Formyl peptide receptor 2 mediated chemotherapeutics drug resistance in colon cancer cells.

OBJECTIVE: To determine the expression of formyl peptide receptor 2 (FPRL2) and its drug resistance role in cancer colon cells, and its underlying mechanisms. PATIENTS AND METHODS: The expression of FPRL2 and its legend (F2L) in colon cancer tissues or cancer cells was determined by immunohistochemistry assay and Real-time polymerase chain reaction (PCR), respectively. Chemosensitivity of 5-Fu and MMC in colon cancer cells were tested by cell counting kit-8 (CCK-8) method. Expression of p-ERK was determined by Western blot assay. RESULTS: The expression of FPRL2 and its legend was significantly higher in resistant colon cancer tissues than those in non-resistant colon cancer tissues. The FPRL2 positive cells were two-thirds in tested cell lines. All of cells were F2L positive. The IC50 (inhibitory concentration 50) by 5-Fu and MMC was significantly higher in FPRL2 positive cells than those negative cells. The expression of p-AKT was markedly increased in FPRL2 positive cells. Pretreatment with AKT inhibitor enhanced the drug-sensitivity of these cells to 5-Fu and MMC. CONCLUSIONS: The FPRL2 played a significant role in colon cancer drug resistance and this effect was through AKT pathway.

Clinical significance of pituitary tumor transforming gene 1 and transgelin-2 in pancreatic cancer.

Human pituitary tumor transforming gene 1 (PTTG1) is an oncogenic transcription factor that is overexpressed in many malignancies, especially cancers with metastatic potential, while transgelin-2 (TAGLN2) is an actin-binding protein shown to be a tumor suppressor. However, the expression and clinical significance of PTTG1 and TAGLN2 in pancreatic cancer remain unclear. The present study aimed to investigate the expression and clinical significance of PTTG1 and TAGLN2 in human primary pancreatic cancer. Seventy-five cases of human pancreatic cancer tissues were collected. The expression of PTTG1 and TAGLN2 protein was assessed using immunohistochemistry (IHC) through tissue microarray procedure. The clinicopathologic characteristics of all patients were analyzed. As a result, the expression of PTTG1 and TAGLN2 in cancerous tissues showed the positive staining mainly in the cytoplasm, and they were found in cancerous tissues with higher strong reactivity rate compared with the adjacent non-cancer tissues (ANCT) (56.0 percent vs 22.7 percent, P less than 0.001; 100 percent vs 84 percent, P=0.002), elevating with the ascending order of tumor malignancy. Furthermore, the positive expression of PTTG1 was associated with the gender of pancreatic cancer patients, but did not correlate with their age, pathological styles, tumor size, tumor sites, TNM staging, perineural infiltration and distant metastasis (each P greater than 0.05). In addition, Spearman rank correlation analysis showed the positive correlation of PTTG1 with TAGLN2 (r=0.624, P less than 0.001). Taken together, PTTG1 and TAGLN2 are highly expressed in human pancreatic cancer, and the positive expression of PTTG1 is associated with the gender of cancer patients, suggesting that it may represent a potential therapeutic target for the treatment of pancreatic cancer.

Nephrogenic fibrosing dermopathy.

This report details the histopathologic findings in a unique fibrosing disorder that recently emerged among patients with renal disease. The affected patients were initially identified among recipients of renal transplants at a single institution, but later cases at other centers were identified, and included patients receiving renal dialysis for a variety of different kidney diseases. The cutaneous changes consisted largely of indurated plaques and papules on the extremities and trunk. Systemic findings seen in scleromyxedema, which the condition resembles in some respects, were absent. By routine microscopy, the findings range from a very subtle proliferation of dermal fibroblasts in early lesions, to a florid proliferation of fibroblasts and dendritic cells in fully developed cases. Thick collagen bundles with surrounding clefts are a prominent finding, and a variable increase in dermal mucin and elastic fibers was usually evident with special stains. CD-34 positive dermal dendrocytes were floridly abundant, with dendritic processes aligned with elastic fibers and around collagen bundles in a dense network. Factor XIIIa and CD-68 positive mono-and multinucleated cells are also present in increased numbers. Electron microscopy highlighted increased elastic fibers closely apposed to dendritic cell processes. The entire dermis was commonly involved, with increased spindle cells, collagen, mucin, and elastic fibers extending through the subcutis along the septa of fatty lobules. In some instances, the process resembled a sarcoma on histopathologic examination. The recent emergence of this condition and the apparent clustering of cases in specific dialysis centers initially suggested a possible infectious and/or toxic agent. To date, however, no such agent has been identified. We propose the term "nephrogenic fibrosing dermopathy (NFD)" until a specific cause can be identified.

Scleromyxoedema-like cutaneous diseases in renal-dialysis patients.

15 renal dialysis patients have been identified with a skin condition characterised by thickening and hardening of the skin of the extremities and an increase in dermal fibroblast-like cells associated with collagen remodelling and mucin deposition. The disease closely resembles scleromyxoedema, yet has significant enough clinical and histopathological differences to warrant its designation as a new clinicopathological entity.

Co-expression of CD56 and CD30 in lymphomas with primary presentation in the skin: clinicopathologic, immunohistochemical and molecular analyses of seven cases.

BACKGROUND: Natural killer and natural killer-like T-cell lymphomas presenting in the skin usually demonstrate aggressive behavior, an angiocentric distribution and a characteristic immunophenotype. In contrast, primary cutaneous CD30+ lymphoproliferative disorders form a heterogeneous spectrum including anaplastic large cell lymphomas, the majority of which display a good prognosis. Lymphomas with co-expression of CD56 and CD30 are extremely rare and the significance of this co-expression is unknown. METHODS: Seven retrospectively identified cases of lymphomas with co-expression of CD56 and CD30 presenting in the skin comprise this study. Immunohistochemistry, in situ hybridization for Epstein-Barr virus and T-cell receptor gene rearrangement studies were performed on paraffin sections. RESULTS: This subset of cutaneous lymphomas showed a variable clinical course that ranged from resolution without treatment, treatment-failure and recurrence, to death from disease. Histologic, immunophenotypic and molecular studies were of limited utility in predicting prognosis. CONCLUSIONS: Cutaneous lymphomas co-expressing CD56 and CD30 share many clinicopathologic features with natural killer and natural killer-like T-cell lymphomas or anaplastic large cell lymphomas, two entities with widely disparate clinical behavior. It is important to recognize that these lymphomas may behave more aggressively than primary cutaneous anaplastic large cell lymphomas do. Longer follow-up and further investigations on larger numbers of cases are necessary to fully characterize this rare subset of cutaneous lymphomas.

Lymphoma- and leukemia-associated cutaneous atypical CD30+ T-cell reactions.

Cutaneous CD30+ lymphoid infiltrates appear cytologically atypical and occasionally may be misinterpreted as recurrent disease when they occur in patients treated for other primary hematologic malignancies. We recently encountered two such cases and present our findings. One patient with B-cell lymphoma and another with myeloid leukemia developed cutaneous eruptions after chemotherapy displaying highly atypical perivascular lymphoid cells on histology that mimicked recurrent disease. In both cases, the lymphocytes were CD30+ T cells by immunohistochemistry. The skin lesions spontaneously resolved and have not recurred. Because one case was initially misinterpreted as recurrent leukemia, we conclude that close clinical correlation and immunophenotypic confirmation should be done for atypical cutaneous lymphoid infiltrates in patients with primary hematologic malignancies. We discuss the differential diagnosis of atypical CD30+ infiltrates in this setting, which include recurrent lymphoma or myeloid leukemia, primary cutaneous anaplastic large cell lymphoma (ALCL), lymphomatoid papulosis (LyP), carbamazepine-induced CD30+ pseudolymphoma, viral infection and an atypical eruption of lymphocyte recovery.

Lichenoid dermatitis in paraneoplastic pemphigus: a pathogenic trigger of epitope spreading?

BACKGROUND: In select cases, lichen planus has been observed to be a paraneoplastic condition sometimes associated with paraneoplastic pemphigus, a disease featuring autoantibodies directed against plakin proteins, desmogleins 3 and 1, and a still uncharacterized 170-kd antigen. Epitope spreading describes the phenomenon where underlying chronic inflammation leads to the sequential recognition of new epitopes on self-proteins over time. OBSERVATIONS: Five of 6 patients diagnosed as having paraneoplastic pemphigus had concomitant clinical and histological features of lichen planus. In 1 patient, results of the initial indirect immunofluorescence on rat bladder were negative and only 2 of the 5 antigens were identified by immunoprecipitation. After 1 year of worsening disease, repeated testing confirmed the presence of antibodies directed against all 6 of the implicated antigens, supportive of our hypothesis that epitope spreading may occur in paraneoplastic pemphigus. CONCLUSIONS: Lichenoid eruptions may predispose to an early evolutionary stage of paraneoplastic pemphigus. Cell-mediated autoimmunity at the dermoepidermal junction may promote the exposure of self-antigens and the development of subsequent and progressive humoral autoimmunity. As such, paraneoplastic pemphigus may demonstrate epitope spreading in a human, humoral-mediated autoimmune disease.

Clinical, histopathologic, and molecular aspects of cutaneous human papillomavirus infections.

Human papillomaviruses comprise a large family of double stranded DNA viruses that are the etiologic agents of benign warts and anogenital cancers. At least 82 different human papillomavirus types have been identified and many remain yet uncharacterized. The development of new molecular techniques in recent years has led to an increased understanding of human papillomaviruses and their roles in carcinogenesis. Several clinicopathologic entities arising from human papillomavirus infection encountered by the dermatologist are the subject of the article. The epidemiology, molecular biology, clinical presentation, histologic findings, and treatment of each disorder, where applicable, is discussed.

Inflammatory myofibroblastic tumor: cytogenetic evidence supporting clonal origin.

The inflammatory myofibroblastic tumor (IMT) is a distinctive but controversial lesion, usually occurring during childhood, composed of fascicles of bland myofibroblastic cells admixed with a prominent inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils. Often affecting the lung and associated with constitutional symptoms, this lesion has been variously termed plasma cell granuloma, inflammatory pseudotumor, inflammatory myofibrohistiocytic proliferation, and inflammatory fibrosarcoma to reflect divergent views concerning its pathogenesis and level of malignancy. Cytogenetic analysis of an intra-abdominal myxoid hamartoma, a probable variant of this lesion, and a pulmonary IMT demonstrated clonal chromosomal abnormalities, lending support to the view that the IMT might be a neoplasm. There have been few cases studied to date, however, and the extent of cytogenetic anomalies in IMTs is not known. Karyotype analyses were performed on IMTs showing typical histologic features from three children. In addition, one case was studied by fluorescence in situ hybridization. Seventeen of 20 metaphase cells examined from a pulmonary IMT in a 5.5-year-old girl had an abnormal 47,XX+r(ring) karyotype. Fluorescence in situ hybridization studies demonstrated that the ring chromosome contained sequences of chromosome 8. Of 40 metaphase cells studied from a mesenteric IMT in an 8-month-old boy, 12 showed clonal aberrations, characterized as 43,XY,add(1)(p36),add(2)(p24),-6,der(14,22)(q10;q10),-19. Each of 20 metaphase cells examined from a retroperitoneal IMT in a 14-year-old girl contained complex clonal and nonclonal aberrations, characterized as 46-47,X,-X,add(2)(p22),add(2)(q13),+add(2)(q13),+5,-6,+i(7)(p10),add(8)( p11.2),+del(9)(p13),add(11)(p11.2)add(11)(q25),-13,-16,-18,add(19)(q13.1 ),add(19)(q13.1),+20,-21,-22,+mar1,+1-2mars. The presence of clonal chromosomal aberrations in all of the three tumors indicates that the IMT is a neoplastic proliferation.

The effects of exogenous free fatty acids on lipoprotein migration in serum high-resolution electrophoresis: addition of free fatty acids improves visualization of normal and abnormal alpha1-antitrypsin.

Abnormalities in the alpha1 region are occasionally difficult to interpret on high-resolution electrophoresis (HRE) gels because alpha1-antitrypsin (A1AT) can be obscured by elevated levels of lipoprotein. The addition of saturated free fatty acids (SFFAs) to serum samples causes a selective anodal migration of lipoproteins when examined by HRE. This "clearing" of the alpha1 region improves visualization of A1AT. In this study, we evaluated 6- to 24-carbon SFFAs for their ability to cause anodal migration of serum lipoproteins; identified the optimal SFFA and determined its effects on other proteins; and applied the SFFA to problematic serum samples, including those containing dense alpha lipoprotein regions. When added to serum samples, a mixture of medium-chain (12-18 carbon) SFFAs caused a dose-dependent anodal migration of the alpha and beta lipoproteins and albumin. Lauric acid (C(12:0); 3.2-6.5 mmol/L) caused an optimal effect--maximal anodal migration of alpha lipoproteins and clearing of the alpha1 region, facilitating inspection of that area for A1AT variants. At the optimal C(12:0) concentration, the migration and resolution of A1AT were minimally affected, anodal slurring of beta lipoproteins and albumin were slight, and there was no effect on interpretation of monoclonal proteins. At higher concentrations, C(12:0) increased anodal migration of beta lipoproteins and decreased the resolution of A1AT. C(12:0) at 3.2 mmol/L in serum samples of heparinized patients showed an exaggerated effect similar to higher concentrations of C(12:0) in nonheparinized serum samples. Hyperbilirubinemia did not alter the effect of C(12:0) on serum proteins. C(12:0) treatment of serum samples displaying dense alpha lipoprotein bands on HRE dramatically improved visualization of A1AT. We report the incidental identification of A1AT variants in two such samples treated with C(12:0). The addition of C(12:0) to serum samples markedly improves visualization of normal and abnormal A1AT in the alpha1 region in HRE.

The t(2;5)-associated p80 NPM/ALK fusion protein in nodal and cutaneous CD30+ lymphoproliferative disorders.

A high percentage of extracutaneous CD30+ anaplastic large cell lymphomas (nodal ALCL) carry a specific chromosomal translocation, t(2;5) (p23;q35), that results in abnormal expression of p80 NPM/ALK chimeric protein (p80). The protein p80 may be detected by immunohistochemistry using polyclonal (anti-p80) or monoclonal (ALK1) antibody directed against the ALK epitope. Although nodal ALCL, primary cutaneous ALCL, and lymphomatoid papulosis type A (lyp A) have similar histologic and immunohistochemical features, the expression of p80 in these cutaneous lesions has not been extensively studied. We immunostained tissues from 10 nodal ALCL, 8 primary cutaneous ALCL, 24 lyp A, and positive and negative controls using polyclonal rabbit anti-p80 and the avidin-biotin-peroxidase labeling method. Reactivity was determined by comparing staining intensity to positive controls [4 nodal ALCL with t(2;5)] and negative controls (21 non-ALCL lymphomas). Only cutaneous lesions staining positively with anti-p80 were further studied with the monoclonal antibody ALK1 and reverse transcription polymerase chain reaction (RT-PCR) for p80 messenger RNA. All positive controls (4/4), but none of the negative controls (0/21) nor lyp A (0/24), were immunoreactive for anti-p80. Sixty percent (6/10) of nodal ALCL and a single case (12%) of primary cutaneous ALCL were immunoreactive for anti-p80. In this exceptional cutaneous lesion, although we did not find NPM/ALK by RT-PCR, we detected strong expression of ALK using ALK1. We conclude that t(2;5) is rarely involved in the pathogenesis of cutaneous CD30+ lymphoproliferative disorders.

Effects of gamma radiation on the OM431 human ocular melanoma cell line.

In order to determine the dose responsiveness to radiation of ocular melanoma, we conducted an in vitro dose-response study on a monolayer cell culture using a clonogenic assay. The effects on cell survival were determined relative to unirradiated controls. A human epithelioid ocular melanoma cell line, OM431, was maintained in tissue culture and serial dilutions of viable cells were plated in flasks, allowed to settle and attach for 48 h, and subsequently irradiated with 1-10 Gy in single fractions. After 2 weeks, the number of reproducing clones (forming colonies with greater than 32 cells or five generations) were counted. The surviving fractions of cells were plotted on a cell survival curve using the linear quadratic model. The survival curve showed a large initial shoulder followed by an exponential decline in growth. Our data suggest that the OM431 ocular melanoma cell line responds to irradiation in a manner similar to other melanoma cell lines and is relatively radioresistant especially at lower doses.

[Correlation between various autoantibodies in scleroderma patients and their clinical features].

We studied the antibodies of cell structural localized antibody and the correlation between the new classifications and their clinical features. The results suggest that antikinetochore antibody is the apparent indicator of CREST syndrome, anticentrosome antibody the apparent indicator of local scleroderma with mild clinical features and better prognosis, antinucleous antibody the apparent indicator of diffuse scleroderma with most severe clinical features, high mortality and poor prognosis. New classifications 13 of diagnostic value in clinical grouping and prognosis estimation.

Growth of vascularized composite mandibular allografts in young rabbits.

Forty-one hemimandible allografts were transplanted in young rabbits immunosuppressed with cyclosporine. The majority of the grafts demonstrated normal wound healing, and growth of hair, bone, and teeth. The mandibular body and the premolars showed significant growth in length. The allografted mandibles functioned sufficiently that the rabbits took oral nourishment soon after surgery. Long-term survival was limited by a toxic "wasting syndrome" specific for rabbits under treatment with cyclosporine.