Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity.

Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention.

[Medication versus health education for patients with type â ¢ prostatitis-like symptoms: A prospective randomized control study].

OBJECTIVE: To investigate the necessity of medication for patients with type Ⅲ prostatitis-like symptoms for less than 3 months. METHODS: We enrolled in this study 171 outpatients with type Ⅲ prostatitis-like symptoms for less than 3 months in our hospital from November 2016 to October 2017, and randomly divided them into groups A (n = 57), B (n = 57) and C (n = 57). The patients of group A received tamsulosin, levofloxacin and health education, those of group B tamsulosin and health education, and those of group C health education only. Three months later, we evaluated the therapeutic effects according to the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scores of the patients, 4-point reduction in the total score indicating effectiveness. RESULTS: After 3 months of treatment, the total NIH-CPSI scores of the patients in groups A, B and C were decreased by (9.0 ± 2.9), (8.2 ± 3.4) and (8.6 ± 3.2) points respectively, all indicating effectiveness, the pain scores (4.2 ± 1.8), (4.0 ± 1.9) and (4.2 ± 1.6) points, the urinary symptom scores decreased by decreased by (2.4 ± 1.2), (2.4 ± 1.4) and (2.2 ± 1.2) points, and quality of life scores decreased by (2.4 ± 1.4), (1.9 ± 1.4) and (2.2 ± 1.3) points, none with statistically significant difference among the three groups (P > 0.05). CONCLUSIONS: Health education is proved to have a therapeutic effect on type Ⅲ prostatitis-like symptoms similar to that of alpha receptor blockers.

Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set.

BACKGROUND: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. METHODS: We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method. RESULTS: PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R2 = 0.73 and R2 = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). CONCLUSIONS: The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer.

Broad cross-presentation of the hematopoietically derived PR1 antigen on solid tumors leads to susceptibility to PR1-targeted immunotherapy.

PR1 is a HLA-A2-restricted peptide that has been targeted successfully in myeloid leukemia with immunotherapy. PR1 is derived from the neutrophil granule proteases proteinase 3 (P3) and neutrophil elastase (NE), which are both found in the tumor microenvironment. We recently showed that P3 and NE are taken up and cross-presented by normal and leukemia-derived APCs, and that NE is taken up by breast cancer cells. We now extend our findings to show that P3 and NE are taken up and cross-presented by human solid tumors. We further show that PR1 cross-presentation renders human breast cancer and melanoma cells susceptible to killing by PR1-specific CTLs (PR1-CTL) and the anti-PR1/HLA-A2 Ab 8F4. We also show PR1-CTL in peripheral blood from patients with breast cancer and melanoma. Together, our data identify cross-presentation as a novel mechanism through which cells that lack endogenous expression of an Ag become susceptible to therapies that target cross-presented Ags and suggest PR1 as a broadly expressed tumor Ag.

A BIGRU-Based Stacked Attention Network for Biomedical Named Entity Recognition with Chinese EMRs.

Biomedical named entity recognition (BNER) is an effective method to structure the medical text data. It is an important basic task for building the medical application services such as the medical knowledge graphs and the intelligent auxiliary diagnosis systems. Existing medical named entity recognition methods generally leverage the word embedding model to construct text representation, and then integrate multiple semantic understanding models to enhance the semantic understanding ability of the model to achieve high-performance entity recognition. However, in the medical field, there are many professional terms that rarely appear in the general field, which cannot be represented well by the general domain word embedding model. Second, existing approaches typically only focus on the extraction of global semantic features, which generate a loss of local semantic features between characters. Moreover, as the word embedding dimension becomes much higher, the standard single-layer structure fails to fully and deeply extract the global semantic features. We put forward the BIGRU-based Stacked Attention Network (BSAN) model for biomedical named entity recognition. Firstly, we use the large-scale real-world medical electronic medical record (EMR) data to fine-tune BERT to build the proprietary embedding representations of the medical terms. Second, we use the Convolutional Neural Network model to extract semantic features. Finally, a stacked BIGRU is constructed using a multi-layer structure and a novel stacking method. It not only enables comprehensive and in-depth extraction of global semantic features, but also requires less time. Experimentally validated on the real-world datasets in Chinese EMRs, the proposed BSAN model achieves 90.9% performance on F1-values, which is stronger than the BNER performance of other state-of-the-art models.

Visualizing fewer than 10 mouse T cells with an enhanced firefly luciferase in immunocompetent mouse models of cancer.

Antigen specific T cell migration to sites of infection or cancer is critical for an effective immune response. In mouse models of cancer, the number of lymphocytes reaching the tumor is typically only a few hundred, yet technology capable of imaging these cells using bioluminescence has yet to be achieved. A combination of codon optimization, removal of cryptic splice sites and retroviral modification was used to engineer an enhanced firefly luciferase (ffLuc) vector. Compared with ffLuc, T cells expressing our construct generated >100 times more light, permitting detection of as few as three cells implanted s.c. while maintaining long term coexpression of a reporter gene (Thy1.1). Expression of enhanced ffLuc in mouse T cells permitted the tracking of <3 x 10(4) adoptively transferred T cells infiltrating sites of vaccination and preestablished tumors. Penetration of light through deep tissues, including the liver and spleen, was also observed. Finally, we were able to enumerate infiltrating mouse lymphocytes constituting <0.3% of total tumor cellularity, representing a significant improvement over standard methods of quantitation including flow cytometry.

Multimolecular complex of Par-4 and E2F1 binding to Smac promoter contributes to glutamate-induced apoptosis in human- bone mesenchymal stem cells.

Neural cells undergo glutamate-induced apoptosis in ischaemic brain tissue, in which prostate apoptosis response-4 gene (Par-4) is involved. Human-bone mesenchymal stem cells can be utilized as an effective therapy for ischemic brain injury. In this study, we found that glutamate could induce apoptosis in human-bone mesenchymal stem cells, accompanied by increased expression of Par-4 gene and Smac release from mitochondria. Repressing Par-4 expression attenuated the glutamate-induced apoptosis. Both Par-4 protein and E2F1 protein could bind to E2F1-binding BS3 site on Smac promoter and participated in the formation of a proteins-DNA complex. Moreover, in the complex, E2F1, not Par-4, was found to be directly bound to the Smac promoter, suggesting that Par-4 exerted indirectly its transcriptional control on the Smac gene though interacting with E2F1. Expression of full-length Par-4 in human-bone mesenchymal cells resulted in increased activity of the Smac promoter. In addition, the indirect transcripional regulation of Par-4 on Smac depended on its COOH terminus-mediated interaction between Par-4 and E2F1. We conclude that the formation of proteins-DNA complex, containing Par-4 protein, E2F1 protein and the Smac promoter, contributes to the pro-apoptotic effect on glutamate-treated human-bone mesenchymal stem cells.

[Inhibition and significance of pigment epithelium-derived factor in the development and metastasis of prostate cancer].

OBJECTIVE: To study the inhibition and significance of pigment epithelium-derived factor (PEDF) in the development and metastasis of prostate cancer. METHODS: The expression of PEDF was examined in the normal prostate tissue, benign prostatic hyperplasia, prostate cancer tissue and prostate cancer cell lines, PC-3 and Lncap by immunohistochemical SP method and Western blot. In combination with clinical data, statistical analysis was performed to evaluate the relation of the expression level of PEDF in prostate cancer and the relationship between different histological grades of prostate cancer. RESULTS: In normal prostate tissue and benign prostate tissue, the expression of PEDF were elevated and it was far higher than the prostate cancer and prostate cancer cell line. The expression of PEDF and the pathological grade of prostate cancer were related to the differentiated carcinoma of prostate tissue, and the expression level of PEDF in poorly differentiated carcinoma below the highly differentiated carcinoma of prostate cancer. In metastatic prostate cancer, the expression of PEDF was lower than that of prostate cancer without metastasis (12% vs 43.1%). CONCLUSION: The expression of PEDF and the incidence of prostate cancer have a negative correlation. The lower grade of prostate cancer cells, the less the tissue expression of PEDF and the higher tendency of invasion and metastasis.

CREB and Sp1 regulate the human CD2AP gene promoter activity in renal tubular epithelial cells.

The human CD2-associated protein (CD2AP) is involved in several molecular signaling pathways and is an important factor responsible for nephrotic syndrome. Here we report the identification of the transcription start point and promoter region of the human CD2AP gene in renal tubular epithelial cells. With luciferase assays and deletion analysis, we found that the region between -558 and -1bp ahead of the transcription start point is indispensable for the promoter activity of the human CD2AP gene. A CREB site and two Sp1 sites were essential for maintaining the basal transcriptional activity of the human CD2AP promoter. Overexpression of phosphorylated CREB and Sp1 transactivated the human CD2AP promoter, whereas small interfering RNA-mediated blockage of CREB and Sp1 genes expressions inhibited markedly its activity. These findings provide the first analysis of the human CD2AP gene promoter and demonstrate that not only CREB but also Sp1 plays a critical role in regulating basal CD2AP promoter activity in renal tubular epithelial cells.

Cytologic features, immunocytochemical findings, and DNA ploidy in four rare cases of epithelioid hemangioendothelioma involving effusions.

BACKGROUND: Epithelioid hemangioendothelioma (EHE) involving serous effusion is extremely rare, and the diagnosis can be challenging. DNA ploidy quantitation of EHE in effusion fluids has not been previously described in the English-language literature. METHODS: Specimens of cytological diagnosed with EHE in effusion fluids between 2002 and 2009 were retrieved from the pathology files at MD Anderson Cancer Center. A total of four cases of EHE involving or arising from effusion fluids were found, and we reviewed cytospin, smears, cell block sections, and immunostained slides. DNA image analysis for ploidy and proliferation evaluation was performed on a destained, papanicolaou-stained slide from each case. RESULTS: The tumor cells were epithelioid with prominent cytoplasmic vacuolization and intracytoplasmic inclusions, which could resemble reactive mesothelial cells, mesothelioma, or adenocarcinoma. The tumor cells were positive for endothelial markers. DNA image analysis in three of the four cases revealed predominantly diploid and tetraploid subpopulations, with few aneuploid cells and fairly low proliferation indices, and these patients had fairly prolonged survival. CONCLUSIONS: DNA image analysis is useful for differentiating EHE from reactive mesothelial cells and high-grade carcinoma. For accurate diagnosis of EHE in effusion fluids, cytologic features should be considered together with clinical history and ancillary studies.

Roles of EGFR-Stat3 signal pathway in carcinogenesis of experimental hepatoma in rats.

The purpose of this study is to investigate if the EGFR-Stat3 signal pathway contributes to the carcinogenesis of hepatoma in rats. Hepatoma was induced in rats by 3'Me-DAB as a model. EGFR, TGFalpha, Stat3, p-Stat3 in different stages of carcinogenesis were detected by immunohistochemistry and Western blot. In situ hybridization was applied to investigate the expression of Stat3 mRNA. The expressions of signal molecules were assessed by KS400 Image Analysis system. The data were statistically evaluated. EGFR, TGFalpha, Stat3 were highly expressed in the stages of liver necrosis and repairment. All hepatocellular carcinoma cases revealed elevated expression of EGFR, TGFalpha. Elevation of Stat3 mRNA and protein levels were identified, increase of activation of Stat3 was also observed. In HCC, there was positive correlation between p-Stat3 level and the expression of TGFalpha and PCNA. Increased expression of Bcl-2 (P < 0.05) coincided with elevated level of p-Stat3. Therefore, the EGFR-Stat3 signal pathway was related to the development of hepatoma in rats. TGFalpha-EGFR autocrine ring formation may lead to the activation of Stat3 and in turn, promote proliferation and regulate the transcription of genes regulating cell apoptosis and cell cycle.

Efficacy and safety of tenofovir disoproxil fumarate in preventing vertical transmission of hepatitis B in pregnancies with high viral load.

This study was a meta-analysis of the literature on the efficacy and safety of tenofovir disoproxil fumarate (TDF) in preventing vertical transmission of hepatitis B in pregnancies with high viral load. Four observational studies and one randomized controlled trial involving 585 pregnant women and 595 newborns were included in the meta-analysis. TDF was more effective than the placebo in reducing vertical transmission in HBeAg-positive chronic hepatitis B (CHB) pregnancies with high serum HBV-DNA levels (OR = 0.21, 95% CI = 0.07-0.61) at 4-12 months, infant HBV DNA seropositivity at delivery (OR = 0.16, 95% CI = 0.07-0.37), and a severe flair in maternal alanine aminotransferase (ALT) levels (OR = 0.43, 95% CI = 0.19-0.95) during pregnancy. In addition, TDF showed more improvement in HBV DNA suppression at delivery (OR = 254.46, 95% CI = 28.39-2280.79). No significant differences were found in HBeAg seroconversion or ALT normalization; or in rates of cesarean section, emergent cesarean section, postpartum hemorrhage, prematurity, congenital malformations, or infant death. However, TDF induced more drug-related adverse events (OR = 2.33, 95% CI = 1.39-3.89) and elevated creatine kinase (CK) (OR = 9.56, 95% CI = 1.17-78.09) than in controls. The available evidence suggests that TDF is effective and safe in preventing vertical transmission of hepatitis B in pregnancies exhibiting a high viral load.

[The value of using an AMACR/34betaE12/p63 cocktail double staining for diagnosis of prostate carcinoma and precarcinomatous lesions].

OBJECTIVE: To investigate the value of using an AMACR/34betaE12/p63 cocktail and double-staining for the diagnosis of small focal protatic carcinoma and precarcinomatous lesions. METHODS: A total of 130 consecutive cases were examined over a 3-month period, including 105 prostate needle biopsy samples, 6 radical prostatectomy specimens and 19 benign prostatic hyperplasia specimens which were excised transurethra or above pubis. 262 paraffin blocks of all the 1030 ones were stained with hematoxylin and eosin and by immunostains for AMACR, 34betaE12, p63, and an antibody cocktail comprising all the three with double-chromogen reaction. The diagnoses were then made according to the immunostaining, HE staining and clinical information. RESULTS: In the sections stained by the 3-antibody cocktail, blue-black cytoplasmic staining was observed in the epithelial cells of prostatic carcinoma and high-grade prostatic intraepithelial neoplasia (HGPIN) the basal cells of benign glands were stained red. There were no red basal cells around the blue-black glandular epithelium of carcinoma, but discontinuous or consecutive red basal cells were present around the blue-black glandular epithelium of HGPIN. Prostatic carcinoma was found in 214 paraffin blocks (82%), including 31 small focal carcinoma. HGPIN were observed in 64 paraffin blocks (24%), including focal HGPIN and small gland alveolus HGPIN. AAH was found in one block. No benign glands were simultaneously positive for AMACR and negative for basal cell markers. CONCLUSION: Inmmunohistochemistry studies using a 3-antibody cocktail and double staining can improve the detection rate of small focal prostatic carcinoma and HGPIN.

PD-L1 expression and prognostic impact in glioblastoma.

BACKGROUND: Therapeutic targeting of the immune checkpoints cytotoxic T-lymphocyte-associated molecule-4 (CTLA-4) and PD-1/PD-L1 has demonstrated tumor regression in clinical trials, and phase 2 trials are ongoing in glioblastoma (GBM). Previous reports have suggested that responses are more frequent in patients with tumors that express PD-L1; however, this has been disputed. At issue is the validation of PD-L1 biomarker assays and prognostic impact. METHODS: Using immunohistochemical analysis, we measured the incidence of PD-L1 expression in 94 patients with GBM. We categorized our results according to the total number of PD-L1-expressing cells within the GBMs and then validated this finding in ex vivo GBM flow cytometry with further analysis of the T cell populations. We then evaluated the association between PD-L1 expression and median survival time using the protein expression datasets and mRNA from The Cancer Genome Atlas. RESULTS: The median percentage of PD-L1-expressing cells in GBM by cell surface staining is 2.77% (range: 0%-86.6%; n = 92), which is similar to the percentage found by ex vivo flow cytometry. The majority of GBM patients (61%) had tumors with at least 1% or more PD-L1-positive cells, and 38% had at least 5% or greater PD-L1 expression. PD-L1 is commonly expressed on the GBM-infiltrating T cells. Expression of both PD-L1 and PD-1 are negative prognosticators for GBM outcome. CONCLUSIONS: The incidence of PD-L1 expression in GBM patients is frequent but is confined to a minority subpopulation, similar to other malignancies that have been profiled for PD-L1 expression. Higher expression of PD-L1 is correlated with worse outcome.

Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.

UNLABELLED: T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. We show that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell-mediated tumor killing and decreases T-cell trafficking into tumors. In patients, PTEN loss correlates with decreased T-cell infiltration at tumor sites, reduced likelihood of successful T-cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell-mediated cell death. Treatment with a selective PI3Kß inhibitor improved the efficacy of both anti-PD-1 and anti-CTLA-4 antibodies in murine models. Together, these findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K-AKT pathway inhibitors. SIGNIFICANCE: This study adds to the growing evidence that oncogenic pathways in tumors can promote resistance to the antitumor immune response. As PTEN loss and PI3K-AKT pathway activation occur in multiple tumor types, the results support the rationale to further evaluate combinatorial strategies targeting the PI3K-AKT pathway to increase the efficacy of immunotherapy.

Epithelioid hemangioendothelioma: a study of 14 cytopathology cases.

INTRODUCTION: The cytopathologic diagnosis of the rare vascular tumor epithelioid hemangioendothelioma (EHE) in patients who have no previous history of EHE or who have a complicated and/or misleading disease history is challenging. Furthermore, few studies have described the cytopathology of EHE. Herein, we identify 14 cases of EHE from 10 patients, some of whom had a history of epithelial tumor, and provide a detailed report of the cytomorphology of EHE, discuss the tumor's differential diagnoses, and describe ancillary examinations that may be helpful in diagnosing EHE cytologically, especially in patients with a complex disease history. MATERIALS AND METHODS: We retrieved the slides of 14 cases of EHE archived between 2002 and 2009 in our institution's cytology section. Conventional direct smears and cell block sections were prepared from most fine-needle aspiration samples and from all effusion samples. Cell block sections were subjected to immunostaining for vascular, mesothelial, and epithelial markers. RESULTS: EHE shared many morphologic features with other, more common tumors such as adenocarcinoma and mesothelioma. The defining cytologic feature of EHE was an intracellular lumen containing entrapped intact and degenerating erythrocytes, which was not present in every case. EHE cells were positive for the vascular markers CD34, CD31, factor VIII, and friend leukemia integration 1 transcription factor (FLI-1) and negative for epithelial and mesothelial markers. Clinicians provided information important to the diagnosis of EHE. CONCLUSIONS: Carefully examining the smear and cell block sections for morphologic features indicative of EHE (eg, prominent cytoplasmic vacuolization, intranuclear cytoplasmic inclusions, and intracellular lumen containing entrapped intact and degenerating erythrocytes), confirming these findings with immunocytochemical staining, and communicating with clinicians are all important to correctly diagnosing EHE.

Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy.

PURPOSE: Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy (ACT). The expansion of tumor-reactive CD8(+) T cells with interleukin-2 (IL2) in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8(+) T cells recently found to constitute the majority of tumor-specific T cells. EXPERIMENTAL DESIGN: We used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB costimulation. RESULTS: We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8(+) TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL2 responsiveness, in the CD8(+) T cells in the fragments and emerging from the fragments. Early provision of 4-1BB costimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8(+) T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8(+) TIL outgrowth. CONCLUSIONS: Our results highlight a previously unrecognized concept in TIL ACT that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics.

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties.

In a recent adoptive cell therapy (ACT) clinical trial using autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, we found an association between CD8+ T cells expressing the inhibitory receptor B- and T-lymphocyte attenuator (BTLA) and clinical response. Here, we further characterized this CD8+BTLA+ TIL subset and their CD8+BTLA- counterparts. We found that the CD8+ BTLA+ TILs had an increased response to IL-2, were less-differentiated effector-memory (TEM) cells, and persisted longer in vivo after infusion. In contrast, CD8+BTLA- TILs failed to proliferate and expressed genes associated with T-cell deletion/tolerance. Paradoxically, activation of BTLA signaling by its ligand, herpes virus entry mediator (HVEM), inhibited T-cell division and cytokine production, but also activated the Akt/PKB pathway thus protecting CD8+BTLA+ TILs from apoptosis. Our results point to a new role of BTLA as a useful T-cell differentiation marker in ACT and a dual signaling molecule that curtails T-cell activation while also conferring a survival advantage for CD8+ T cells. These attributes may explain our previous observation that BTLA expression on CD8+ TILs correlates with clinical response to adoptive T-cell therapy in metastatic melanoma.

[The relationship between IL-13 gene polymorphism and the levels of serum IL-13 and serum eosinophil cation protein in asthmatic children].

OBJECTIVE: To explore the relationship between IL-3 gene polymorphism and the levels of serum IL-3 and eosinophil cation protein (ECP) for understanding the role of IL-3 gene polymorphism in the mechanism of childhood asthma. METHODS: The method of restriction fragment length polymorphism (RFLP) was adopted in detecting +1923 site polymorphism of IL-13 gene in intron 3 region, ELISA was employed in detecting the level of serum IL-13, and fluorescent enzyme-linked immunoassay was used to detect the level of serum ECP. RESULTS: The frequency distribution of TT, TC genotypes of IL-13 Intron 3+1923 site in asthmatic children was higher than that of CC genotype in normal control (P<0.05), and the levels of serum IL-13 and ECP of TT, TC genotypes were significantly higher than those of CC genotype respectively (P<0.01). CONCLUSION: The close relationship of IL-3 gene polymorphism with the levels of serum IL-13 and ECP suggests that IL-3 gene polymorphism may play an important role in the mechanism of childhood asthma.

[Clinicopathologic analysis of 154 cases of tumors and tumor-like lesions in the bones of hands and feet].

OBJECTIVE: To study the clinical and pathologic features of tumors and tumor-like lesions in the bones of hands and feet. METHODS: Clinical, X-ray and pathologic features of 154 cases of tumors and tumor-like lesions in the bones of hands and feet between 1991 and 2002 were investigated. RESULTS: In the bones of hands and feet the frequency and distribution of many lesions were distinctive when compared to those of other skeletal sites. Cartilaginous lesions were most common (60%), and 72% of them were enchondromas. Enchondromas were most often situated in the second to fifth phalanges and metacarpal bones. Chondroblastomas most frequently involved the irregular bones (such as calcaneus, talus and osnaviculare) of the feet. Whereas the occurance of osteochondromas in the bones of the hands and feet was lower than in the long bones. Most "osteochondromas" of the phalanges were subungual exostoses. A group of reactive or reparative lesions, which are related to trauma, such as subungual exostosis, giant cell reparative granuloma, florid reactive periostitis and bizarre parosteal osteochondromatous proliferations typically occurred in the bones of the hands and feet, but these tumor-like lesions were often misdiagnosted. Another feature of lesions in the bones of the hands and feet was that there were much more benign than malignant lesions (21:1), and that chondrosarcomas were common in malignancies. The diagnostic criteria for benign and malignant cartilaginous tumors in the bones of hands and feet were different from those in long bones and flat bones. CONCLUSIONS: Bone tumors of the hands and feet are different from that of long bones, flat bones and axial bones. Because the hands and feet are frequently exposed to trauma, reactive and reparative lesions often occur in these sites. These tumor-like lesions may simulate benign and malignant neoplasia. Knowledge of different types of lesions which commonly affect these sites is of benefit in assessing lesions of the bones of hands and feet.