Myxoid liposarcoma with cartilaginous differentiation: A case study with fish analysis and review of the literature.

Cartilaginous differentiation is rarely encountered in myxoid liposarcomas. To date, a small number of such cases have been described, and molecular or cytogenetic analysis was performed only in few of them. In the present study, we describe a primary myxoid liposarcoma with cartilaginous differentiation which arised in the left thigh of a 37-year-old man. Miscroscopically, the tumor consisted of areas with typical myxoid liposarcoma morphology and areas of sharply demarcated hyaline cartilage nodules. Here, we present the results of Fluorescence In Situ Hybridization (FISH) analysis that revealed the presence of FUS and DDIT3 gene rearrangements in both the liposarcomatous and cartilaginous components of the tumor. These findings confirm the neoplastic nature of the cartilage component in this rare tumor.

TNFα induces expression of HIF-1α mRNA and protein but inhibits hypoxic stimulation of HIF-1 transcriptional activity in airway smooth muscle cells.

Airway smooth muscle cells (ASMCs) participate in tissue remodeling characteristic of airway inflammatory diseases like asthma. Inflammation and hypoxia pathways are often interconnected and the regulatory subunit of the hypoxia inducible factor, HIF-1α, has been recently shown to be induced by cytokines. Here we investigate the effect of individual or combined treatment of ASMCs with the inflammatory mediator TNFα and/or hypoxia on the expression of HIF-1α, HIF-1 targets and inflammation markers. TNFα enhances HIF-1α protein and mRNA levels, under both normoxia and hypoxia. TNFα-mediated induction of HIF-1α gene transcription is repressed by inhibition of the NF-κB pathway. Despite the up-regulation of HIF-1α protein, the transcription of HIF-1 target genes remains low in the presence of TNFα at normoxia and is even reduced at hypoxia. We show that the reduction in HIF-1 transcriptional activity by TNFα is due to inhibition of the interaction of HIF-1α with ARNT and subsequent blocking of its binding to HREs. Comparison between hypoxia and TNFα for their effects on the expression of inflammatory markers shows significant differences: hypoxia up-regulates the expression of IL-6, but not RANTES or ICAM, and reduces the induction of VCAM by TNFα. Finally, ex vivo treatment of rabbit trachea strips with TNFα increases HIF-1α protein levels, but reduces the expression of HIF-1 targets under hypoxia. Overall, TNFα induces HIF-1α mRNA synthesis via an NF-κB dependent pathway but inhibits binding of HIF-1α to ARNT and DNA, while hypoxia and TNFα have distinct effects on ASMC inflammatory gene expression.

Differential expression of hypoxia-inducible factor 1α in non-small cell lung cancer and small cell lung cancer

OBJECTIVES: The aim of this study was to compare the expression of hypoxia-inducible factor 1α and vascular endothelial growth factor in small cell lung cancer and subtypes of non-small cell lung cancer and examine their relationships with clinicopathologic factors, response to treatment and survival. METHODS: We examined samples obtained by bronchial endoscopic biopsy from 55 patients with inoperable lung cancer (16 with adenocarcinoma, 17 with squamous cell carcinoma, and 22 with small cell lung cancer). Hypoxiainducible factor 1α and vascular endothelial growth factor were detected using immunohistochemistry. The diagnosis, treatment, and follow-up of patients were conducted according to the standard practice. RESULTS: A significant difference (p=0.022) in hypoxia-inducible factor 1α expression was observed between nonsmall cell lung cancer (75.8% positive) and small cell lung cancer (45.5% positive). The frequency of hypoxiainducible factor 1α nuclear expression was 88.2% in squamous cell carcinoma, 62.5% in adenocarcinoma, and 45.5% in small cell lung cancer. A significant correlation was observed between hypoxia-inducible factor 1α and vascular endothelial growth factor expression (Fisher's exact test, p=0.001) when all types of lung cancer were examined, either collectively or separately. CONCLUSIONS: The expression of hypoxia-inducible factor-1α differs significantly between subtypes of lung cancer. These findings could help elucidate the biology of the different types of non-operable lung carcinomas and have implications for the design of new therapeutic approaches for lung cancer.

Differential expression of hypoxia-inducible factor 1α in non-small cell lung cancer and small cell lung cancer.

OBJECTIVES: The aim of this study was to compare the expression of hypoxia-inducible factor 1α and vascular endothelial growth factor in small cell lung cancer and subtypes of non-small cell lung cancer and examine their relationships with clinicopathologic factors, response to treatment and survival. METHODS: We examined samples obtained by bronchial endoscopic biopsy from 55 patients with inoperable lung cancer (16 with adenocarcinoma, 17 with squamous cell carcinoma, and 22 with small cell lung cancer). Hypoxiainducible factor 1α and vascular endothelial growth factor were detected using immunohistochemistry. The diagnosis, treatment, and follow-up of patients were conducted according to the standard practice. RESULTS: A significant difference (p=0.022) in hypoxia-inducible factor 1α expression was observed between nonsmall cell lung cancer (75.8% positive) and small cell lung cancer (45.5% positive). The frequency of hypoxiainducible factor 1α nuclear expression was 88.2% in squamous cell carcinoma, 62.5% in adenocarcinoma, and 45.5% in small cell lung cancer. A significant correlation was observed between hypoxia-inducible factor 1α and vascular endothelial growth factor expression (Fisher's exact test, p=0.001) when all types of lung cancer were examined, either collectively or separately. CONCLUSIONS: The expression of hypoxia-inducible factor-1α differs significantly between subtypes of lung cancer. These findings could help elucidate the biology of the different types of non-operable lung carcinomas and have implications for the design of new therapeutic approaches for lung cancer.

Transcriptional activation of hTERT in breast carcinomas by the Her2-ER81-related pathway.

Her2 and ER81 (a member of ETS family) have been suggested to cause a synergistic increase in the transcriptional activation of hTERT. Our study aimed to offer further confirmation in clinical material. We determined the mRNA levels of Her2, ER81, and hTERT, by QRT-PCR, in 43 breast carcinomas. In the specimens showing hTERT transcriptional activation, Her2 and ER81 were increased in statistically significant tumor subgroups (61% and 79% correspondingly). The 86% of specimens with both Her2 and ER81 increased expression showed hTERT transcriptional activation. Synchronous transcriptional activation of hTERT, Her2, and ER81 elevated expression was noted in 42% of the samples. In conclusion, we agree with a previous study that Her2 overexpression may increase the hTERT transcriptional activation. Our data indicate that the mechanism may involve Her2-ER81 interaction(s) and that the activation of hTERT could be mainly mediated by transcriptional activation of ER81.

Effect of transosseous application of low-intensity ultrasound at the tendon graft-bone interface healing: gene expression and histological analysis in rabbits.

The present study investigates the effect of transosseous low-intensity pulsed ultrasound (LiUS) on the healing at tendon graft-bone interface, in molecular and histological level. The anterior cruciate ligament (ACL) in both knees of 52 New Zealand White rabbits was excised and replaced with the long digital extensor. A custom-made ultrasound transducer was implanted onto the medial tibial condyle, adjacent to the surface of the bone tunnel at both knees of the rabbits. The LiUS-treated right knees received 200-mus bursts of 1 MHz sine waves at a pulse repetition rate of 1 kHz and with 30 mW/cm(2) spatial-average temporal-average intensity for 20 min daily (study group), while the left knee received no LiUS (control group). Thirty-six rabbits were used to perform semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis from both study and control groups for transforming growth factor-beta1 (TGF-beta1), biglycan and collagen I. RT-PCR products showed statistically significant upregulation of biglycan and collagen I gene expression in the study group, while TGF-beta1 gene expression exhibited a bimodal profile. Histological examination performed in 16 rabbits from both groups supported the findings of the molecular analysis, indicating a faster healing rate and a more efficient ligamentization process after ultrasound treatment. These findings suggest that transosseous application of LiUS enhances the healing rate of the tendon graft-bone interface, possibly by affecting the expression levels of genes significant for the tendon to bone healing process.

Immunohistochemical evaluation of 95 bone marrow reactive plasmacytoses.

We histologically and immunohistochemically studied 95 bone marrow (BM) reactive plasmacytoses. Ten biopsies from plasma cell myeloma (PCM) patients served as a control group. In addition, we studied 10 monoclonal gammopathy of undetermined significance (MGUS) cases. Histologically, plasmacytosis varied between 5% and 25% with an interstitial pattern of plasma cell (PC) distribution being characteristically displayed. Immunohistochemically, we did not find any CD56/NCAM nor cyclin D1 expression in all biopsies (95 of 95, 100%), not even a weak, doubtful one; PCs were all polyclonal and CD138 positive. On the contrary, myeloma-associated PCs showed monoclonality for kappa- or lambda- light chain and strong CD56/NCAM immunoreactivity (8 of 10, 80%); four of them were cyclin D1 positive. Osteoblasts exhibited similar CD56/NCAM expression in both groups. Our data confirm the diagnostic utility of CD56/NCAM in the phenotypic characterization of polyclonal plasma cells, suggesting an important role of this particular immunomarker in the BM trephine study of polyclonal versus neoplastic plasmacytic infiltrations.

Phenotypic mismatch repair hMSH2 and hMLH1 gene expression profiles in primary non-small cell lung carcinomas.

BACKGROUND: Defects in the human DNA mismatch repair genes (MMR) hMSH2 and hMLH1 are responsible for the development of sporadic and hereditary colorectal cancers. The role of MMR genes in the pathogenesis of lung cancer has not been elucidated. The aim of this study was to address the phenotypic mRNA expression profiles of mismatch DNA repair system in lung cancer. MATERIALS AND METHODS: We evaluated the mRNA levels of the hMSH2 and hMLH1 components of the mismatch DNA repair (MMR) system in 29 unselected frozen pairs of primary non-small cell lung carcinomas (NSCLCs) and their adjacent normal tissue (ANTs) specimens by quantitative real-time PCR analysis relative to housekeeping Porphobilinogen deaminase (hPBGD) mRNA. To simplify and potentially improve the analysis of data, we defined for each individual MMR mRNA two possible phenotypes: a regular (R(2): hMSH2/hPBGD mRNAs> or =1 and R(1): hMLH1/hPBGD mRNAs> or =1) and a reduced (r(2): hMSH2/hPBGD mRNAs<1 and r(1): hMLH1/hPBGD mRNAs<1). The presence of MMR gene expression was evaluated after conversion of the molecular mRNA levels into clinically distinct phenotypic entities by these working criteria, based on the hypothesis that reduced mRNA and protein levels result in lower or non-functional MMR. RESULTS: Phenotyping defined four distinct MMR system expression profiles, R(2)R(1), r(2)R(1), R(2)r(1) and r(2)r(1) by ascending tumor progression rate and identified a previously unrecognized disease-associated phenotypic entity (r(2)r(1)). The phenotype-based biological aspects of the MMR system suggested that its two components: (1) function independently and (2) are not directly involved in the onset of the transformation process, since healthy lung tissue was devoid of r(2)r(1) phenotypes. CONCLUSION: These findings link MMR mRNA levels of paired lung tissue specimens to patients' clinical condition and suggest that phenotypic translation of molecular MMR data refines the biology of the MMR system with consequent diagnostic implications in the clinical assessment of lung cancer patients.

Cysteinyl leukotriene receptors are expressed by tonsillar T cells of children with obstructive sleep apnea.

BACKGROUND: Increased expression of cysteinyl leukotriene receptors (cysteinyl leukotriene receptor-1 [LT1-R]; cysteinyl leukotriene receptor-2 [LT2-R]) has been detected in adenotonsillar tissue from children with sleep-disordered breathing (SDB) compared to control subjects. LT1-R has been localized in myeloperoxidase-positive cells. This phenomenon possibly contributes to lymphoid tissue enlargement and may be related to systemic inflammation. OBJECTIVE: To characterize cells expressing LT1-R and LT2-R in tonsillar tissue and assess serum C-reactive protein (CRP) levels in children with and without SDB. METHODS: Immunohistochemistry with LT1-R and LT2-R antibodies was used to examine tonsils from children who had tonsillectomy (with or without adenoidectomy) for SDB and from control subjects operated for recurrent tonsillitis/otitis. All participants underwent preoperative polysomnography and measurement of morning serum CRP. RESULTS: Fifteen children with SDB (mean age +/- SD, 6.4 +/- 2.1 years; apnea-hypopnea index, 9.6 +/- 5.6 episodes per hour) and 11 control subjects (age, 7.5 +/- 2.8 years; apnea-hypopnea index, 7 +/- 0.3/h) were examined. Immunoreactivity for LT1-R and LT2-R was detected in tonsillar extrafollicular areas of all subjects with SDB but not of control subjects. Cells expressing leukotriene receptors were CD3+ lymphocytes. Children with SDB and control subjects were similar regarding CRP levels: 0.11 +/- 0.15 mg/dL vs 0.09 +/- 0.15 mg/dL, respectively (p > 0.05). CONCLUSIONS: Tonsils of children with SDB but not of control subjects have enhanced expression of cysteinyl leukotriene receptors in T lymphocytes without an associated increase in serum CRP concentration. Up-regulation of LT1-R and LT2-R could potentially promote tonsillar enlargement in children with obstructive sleep apnea.

Exposure of differentiated airway smooth muscle cells to serum stimulates both induction of hypoxia-inducible factor-1{alpha} and airway responsiveness to ACh.

Airway smooth muscle (ASM) cells are characterized by phenotypic plasticity and can switch between differentiated and proliferative phenotypes. In rabbit tracheal ASM cells that had been differentiated in vitro by serum starvation, readdition of FBS caused initiation of proliferation and induction of nuclear and transcriptionally active hypoxia-inducible factor (HIF)-1alpha. In addition, FBS stimulated the induction of HIF-1alpha by the hypoxia mimetic cobalt. Treatment with actinomycin D, cycloheximide, the phosphatidylinositol 3-kinase inhibitors LY-294002 and wortmannin or the reactive oxygen species scavenger diphenyleneiodonium inhibited the FBS-dependent induction of HIF-1alpha. These data indicate that, in differentiated ASM cells, FBS upregulates HIF-1alpha by a transcription-, translation-, phosphatidylinositol 3-kinase-, and reactive oxygen species-dependent mechanism. Interestingly, addition of FBS and cobalt also induced HIF-1alpha in organ cultures of rabbit trachea strips and synergistically increased their contractile response to ACh, suggesting that HIF-1alpha might be implicated in airway hypercontractility.

Plasmacytoid transitional cell carcinoma of the urinary bladder.

A case of rare plasmacytoid transitional cell carcinoma of the urinary bladder in a 60-year old man is described. The presence of end-stage disease did not allow for any efficacious therapy. Immunohistochemistry showed the tumor cells to be reactive for epithelial markers and syndecan-1 (CD138).