Transcriptome sequencing analysis of ursolic acid-mediated proliferation suppression on cutaneous T-cell lymphoma cells

Background:Ursolic acid is a triterpenoid compound found in natural plants that exhibits antiproliferative effects in various cancer cells.Our study is the first to demonstrate the strong inhibitory effects of ursolic acid on the proliferation of cutaneous T-cell lymphoma(CTCL)cells.We aimed to further investigate the underlying mechanism of the proliferation inhibition induced by ursolic acid in CTCL cells using transcriptome sequencing.Methods:Cell counting kit-8 assays were used to observe the effects of six traditional medicine monomers on the proliferation of CTCL cells.Transcriptome sequencing was used to identify differentially expressed genes after ursolic acid treatment.Bioinformatics analysis was performed to determine the potential mechanism.Real-time quantitative PCR and western blotting analyses were performed to confirm the sequencing results and verify the possible mechanisms of ursolic acid-mediated proliferation inhibition in CTCL cells.Results:Ursolic acid exhibited the strongest inhibitory effect on the proliferation of CTCL cells among the six traditional medicine monomers.Transcriptome sequencing analysis showed that 2,466 genes were significantly altered.Combined with Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis and protein-protein interaction network analysis,the interaction of various pathways and signaling molecules,such as tumor necrosis factor-α,NLR family pyrin domain containing 1,c-Jun N-terminal kinase,and melanoma differentiation-associated gene 5,accounted for the anti-tumor effects of ursolic acid in CTCL cells.Conclusion:Ursolic acid significantly inhibited the proliferation of CTCL cells,and our study laid a theoretical foundation for the future treatment of CTCL using ursolic acid.

Epigenetics of cutaneous T-cell lymphoma:biomarkers and therapeutic potentials

Cutaneous T-cell lymphomas(CTCLs)are a heterogeneous group of skin-homing non-Hodgkin lymphomas.There are limited options for effective treatment of patients with advanced-stage CTCL,leading to a poor survival rate.Epigenetics plays a pivotal role in regulating gene expression without altering the DNA sequence.Epigenetic alterations are involved in virtually all key cancerassociated pathways and are fundamental to the genesis of cancer.In recent years,the epigenetic hallmarks of CTCL have been gradually elucidated and their potential values in the diagnosis,prognosis,and therapeutic intervention have been clarified.In this review,we summarize the current knowledge of the best-studied epigenetic modifications in CTCL,including DNA methylation,histone modifications,micro RNAs,and chromatin remodelers.These epigenetic regulators are essential in the development of CTCL and provide new insights into the clinical treatments of this refractory disease.

Low Dose Total Skin Electron Beam Radiation in Cutaneous T-Cell Lymphoma: Review

The treatment of advanced stage MF is especially challenging as single agent overall response rates are in the 35% range and chronic recurrence is the rule. The treatment of CTCL across all stages of disease is aimed at the goal of achieving and sustaining remission. Increasingly, low dose total skin electron beam therapy (TSEBT) is being utilized as a skin directed component in combination therapy for advanced stage CTCL. Researchers are seeking to better define the utility of low dose TSEBT as a method of debulking skin disease while simultaneously treating other disease compartments and in combination with sustained maintenance therapies of both the skin directed and systemic varieties. Data exists showing the efficacy of low dose TSEBT in early and advanced disease. There is also data documenting prolonged treatment responses with TSEBT plus adjuvant skin directed therapies such as PUVA and topical nitrogen mustard. Emerging data examining the role of low dose TSEBT in the prestem cell transplant preparation is also promising. This brief review summarizes the utility of low dose TSEBT in multiagent treatment regimens in CTCL.

Atypical Cutaneous Lymphoproliferative Disorder: A Fatal Mimic of Cutaneous T-Cell Lymphoma in a Patient with HIV Infection

Atypical cutaneous lymphoproliferative disorder (ACLD) is a rare condition that has been associated with HIV infection. Patients with ACLD present with diffuse, erythematous and pruritic skin lesions accompanied by generalized lymphadenopathy. The clinical characteristics of ACLD overlap most notably with several other conditions including Mycosis Fungoides/Sézary Syndrome (MF/SS), a cutaneous lymphoma of T-cell lineage. Unlike Mycosis Fungoides, the noxious infiltrates of ACLD are not monoclonal but polyclonal and consist of cytotoxic CD8+ T-cells instead of CD4+ T-cells or B-cells. Highly active antiretroviral therapy (HAART) has been reported to improve ACLD. We describe the case of a Caucasian man with longstanding HIV infection who presented with severe erythroderma. Skin and lymph node biopsies showed polyclonal CD8+ T-cell infiltrates. Gene rearrangement studies did not reveal an obvious clonal disorder. Hallmark peripheral blood findings consisting of a severe depletion of CD4+ T-lymphocytes and markedly elevated CD8+ cells provided an important diagnostic clue. Despite the purported benefits of HAART in ameliorating this disorder, erythroderma and extreme pruritus improved only after the patient began taking mycophenolate mofetil and hydroxyurea. Unfortunately, he succumbed to complications of methicillin-resistant Staphylococcus aureus septicemia. We alert readers to this rare HIV-associated condition which may mimic other benign and malignant skin conditions and briefly discuss diagnostic and therapeutic options.

Rothmund-thomson syndrome and cutan T-cell lymphoma in childhood

We report a 3-year-old girl suffering from RothmundThomson Syndrome (RTS). The patient at birth had multiplex anomalies: poikilodermatous rash, sceletal abnormalities: palatoschisis, micrognathi, aplasia radii, hypoplastic right and left thenar and thumbs, pesequinus on both site, ectopy renis. The patient in the later ages was detected dental malformation, facial dysmorfism. At the age 3, she had lasion in her muscle. After biopsy, histological examination showed cutan T-cell lymphoma. The patient is the first case who had cutan T-cell lymphoma associated with RTS in this young age.

Primary Cutaneous Gamma Delta T Cell Lymphoma: A Clinicopathological Analysis

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a very uncommon and extremely aggressive tumor, and is described in the newly re-vised World health organization for research and treatment of cancer classification of cutaneous lymphomas. A 43-year-old male patient presented with a 4 months history of cutaneous lesion over upper lip, without plaque and any constitutional symptom. Histopathological examination of skin biopsy revealed infiltration of atypical lymphocytes with hyperchromatic irregular nuclei. Immunophenotyping pattern of skin biopsy was compatible with PCGD-TLC. It is a highly aggressive tumor resistant to chemotherapy, immunotherapy, and radiation therapy. The GDTCL is characterized by a worse prognosis with a median survival of 15 months. Early diagnosis is essential and aggressive therapy is necessary.

Primary cutaneous anaplastic large cell lymphoma with subsequent leg involvement

Primary cutaneous anaplastic large cell lymphoma(CALCL)is regarded as an indolent type of cutaneous T-cell lymphoma.However,a few recent publications revealed that C-ALCL patients with initial leg involvement had significantly worse survival than those without initial leg involvement.Herein,we report a case of C-ALCL with subsequent leg involvement,which led to death after chemoradiation therapy.A 75 years old Japanese man presented with multiple erythematous nodules in his left arm and the side of his left chest.Histopathological and immunohistochemical studies led to the diagnosis of primary C-ALCL.At the initial diagnosis,no leg lesion was found.One year after the initial diagnosis,C-ALCL appeared in his right lower thigh and left hip.Radiation therapy,low-dose etoposide and CHOP therapy were performed;however,the patient died of malignant lymphoma 4 years after the initial diagnosis.We speculated that the occurrence of subsequent leg involvement may also be indicative of a worse prognosis,as in the case with initial leg involvement in C-ALCL.Therefore,we propose that C-ALCL patients with initial or subsequentleg involvement should be classified as a distinct clinicopathological variant of C-ALCL("leg-type"involvement)and that they may require intense therapy.

基于GC/MS的皮肤T细胞淋巴瘤(CTCL)异种移植小鼠血浆和皮肤组织的代谢组学分析

目的探讨皮肤T细胞淋巴瘤(cutaneous T-cell lymphoma,CTCL)异种移植小鼠血浆和皮肤组织代谢组的变化,寻找与其相关的差异代谢物。方法将21只Balb/c雌性裸鼠分为实验组和对照组,利用HH细胞(T细胞淋巴瘤ATCC CRL-2105)造模,基于GC/MS对CTCL荷瘤鼠的血浆和肿瘤组织样品进行代谢组学分析。结果共有62种差异代谢物,其中13种在血浆和组织样品中均有出现,结合课题组之前基于LC/MS的CTCL荷瘤鼠血浆和肿瘤组织的代谢组学的研究结果,有9种差异代谢物在GC/MS和LC/MS分析方法中同时出现。血浆中支链氨基酸和葡萄糖升高,血浆和肿瘤组织中3-磷酸甘油升高,血浆中鞘氨醇-1-磷酸盐降解的o-磷酸乙醇胺升高。结论62种差异代谢物可以提高对CTCL代谢物及其相关通路的认识,有助于CTCL的临床诊断。

Clinicopathology, immunophenotype, T cell receptor gene rearrangement, Epstein-Barr virus status andp53 gene mutation of cutaneous extranodal NK/T-cell lymphoma, nasal-type

Background Extranodal natural killer/T-cell （NK/T cell） lymphoma, nasal-type, is a rare lymphoma. Skin is the second most common site of involvement after the nasal cavity/nasalpharynx. The aim of this study was to investigate the clinicopathologic features, immunophenotype, T cell receptor （TCR） gene rearrangement, the association with Epstein-Barr virus （EBV） infection and p53 gene mutations of the lymphoma. Methods The clinicopathologic analysis, immunohistochemistry, in situ hybridization for EBERI/2, TCR gene rearrangement by polymerase chain reaction （PCR）, mutations of p53 gene analyzed by PCR and sequence analysis were employed in this study. Results In the 19 cases, the tumor primarily involved the dermis and subcutaneous layer. Immunohistochemical staining showed that most of the cases expressed CD45RO, CD56, CD3E, TIA-1 and GrB. Three cases were positive for CD3 and two cases were positive for CD30. Monoclonal TCRy gene rearrangement was found in 7 of 18 cases. The positive rate of EBERI/2 was 100%. No p53 gene mutation was detected on the exon 4-9 in the 18 cases. Fifteen cases showed Pro （proline）/Arg （arginine） single nucleotide polymorphisms （SNPs） on the exon 4 at codon 72. The expression of p53 protein was 72% （13/18）immunohistochemically. Conclusions Cutaneous NK/T-cell lymphoma is a rare but highly aggressive lymphoma with poor prognosis. No p53 gene mutation was detected on the exon 4-9, and Pro/Arg SNPs on p53 codon 72 were detected in the cutaneous NK/T-cell lymphoma. The overexpression of p53 protein may not be the result of p53 gene mutation.

Sezary syndrome： a rare form of cutaneous T-cell lymphoma

Sezary syndrome （SS） is an erythrodermic, aggressive, cutaneous T-cell lymphoma （CTCL） characterized by a malignant T-cell clone that localizes in the blood and skin, and its diagnosis is based on clinical, histological and biological features. Here we describe a typical case of SS.

肉芽肿性皮肤松弛症4例分析

目的分析肉芽肿性皮肤松弛症(GSS)的临床病理特点、诊断和治疗,提高对本病的认识。方法回顾性分析近5年北京协和医院诊治的4例GSS患者的临床和实验室检查资料。结果 4例患者平均发病年龄25.5岁,早期临床表现不特异,最后均出现GSS典型的皮损及组织病理表现;患者有不同程度外周血嗜酸性粒细胞(EOS)计数、血清β2微球蛋白(β2-MG)和血清血管紧张素转换酶(ACE)水平升高,血清白蛋白(Alb)水平降低;3例皮损TCR基因重排阳性,1例阴性;予多种方法治疗后取得一定疗效。结论 GSS的诊断应结合临床特点、组织病理学、免疫组化、弹力纤维染色和基因重排检测。本病治疗困难,其标准治疗方案还需进一步研究。

伴面部严重肿胀的种痘样水疱病样皮肤T细胞淋巴瘤1例

报告1例伴面部严重肿胀的种痘样水疱病样皮肤T细胞淋巴瘤。患者男,23岁,面、颈、上胸部、双手背出现丘疹、丘疱疹、坏死、结痂、痘疮样瘢痕形成伴面部肿胀6年,加重4年。皮损组织病理及免疫组化检查符合种痘样水疱病样T细胞淋巴瘤。

对T细胞受体克隆型肽类的免疫应答(英文)

目的：皮肤Ｔ细胞淋巴瘤（ＣＴＣＬ）是记忆性诱导Ｔ细胞肿瘤，表达独特的Ｔ细胞受体（ＴＣＲ）的α和β链，两者各含有克隆性独特蛋白序列。这些序列由独特型或第３决定簇互补区（ＣＤＲ３）组成。理论上，来源于ＴＣＲＣＤＲ３的肽类可作为由主要组织相容性复合体（ＭＨＣ）Ⅰ类分子提呈的肿瘤特异抗原。本研究旨在确定细胞毒性Ｔ淋巴细胞（ＣＴＬ）是否识别ＣＤＲ３来源的肽类。方法：首先培育出能裂解２例ＣＴＣＬ病人自身的肿瘤细胞的ＣＴＬ（ＣＤ８＋）细胞株，然后检测这些ＣＴＬ对由原始Ｂ淋巴细胞提呈的源于自身恶性细胞ＴＣＲＣＤＲ３序列的合成肽产生应答的能力。结果：ＣＴＬ分泌肿瘤坏死因子（ＴＮＦα），对自身ＴＣＲβ链独特型肽产生应答，但对来源于其他ＴＣＲβ链独特型区的肽或对照肽不产生应答。抗ＭＨＣⅠ类分子的单克隆抗体（Ｗ６／３２）能阻断其肽的识别。结论：首先表明ＣＴＬ可识别具有ＣＴＣＬ病人个体独特性的恶性淋巴细胞克隆的特异ＭＨＣⅠ类分子相关肽并对其产生应答；又提示起刺激作用的肽来源于ＴＣＲβ链独特型区。该研究建立了这种机制，其他Ｔ细胞可通过此机制调解既定的抗原特异性Ｔ细胞。ＣＴＣＬ的肿瘤特异性表位的鉴定，可能有助开发强化或启动ＣＤ８介导的?

基于大数据库寻找皮肤T细胞淋巴瘤潜在治疗药物

目的:通过基于大数据库的生物信息学分析,寻找皮肤T细胞淋巴瘤(CTCL)治疗新方法。方法:通过重新质控并整合分析CTCL细胞经罗米地辛处理前、后的基因表达谱(GSE110248),筛选差异表达基因,通过DAVID数据库进行GO分析和KEGG信号通路富集;将差异基因导入Connectivity Map(CMap)数据库获得可对差异基因产生作用的药物分子,结合SubpathwayMiner软件包对CMap数据库中药物分子作用数据进行通路分析的结果筛选药物分子作用通路;利用STRING和Cytoscape 3.5.1构建蛋白-蛋白对接通路网络和药物-蛋白对接通路网络;利用Sybyl X-2.1.1进行分子对接验证候选药物与核心差异基因相互作用关系。结果:对GSE110248整合分析共获得630个差异表达基因,通过对差异基因富集后得到的12个CTCL相关KEGG通路和33个CMap数据库药物分子作用通路取交集,得到2条重叠通路和CMap数据库中14种作用于这2条通路的药物;通过绘制2个重叠通路中差异基因表达蛋白分子的PPI网络,确定WNT3为核心基因;最后,通过分子对接验证结果,筛选出茴香霉素、伊立替康、舒洛地尔、米安色林、罗格列酮、甲氟喹和屈氟尿苷为CTCL最具潜力的候选治疗药物。结论:生物信息学分析揭示CTCL药物治疗的分子机制,并为CTCL的抗肿瘤治疗提供新的思路。

A case of advanced mycosis fungoides with comprehensive skin and visceral organs metastasis:sensitive to chemical and biological therapy

Mycosis fungoides is a common cutaneous T-cell lymphoma,which is usually characterized by chronic,indolence progression,with absence of typical symptoms in early stage,metastasis to lymph nodes,bone marrow and visceral organs in later stage and ultimately progression to systemic lymphoma.It can result in secondary skin infection which is a frequent cause of death. At present,no curative therapy existed.Therapeutic purpose is to induce remission,reduce tumor burden and protect immune function of patients.A case of patient with advanced severe mycosis fungoides receiving CHOP plus interferon a -2a was reported here,with disease-free survival of 7 months and overall survival of over 17.0 months,and current status as well as developments of mycosis fungoides were briefly introduced.

Overview of genetic signaling pathway interactions within cutaneous malignancies

Melanoma and non-melanoma cutaneous malignancies are some of the leading causes of cancer-related death in the United States.Though melanoma is more known to have a high mortality rate,the total mortality per year is nearly equal for between melanoma and non-melanoma skin cancer.Moreover,the non-melanoma types of cutaneous malignancies have potential to become locally invasive and even metastasize with very little to no treatment options when advanced.The development of these malignancies involves various genetic pathways through the four hallmarks of cancer development:malignant cell growth,apoptosis evasion,the use of supporting stroma and vascularization,and modulating and promoting an inadequate immune response.The genetic signaling pathways of basal cell carcinoma,squamous cell carcinoma,verrucous carcinoma,basosquamous cell carcinoma,melanoma,and cutaneous T-cell lymphoma interact with each other through genetic predisposition as well as with environmental exposures.Furthermore,solar ultraviolet radiation and chronic inflammatory states are found to initiate the progression of many of these cutaneous malignancies.This paper includes validated models of genetic pathways,emerging pathways,and crosstalk between genetic pathways through the four hallmarks of cancer development.Moreover,unlike most reviews addressing oncogenetics of the well-recognized,as well as newly discovered,genetic pathway mutations,this review stresses that these pathways are not fixed but rather exist in dynamic,interrelated,interactive,complex,and adaptive flux states.

High Dose Rate (HDR) Brachytherapy for Mycosis Fungoides of the Wrist

Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma accounting for approximately half of all cutaneous T-cell lymphomas. Radiation therapy is an effective treatment for early stage MF and has been shown to result in long-term disease-free intervals, with even curative potential. Radiation is also effective as palliative treatment for the localized lesion resistant to the topic or other treatments. In the current study, we report using high dose rate (HDR) radiation treatment for a patient with resistant mycosis fungoides involving the wrist. We report a convenient treatment with an ideal radiation dose distribution, and a excellent clinical outcome.

组织蛋白去乙酰化酶抑制剂伏瑞斯特的药理与临床

伏瑞斯特是一种口服的组蛋白去乙酰化酶抑制剂,FDA批准其用于治疗其他药物治疗期间或以后仍持续、恶化或复发的皮肤T细胞淋巴瘤。现对伏瑞斯特的药理作用、药动学、药物相互作用、治疗和安全性进行综述。

皮肤T细胞淋巴瘤的免疫治疗进展

皮肤T细胞淋巴瘤(cutaneous T-cell lymphoma,CTCL)是一组异质性的T细胞来源的恶性肿瘤,以皮肤损害为初发和突出表现.近年来,其发生率和病死率呈上升趋势,严重威胁人类的健康.早期CTCL治疗效果一般较好,但对中晚期CTCL目前尚无有效的治疗方法.随着对抗肿瘤免疫机制的深入了解和CTCL生物学特性的深入研究,免疫治疗已逐渐成为CTCL临床上重要而有效的辅助治疗手段.

伏立诺他临床应用新进展

伏立诺他作为一种组蛋白去乙酰化酶抑制剂,已在2006年被美国FDA批准用于皮肤T细胞淋巴瘤(CTCL)的治疗,近年来随着研究的不断深入,伏立诺他在其他肿瘤治疗领域也有了较好的疗效,伏立诺他联合吉妥单抗及阿扎胞苷治疗老年复发性或难治性急性髓系细胞白血病(AML)有效率可达40%,联合地西他滨治疗复发性或难治性急性淋巴细胞白血病(AL)有效率为46.2%,联合硼替佐米治疗多发性骨髓瘤(MM)无疾病进展生存期为7.63个月,另外在晚期乳腺癌和骨髓移植患者免疫功能改善方面都有较好的作用。本文通过对伏立诺他近期国外的临床应用进行了文献检索,并将其应用新进展进行综述。