, as well as in two thyroid carcinoma cell lines, ARO and NPA. These variants did not have the N-terminal auto-inhibitory domain of wild-type B-Raf, resulting in an in-frame truncated protein that contained only the C-terminal kinase domain and caused constitutive activation of B-Raf. These variants were significantly associated with advanced disease stage and BRAF(V600E) mutation (p < 0.001, Fisher exact test). Furthermore, expression of these variants in NIH3T3 and CHO cells could activate the MAP kinase signalling pathway, transform them in vitro, and induce tumours in nude mice. These data suggest that BRAF splicing variants may function as an alternative mechanism for oncogenic B-Raf activation. Combination of the BRAF(V600E) mutation and its splicing variants may contribute towards disease progression to poorly differentiated thyroid carcinoma.

Introduction and aim. Management of complicated wounds after tumor extipiration of pelvic and proximal lower limb musculoskeletal sarcoma represents an essential component in the outcome of these patients. The authors present modified vertical rectus abdominis musculocutaneous (VRAM) flap techniques to reconstruct extensive defects after debridment of these complicated wounds.Material and Methods. Over a period of 4 years (2002–2005), 5 men and 2 women were managed. Median age was 21 years (range 15–49). The patients were managed for complicated lower trunk, groin, and upper thigh wounds after resection of three pelvic chondrosarcomas as well as two pelvic and two proximal femur osteosarcomas. The modifications included a VRAM flap with lateral and tongue-like extension design of the skin paddle (5 cases) or a delayed extended VRAM flap (2 cases).Results. All flaps showed complete survival and healing with no ischemic events providing stable coverage. All patients were ambulant with good limb functions in terms of walking and gait after adequate rehabilitation, 2 needed support with crutches.Conclusion. The modified VRAM flaps offer reliable reconstructive tools for coverage of complex groin and thigh defects by providing larger well-vascularized soft tissue with acceptable donor site.

The molecular mechanisms of tumor invasion and metastasis are yet to be fully elucidated. A potential tumor-metastasis-suppressor gene nm23 has been described in certain rodent and human tumors. In the present study, we examined the potential anti-invasive and anti-metastatic effect of nm23 gene in B16F10 cells, a malignant murine melanoma cell line. Transfection of nm23 gene into B16F10 melanoma ceils resulted in significant suppression of the invasiveness and metastatic ability of melanoma cells and significantly enhanced the survival of tumor-bearing mice. B16F10 melanoma cells transfected with nm23 produced significantly less soluble ICAM-I and were more susceptible to LAK-cell-mediated cytotoxicity. Co-culture of B16F10 melanoma cells with IL-2 had no effect on nm23 expression, whereas treatment with PGE2, TNF-α and IFN-γ resulted in down-regulation of nm23 expression. Concomitantly, in vivo treatment with TNF-α or IFN-γ in experimental mice increased pulmonary metastases and lowered the overall survival period, as compared with IL-2 treatment alone. These results provide evidence that nm23, in addition to its anti-metastatic function, could also be involved in modulating tumor-target-structure expression, in down-regulating invasive potential and in production of soluble intracellular adhesion molecules. The down-regulation of nm23 by TNF-α, IFN-γ and particularly by PGE2 warrants re-examination of current immunotherapeu-tic protocols and of the role played by PGE2 in tumor progression. © 1995 Wiley-Liss, Inc.

A C825T polymorphism has been demonstrated in the GNB3 gene that encodes the Gβ3 subunit of heterotrimeric G proteins. Due to enhanced G protein activation, the GNB3 825T allele is associated with an increased signal transduction activity. To elucidate a possible role in the development and course of thyroid tumours of follicular cell origin, C825T polymorphism genotypes and allele frequencies were investigated in a series of adenomas and differentiated carcinomas. Genotypes and the allele frequency of the Gβ3 polymorphism were investigated in samples from 361 patients (all white Caucasians) with differentiated thyroid tumours of follicular cell origin [80 adenomas and 95 follicular (FTCs) and 186 papillary carcinomas (PTCs)]. The results were compared with those of 1859 healthy controls. Both the genotype distribution (p = 0.029) and the allele frequency (p = 0.028) of the adenoma group were statistically significantly different from those of the control group. Thyroid adenomas also differed for both parameters significantly from FTCs (p = 0.042 and 0.033, respectively) and PTCs (0.0018 and 0.0081, respectively), whereas no statistical difference was noted between the FTC and PTC groups. Although the biological significance of these observations remains obscure, the results are suggestive of a putative role for the GNB3 polymorphism in thyroid tumour development and/or progression. Further research has to elucidate if, and to what extent, this common germ-line variation influences the TSH-triggered signalling pathways responsible for thyroid function and proliferation. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Tumour cell invasion and metastasis are the hallmark of malignant neoplasm. S100A4 is a member of small calcium-binding protein family and is involved in the cell proliferation and cancer progression. S100A4 is capable of inducing metastasis in animal models and is associated with aggressive phenotype of human tumours. We previously identified S100A4 as a candidate gene involved in anaplastic thyroid cancer metastasis by microarray analysis. To further determine whether S100A4 overexpression is associated with thyroid tumour invasion and metastasis, in the present study, we examined S100A4 gene expression in six benign multinodular goitres (MNG) and 28 matched samples of adjacent normal thyroid tissue (N), primary (T) and metastatic (M) papillary thyroid carcinomas (PTC) by immunohistochemistry and real-time reverse transcription–polymerase chain reaction (RT-PCR) analysis. This gave us the advantage of directly comparing levels of S100A4 expression within the same genetic background. Using immunohistochemistry, we found that high levels of S100A4 were detected in 24 of 28 (86%) PTC specimens and their local regional lymph node or distant metastases. No S100A4 staining was observed in normal thyroid tissues and simple MNG. However, in MNG coexistent with PTC, moderate focal staining could be found in 11 of 15 MNG adjacent to PTC. The S100A4 was stained more intensely in invading fronts than in central portions of both T and M. Real-time RT–PCR analysis of primary tumours and their matched lymph node metastasis demonstrated that significantly higher S100A4 transcripts were present in metastatic tumours as compared to the primary tumours (P

BACKGROUND Using serologic human lymphocyte antigen (HLA) typing, the authors previously described a strong association between well differentiated thyroid carcinoma and HLA D-related 1 (HLA-DR1) in a population of unselected patients from Eastern Hungary. METHODS In the current study, the authors used polymerase chain reaction-single strand conformational polymorphism to determine the HLA-DR type in 75 patients with well differentiated thyroid carcinoma from the same area as their previous population, and they compared the current results with the results from a group of 170 healthy controls. RESULTS A significant increase in HLA-DR11, rather than HLA-DR1, was observed in patients with well differentiated thyroid carcinoma among a population of patients from the same area that was studied previously. After excluding technical reasons to account for differences in disease association, they postulated that interim environmental factors, possibly radiation fall-out, may have resulted in differences in genetic susceptibility to thyroid carcinoma. Consideration of the potential antigenic peptides that may be restricted by the two HLA-DR alleles may have allowed for the binding of similar peptides to initiate an immune response, likely leading to progressive immunomodulation of the tumor. Discriminat function analysis indicated a significant relation between tumor size and metastases and less lymphocytic infiltration of the tumor, but this was not related to HLA-DR phenotypes. CONCLUSIONS The authors found that the study of major histocompatability complex alleles holds promise for understanding the events that initiate and maintain tumor immunomodulation. Cancer 2005. © 2005 American Cancer Society.

Tumor cell invasion and metastasis are the hallmark of malignant neoplasm. Despite advances in the management of thyroid carcinoma and other solid tumors, metastasis continues to be the most significant cause in cancer mortality. To gain new insights into this complex process in thyroid carcinoma, we established a thyroid carcinoma cell line (ARO-met2) with high metastatic capacity to the lung by sequential passage of a human anaplastic thyroid cancer cell line (ARO) through the lung of a nude mouse. Global patterns of gene expression were analyzed in cells of the parental ARO and the ARO-met2, using Atlas human cancer 1.2 array with 1176 cancer-related genes. In total, 184 genes were differentially expressed more than 1.5 times, and 64 genes were differentially expressed over two times. Among those 64 genes, 43 were overexpressed, and 21 genes were underexpressed. Many genes whose increased expression was thought to be related to tumor progression were identified, such as c-Met, ezrin, integrin, motility-related protein-1, cadherin, and S100A4. The most highly expressed gene is the S100A4 (8-fold higher than control), which is a member of a small calcium binding protein family and is involved in the cell proliferation and cancer progression. The S100A4 overexpression in the ARO-met2 cells was later confirmed by Northern blot and real-time reverse transcriptase-PCR. Analysis of 49 thyroid tumor specimens by real-time reverse transcriptase-PCR (eight benign goiters, 36 papillary, and five anaplastic carcinomas) revealed that S100A4 overexpression was present in most advanced thyroid carcinomas and lymph node metastases, and was associated with poor prognosis. None of the benign goiters was found to have S100A4 overexpression. These data suggest that S100A4 could be used as a prognostic marker for thyroid carcinoma. Given that S100A4 is involved in tumor progression and metastasis, it may be a potential target for therapeutic intervention.

In 1999, we began a study to assess the long-term effect of connective tissue cancer treatment on clinical, social, and psychologic aspects of the lives of surviving patients. A specially designed computer program generated an 85-item questionnaire, which was sent to more than 2000 patients with malignant bone and soft tissue neoplasms. Twelve hundred forty-four patients responded. The data were entered into a computer system and were correlated with the clinical information already contained in the system for the individual patients. Although there are many possible uses for these data, we chose to do a study comparing the lifestyle and physical and sociologic problems for 144 patients treated with chemotherapy and surgery for high-grade osteosarcoma against a control population consisting of 61 patients treated surgically for benign giant cell tumors of bone. The data show a remarkable degree of compensation on the part of the patients with the malignant tumors in terms of some problems but some significant differences particularly in physical status and functional limitations.

Anaplastic thyroid carcinoma is the most aggressive type of thyroid malignancy with a mean survival time of less than 8 months. No effective therapeutic approach is currently available, making the development of novel treatments necessary. Interleukin (IL)-12 is a proinflammatory heterodimeric cytokine with strong antitumor activity. In the present study, we investigated the potential of IL-12 gene therapy for anaplastic thyroid carcinoma in BALB/c (nu/nu) nude mice. A single-chain IL-12 fusion protein construct was created to assure equal expression of its p35 and p40 subunits. Human anaplastic thyroid carcinoma cell line ARO was stably transfected with an IL-12 expression plasmid under the control of cytomegalovirus (CMV) promoter (scIL-12/CMVpDNA). High levels of functional IL-12 (26.78 +/- 4.11 ng/ml per 10(6) cells per 48 hr) were produced by scIL-12-transfected ARO cells (ARO/IL-12). Tumorigenicity in nude mice was completely lost in scIL-12-transfected ARO cells, as demonstrated by the lack of tumor formation after subcutaneous injection of 2 x 10(6) ARO/IL-12 cells, even though there was no difference in cell proliferation between ARO and ARO/IL-12 cells. Tumor growth was observed after challenge with ARO tumor cells, indicating that protective immunity had not developed against the parental cells. Furthermore, the growth rate of established subcutaneous ARO tumors was significantly reduced by either subcutaneous injection of 2 x 10(6) ARO/IL-12 cells weekly or intramuscular injection of 50 microg scIL-12/CMVpDNA twice weekly. The antineoplastic activity of ARO/IL-12 cells was, however, abrogated by intraperitoneal injection of anti-natural killer (NK) cell antibody. Moreover, significantly higher number of ARO/IL-12 cells and ARO cells were killed by splenocytes from nude mice previously treated with ARO/IL-12 compared to those treated with ARO cells (32% vs. 9% when ARO were used as target cells, 43% vs. 17% when ARO/IL12 were used as target cells; p < 0.01) in an in vitro cytotoxicity assay. Again, tumor cell killing was neutralized by the addition of anti-NK cell antibody in the assay. In conclusion, we have demonstrated successful gene therapy with a scIL-12 fusion protein against anaplastic thyroid carcinoma in an in vivo model. The immune response against ARO/IL-12 cells is mediated by NK cells. These results may set the stage for clinical application of IL-12 gene therapy for poorly differentiated thyroid carcinoma.

We describe a kindred from Mauritius with an incomplete variant of multiple endocrine neoplasia type 1 (MEN 1Burin). In this family the syndrome is related to a novel MEN 1 gene mutation (deletion of A) at nucleotide 1021 of codon 304 resulting in frame shift and downstream protein truncation at codon 320. Compared to mainstream MEN 1, MEN 1Burin is characterized by a high prevalence of prolactin-secreting pituitary adenomas, late-onset of hyperparathyroidism and rare pancreatic involvement. The family described represents the fifth in the literature with the MEN 1Burin phenotype; 2 out of the other 4 were related to R460X, Y312X respectively and no mutation within the coding sequence of MEN 1 was found in the other 2. Thus, similar to the classic syndrome, MEN 1Burin phenotype shows poor correlation to MEN 1 genotype.

p53 is a transcription factor with multifaceted regulatory functions in cell cycle progression, DNA repair, and programmed cell death. Inactivating mutations have been described in 50% of human cancers. These mutations appear to be important in tumor progression and response to chemotherapy and radiation treatment and thus clinical outcome. p53 mutations are found in 14% of malignant thyroid tumors and are more frequent in poorly differentiated and anaplastic tumors. Given that p53 is a late event in the notional multistep pathogenesis of cancer, we examined its mutation rates as a measure of genomic instability (hypermutability) of malignant thyroid tumors and also wondered whether radiation enhances that proclivity to genomic instability. To that end we have extracted all available data from the p53 mutation database (http://www.perso@curie.fr), verified, extended, where applicable, and supplemented that information from published reports. We were able to identify 100 entries. The distribution of the p53 mutational events--deletions/insertions, transitions versus transversion mutations--was similar to that of the database as a whole. The silent mutation rate of 17.8%, not different from the expected 25%, is consistent with a random occurrence of these mutations. The silent mutation rate is 120 times that expected and is 6 times that of the database. Moreover, the distribution of p53 mutations is compatible with Poisson's distribution, which taken with silent mutation rates indicates that p53 is particularly hypermutable in thyroid carcinomas. Epigenetic deamination of CpG dinucleotide at highly oncogenic DNA-contact residues is a feature of poorly differentiated tumors and thus associated with tumor progression. The rates of p53 mutations (15.4%) in radiation-related cancers were very similar to those in apparently spontaneously arising tumors, although there was a highly significant heterogeneity (P0.0005) in the residues mutated. None involved CpG deamination. It is apparent that thyroid cancer exhibits remarkable genomic instability evidenced by p53 hypermutability. Spontaneous epigenetic mutational events are involved in tumor progression and while radiation increases the absolute prevalence of thyroid cancer in the susceptible it does not increase the rate of p53 mutation and seemingly targets different non-DNA-contact residues than those in spontaneously arising tumors.

We describe a woman with complete hypogonadotropic hypogonadism and a new compound heterozygous mutation of the GnRH receptor (GnRHR) gene. A null mutation L314X leading to a partial deletion of the seventh transmembrane domain of the GnRHR is associated with a Q106R mutation previously described. L314X mutant receptor shows neither measurable binding nor inositol phosphate production when transfected in CHO-K1 cells compared to the wild-type receptor. The disease is transmitted as an autosomal recessive trait, as shown by pedigree analysis. Heterozygous patients with GnRHR mutations had normal pubertal development and fertility. The present study shows an absence of LH and FSH response to pulsatile GnRH administration (20 μg/pulse, sc, every 90 min). However, GnRH triggered free α-subunit (FAS) pulses of small amplitude, demonstrating partial resistance to pharmacological doses of GnRH. FSH, LH, and FAS concentrations were evaluated under chronic estrogen treatment and repeat administration of GnRH. Not ...

Tumour cell invasion and metastasis is a multistep process that involves the degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs). Tissue inhibitors of metalloproteinases (TIMPs) act as negative regulators of MMPs and thus prevent tumour cell invasion and metastasis by preserving extracellular matrix (ECM) integrity. In the present study we examined the expression of one member of TIMPs, TIMP-1, in 39 thyroid tumour specimens and two thyroid carcinoma cell lines (NPA and SW579). We also investigated the effect of high TIMP-1 expression on the invasive potential of NPA cells. Northern blot analysis showed that TIMP-1 mRNA levels correlated directly with tumour aggressiveness: the highest number of TIMP-1 transcripts was found in stages III and IV vs benign goitre (P < 0.0001). However, TIMP-1 expression was not increased in NPA and SW579 cells, both of which are derived from poorly differentiated thyroid tumours. Immunohistochemical study showed strong TIMP-1 staining in the stroma cells of advanced stages of carcinomas. Overexpression of TIMP-1 by gene transfer resulted in a significant suppression of the malignant phenotype of NPA cells as judged by an in vitro tumour invasion assay. These results suggest that high levels of TIMP-1 transcripts in advanced stages of thyroid carcinoma likely come from stroma rather than thyroid cancer cells, and TIMP-1 may function as a thyroid tumour invasion/metastasis suppressor. © 1999 Cancer Research Campaign

Rad, M., Ahmadi, M., Farid Hosseini, R., Ashkar, A.A., Nejati, M., Tabaraie, B. and Nourozian, D. 2006. Protection against Listeria monocytogenes by ODN containing CpG motifs in BALB/c and C57BL/6 mice. J. Appl. Anim. Res., 29: 145–147. Synthetic oligodeoxynucleotides containing CpG motifs have been shown to be effective immunoprotective agents in murine models for intracellular bacterial, viral and protozoan infections. In the present study, we demonstrated that CpG-ODN can induce protection against Listeria monocytogenes in BALB/c and C57BL/6 mice, the survival rate being higher in BALB/c mice. Further studies to determine the cause have been recommended.

Background & Aims: Ischemic-type biliary lesions (ITBL) are the second most common cause of graft loss after liver transplantation. Though the exact pathophysiology of ITBL is unknown, bile duct injury during graft preservation is considered to be a major cause. Here we investigated whether the release of cholangiocyte-derived microRNAs (CDmiRs) during graft preservation is predictive of the development of ITBL after liver transplantation. Methods: Graft preservation solutions (perfusates) and paired liver biopsies collected at the end of cold ischemia were analysed by RT-qPCR for CDmiR-30e, CDmiR-222, and CDmiR-296 and hepatocyte-derived miRNAs (HDmiRs) HDmiR-122 and HDmiR-148a. MicroRNAs in perfusates were evaluated on their stability by incubation and fractionation experiments. MicroRNA profiles in perfusates from grafts that developed ITBL (n = 20) and grafts without biliary strictures (n = 37) were compared. Results: MicroRNAs in perfusates were proven to be stable and protected against degradation by interacting proteins. Ratios between HDmiRs/CDmiRs were significantly higher in perfusates obtained from grafts that developed ITBL (p

THYROID follicular cell tumors present a unique model for the study of genetic and environmental factors predisposing to benign nodule formation, well differentiated malignant tumors, and anaplastic cancer. Although these histological changes are not necessarily sequential, there is evidence that gradation of proliferative and differentiative potential exists among cells in each thyroid follicle. Conditions conducive to rapid growth ensure that the progeny of cells with high growth potential establish local dominance, a prelude to nodule formation (2). There is also evidence that well differentiated carcinoma may progress to an anaplastic form (3). It is only speculation that benign nodules may develop into well differentiated carcinoma. Cancer is a complex, multistep process (4). Based on the measurements of age-dependent tumor incidence, it was inferred mathematically that a succession of five or six independent steps are involved, each of which is rate limiting (5). This predicted sequence of events ha...

Background. The ret proto-oncogene activation (PTC/retTPC oncogene) in thyroid papillary carcinoma has been reported in different populations with different frequencies. Thyroid papillary carcinoma appears to behave more aggressively in the Persian Gulf region than elsewhere. In the current study, the frequency of PTC/retTPC oncogene in thyroid tumors from Saudi Arabia was investigated. Methods. PTC/retTPC oncogene transcripts were analyzed by the polymerase chain reaction amplification of cDNA synthesized by treatment of total RNA with reverse transcriptase. Seven multinodular goiters, 1 follicular adenoma, 4 follicular carcinomas, 40 papillary carcinomas, and 5 anaplastic carcinomas were studied. Results. Only one papillary carcinoma specimen was found to have PTC/retTPC oncogene transcripts. The breakpoint of the rearranged PTC/retTPC oncogene is identical to that previously described. The PTC/retTPC-positive sample was also examined for p53 tumor suppressor gene mutations in exons 5–8. One transitional point mutation was detected at codon 161 (GCC to ACC), changing Ala to Thr. Conclusions. This study questions the relevance of PTC/retTPC oncogene in the carcinogenesis of thyroid papillary carcinomas in the Saudi population. Genetic background among races may contribute to the different frequencies of PTC/retTPC oncogene in thyroid papillary carcinoma.

The p53 gene has been implicated as a tumor suppressor gene whose inactivation by mutations has been noted in a variety of human malignancies. Using single strand conformation polymorphism analysis of cDNA fragments amplified by reverse transcription-polymerase chain reaction, we analyzed 57 thyroid tumor specimens (8 follicular adenomas and 49 carcinomas) for the presence of mutations in exons 5, 6, 7, and 8 of p53 gene. Twelve of 49 (24.5%) of the thyroid carcinomas tested presented a mutated p53 allele, but none of the 8 benign thyroid tumors did. Mutations were found in 1 of 5 anaplastic carcinomas and 11 of 44 differentiated carcinomas. Three of these 11 differentiated tumor specimens showed foci of solid tissue with evidence of dedifferentiation. Two samples (1 with anaplastic carcinoma, the other with papillary carcinoma) had double mutations on the same allele resulting in a frameshift. Most mutations were point mutations, and 50% of those were G:C to A:T transitions. Seventy-five percent of the mutations were in exons 7 and 8. The presence of p53 mutations was not associated with tumor stage or histological type. Our data suggest that p53 mutations are involved in thyroid carcinogenesis and may play an important role in the malignant transformation of thyroid cells as well as thyroid tumor progression.

The product of Nm23 gene has been proposed as a candidate tumour metastasis suppressor protein. A strong association has been observed between reduced expression of Nm23 gene and acquisition of metastatic behaviour in some tumour cells including breast cancer and melanoma, but not in others such as colon cancer, neuroblastoma, and cervical cancer. In the present study, we examined the abundance of Nm23 mRNA in 39 thyroid tissue specimens including five multinodular goitres, one follicular adenoma, 26 papillary and three follicular carcinomas, and four anaplastic carcinomas. Nm23 was found to be expressed in all the tissue specimens. The expression was, however, variable in different stages of thyroid carcinoma. In stages I through III of differentiated thyroid carcinoma, the average level of Nm23 gene expression was comparable to that in multinodular goitres. In advanced stage of thyroid carcinoma (stage IV and anaplastic), 2-fold increase of Nm23 expression was noted. No mutations were found in the coding region of the gene. Nm23 mRNA level cannot, therefore, be used as a marker of low metastatic potential in thyroid carcinomas. The association of high level Nm23 expression with anaplastic thyroid carcinoma suggests its correlation with rapid cell proliferation. Images Figure 1

Context: The PDS gene (SLC26A4) is responsible for Pendred syndrome (PS). Genetic analysis of PDS using Tunisian samples showed evidence for linkage and association with autoimmune thyroid diseases (AITD) emergence. In addition, the PDS gene product, pendrin, was recently identified as a novel autoantigen in Graves’ disease (GD) or Hashimoto thyroiditis (HT) patients’ sera. Objective: The aim of this study was to quantify the PDS gene expression and to evaluate the pendrin in vivo and in vitro immunolocalisation. Patients: A total of 52 thyroid gland tissue samples (22 GD, 11 HT, 5 multinodular goiter (MNG), 3 normal thyroid tissues, 8 papillary thyroid carcinoma (PTC), 1 follicular thyroid carcinoma (FTC) and 2 medullar thyroid carcinoma (MTC)) were explored. Method PDS and pendrin expression levels were determined using quantitative RT-PCR and immunodetection methods. TSH and thyroglobulin (Tg) effects on pendrin expression were investigated by immunofluorescence on primary cell culture from GD thyroid tissues. Results: The relative quantification using PDS transcript level among GD thyroid tissues was increased compared to normal thyroid tissues used as calibrator (mean: 27.17-fold higher than normal thyroid tissues). However, thyroids with HT, carcinoma and MNG showed a decrease expression level (means: 92.05-, 77.68-, 14.3-fold lower than normal thyroid tissues, respectively). These results were confirmed by immunoanalysis. Immunofluorescence results showed an apical and a cytoplasmic pendrin localisation on GD thyroid tissues and a marked pendrin expression reduction on HT thyroid tissues. GD primary cell cultures under TSH and Tg stimulation showed a trafficking improvement of pendrin apical localisation. Conclusions: Our data point to the presence of a relation between SLC26A4 expression in AITD and thyroid

This study was undertaken 1) to find out whether we can type major histocompatibility class II antigens from the paraffin-embedded series of thyroid tissue, and 2) to investigate whether HLA-DQ genes are involved in conferring a risk of Hashimoto's thyroiditis. To this end we used the polymerase chain reaction to amplify DNA from paraffin-embedded thyroid tissue blocks of histologically proven Hashimoto's disease. We used 46 specimens for HLA-DQA and 32 for DQB typing. The alleles were identified by sequence-specific oligonucleotide hybridizations. Fifty controls from the same geographic region were also typed using peripheral leukocyte DNA. HLA-DQA0301 (in linkage disequilibrium with DR4) was significantly increased (58.7% vs. 32% in controls; chi 2 = 6.73; P less than 0.01) in patients compared to controls. DQB0201 (in linkage disequilibrium with DR3) was also increased in the patient group (66% vs. 36% in controls; chi 2 = 6.63; P less than 0.01). Although DQA0301/DQB0201 heterozygotes (18.8%) were increased in patients compared to controls (6%), the difference was not significant. However, 81% of the patients (26 of 32) were DQA0301 and/or DQB0201 positive compared to 48% of controls (chi 2 5.98; P less than 0.05). We conclude that it is feasible to type HLA antigens from tissue blocks and that susceptibility to Hashimoto's disease is probably mediated through two pathways: DQA0301/DR4 and DQB0201/DR3.

We evaluated the association of epidermal growth factor receptor (EGFR) 142285G>A (R521K) and estrogen receptor alpha (ESR1) 2014G>A (T594T) single nucleotide polymorphisms with breast cancer risk and prognosis in Tunisian patients. EGFR 142285G>A and ESR1 2014G>A were genotyped in a sample of 148 Tunisian breast cancer patients and 303 controls using PCR-RFLP method. Immunohistochemitsry was used to evaluate the expression levels of EGFR, HER2, ESR1, progesterone receptor and BCL2 in tumors. We found no evidence for an association between EGFR R521K polymorphism and breast cancer risk. However, we found that the homozygous GG (Arg) genotype was more prevalent in patients with lymph node metastasis ( 𝑃 = . 0 3 ) and high grade tumors ( 𝑃 = . 0 1 1 ). The ESR1 2014G allele showed significant association with breast cancer risk ( 𝑃 = . 0 2 5 ). The GG genotype was associated with HER2 overexpression and this association withstood univariate and multivariate analyses ( 𝑃 = . 0 0 9 ; 𝑃 = . 0 2 1 , resp.). These data suggest that the R521K might be a prognostic factor, because it correlates with both tumor grade and nodule status. The higher expression of HER2 in ESR1 T594T GG patients suggests the possibility that ESR1 gene polymorphisms accompanied by HER2 expression might influence the pathogenesis of breast cancers.

IntroductionThe majority of autoimmune diseases such as rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) are characterized by a striking female predominance superimposed on a predisposing genetic background. The role of extremely skewed X-chromosome inactivation (XCI) has been questioned in the pathogenesis of several autoimmune diseases.MethodsWe examined XCI profiles of females affected with RA (n = 106), AITDs (n = 145) and age-matched healthy women (n = 257). XCI analysis was performed by enzymatic digestion of DNA with a methylation sensitive enzyme (HpaII) followed by PCR of a polymorphic CAG repeat in the androgen receptor (AR) gene. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X-chromosome.ResultsSkewed XCI was observed in 26 of the 76 informative RA patients (34.2%), 26 of the 100 informative AITDs patients (26%), and 19 of the 170 informative controls (11.2%) (P < 0.0001; P = 0.0015, respectively). More importantly, extremely skewed XCI, defined as > 90% inactivation of one allele, was present in 17 RA patients (22.4%), 14 AITDs patients (14.0%), and in only seven controls (4.1%, P < 0.0001; P = 0.0034, respectively). Stratifying RA patients according to laboratory profiles (rheumatoid factor and anti-citrullinated protein antibodies), clinical manifestations (erosive disease and nodules) and the presence of others autoimmune diseases did not reveal any statistical significance (P > 0.05).ConclusionsThese results suggest a possible role for XCI mosaicism in the pathogenesis of RA and AITDs and may in part explain the female preponderance of these diseases.

Recently, in vitro production of interleukin-2 receptor induced by mitogens have been shown to be impaired in autoimmune disorders including organo-specific autoimmune diseases. The aim of this study was to investigate serum levels of soluble interleukin-2 receptor in 20 untreated patients with Graves' disease and to follow up their changes in relation to clinical picture and TSH-receptor-, anti-thyroglobulin-, anti-microsomal as well as anti-eye muscle antibodies. Soluble interleukin-2 receptor level was significantly increased in newly-diagnosed Graves' patients compared to controls (667 +/- 270 vs. 205 +/- 45 U/ml) (P less than 0.001). Among the patients sera those with active infiltrative ophthalmopathy had higher soluble interleukin-2 receptor levels than those without eye symptoms (810 +/- 313 vs. 525 +/- 180 U/ml). Soluble interleukin-2 receptor level was normalized in Methimazole-treatment-induced remission in the majority of patients except those with ophthalopathy. In five patients the soluble interleukin-2 receptor levels were studied after interruption of thyrostatic therapy; an increase was observed in three patients; thereafter hyperthyrosis relapsed in two cases. Furthermore, a correlation was found between soluble interleukin-2 receptor levels and TSH-receptor antibodies, however, the association with other immune parameters examined was not significant. In conclusion, an enhanced level of soluble interleukin-2 receptor was detected in patients with untreated Graves' disease. This finding might play a significant role in regulation of impaired cell-mediated immune mechanism and has a prognostic value for relapse of autoreactive processes.

In Eastern Hungary, vitiligo is found to be associated with HLA-DR1. When other autoimmune disorders are also present, DR3 is also increased.

The classic ilioinguinal approach is a standard procedure with reportedly high success rates in many displaced fractures of the acetabulum. Intraarticular visualization and exposure of the anterior wall and the quadrilateral plate are its main limitations. We propose a subinguinal approach based on the principle used for oncologic procedures that naturally require large exposures. The approach involves a retroperitoneal access below the inguinal ligament to preserve the integrity of the inguinal canal and allow ample exposure of anterior and medial wall fractures as well as the anterior hip capsule. Despite the apparent magnitude of the procedure, closure is fairly simple and anatomical because repair of the inguinal canal floor is not required. This modification may compensate for the limitations of the classic approach without additional risks or morbidities.

International audience; We study the association between three Vitamin D receptor gene polymorphisms (rs10735810, rs1544410, rs731236) and susceptibility to thyroid autoimmune diseases. Seventy-six affected subjects, belonging to a large family, as well as one hundred unrelated Tunisian patients and one hundred healthy Tunisian controls were genotyped. A family-based association test and a standard chi-square test were used to assess association in family and case-control data, respectively. Our results showed no significant association of the Vitamin D receptor gene polymorphisms with the susceptibility to thyroid autoimmune diseases in the family. Moreover, allele frequencies for the three polymorphisms in the Tunisian population were similar to those reported in the Tunisian control population and none was associated with the disease. These results suggest a lack of association between the Vitamin D receptor gene polymorphisms and susceptibility to thyroid autoimmune diseases in Tunisian population, in agreement with data from the UK, but in conflict with studies from the Far East. © 2007 Springer Science+Business Media, LLC.

The characteristic feature of malignant neoplasm is invasion and metastasis. Despite advances in the management of thyroid carcinoma and other solid tumors, metastasis continues to be the most significant cause in cancer mortality.Our objective was to examine the effects of S100A4 expression knockdown by RNA interference on the growth and metastasis of human anaplastic thyroid carcinoma cells (ARO) and the sensibility of ARO to paclitaxel after S100A4 knockdown.A plasmid construct was made that expressed small hairpin RNA (shRNA) specific for S100A4. The construct was stably transfected into ARO cells (ARO/S100A4-shRNA). The tumorigenicity, metastatic potential, and sensibility of ARO/S100A4-shRNA to paclitaxel were investigated.S100A4 expression was reduced by 71.3 +/- 4.7% in ARO/S100A4-shRNA by real-time RT-PCR analysis. The growth rate of ARO/S100A4-shRNA was reduced by 46 +/- 7.6% in a cell proliferation assay. Cell cycle analysis showed increased G(2)/M accumulation in ARO/S100A4-shRNA. Tumor formation and growth induced by sc injection of 5 x 10(6) ARO/S100A4-shRNA into the nude mice were significantly reduced, and no tumor metastasis was found in any of the mice. We also demonstrated significant induction of apoptosis in ARO/S100A4-shRNA after incubation with 15 nm paclitaxel, indicating that tumor cells were sensitized to chemotherapy as a result of S100A4 knockdown.These data suggest that reduction of S100A4 by RNA interference is a viable approach to inhibit tumor growth and metastasis. Given that S100A4 is overexpressed in many kinds of tumors, the current study provides the proof of concept in its therapeutic potential.