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1.
Int J Mol Sci ; 22(1)2020 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-33375664

RESUMO

Hypericum is a widely present plant, and extracts of its leaves, flowers, and aerial elements have been employed for many years as therapeutic cures for depression, skin wounds, and respiratory and inflammatory disorders. Hypericum also displays an ample variety of other biological actions, such as hypotensive, analgesic, anti-infective, anti-oxidant, and spasmolytic abilities. However, recent investigations highlighted that this species could be advantageous for the cure of other pathological situations, such as trigeminal neuralgia, as well as in the treatment of cancer. This review focuses on the in vitro and in vivo antitumor effects of St. John's Wort (Hypericum perforatum), its derivatives, and other Hypericum species in hematologic malignancies. Hypericum induces apoptosis in both myeloid and lymphoid cells. Other Hypericum targets include matrix metalloproteinase-2, vascular endothelial growth factor, and matrix metalloproteinase-9, which are mediators of cell migration and angiogenesis. Hypericum also downregulates the expression of proteins that are involved in the resistance of leukemia cells to chemotherapeutic agents. Finally, Hypericum and its derivatives appear to have photodynamic effects and are candidates for applications in tumor photodynamic therapy. Although the in vitro studies appear promising, controlled in vivo studies are necessary before we can hypothesize the introduction of Hypericum and its derivatives into clinical practice for the treatment of hematologic malignancies.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Hypericum/química , Extratos Vegetais/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/patologia , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Células Mieloides/patologia , Extratos Vegetais/química , Relação Estrutura-Atividade
4.
Leukemia ; 34(11): 2875-2886, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32624581

RESUMO

The transport of proteins across the nuclear membrane is a highly regulated process, essential for the cell function. This transport is actively mediated by members of the karyopherin family, termed importins, or exportins, depending on the direction of transport. These proteins play an active part in tumorigenesis, through aberrant localization of their cargoes, which include oncogenes, tumor-suppressor genes and mediators of key signal transduction pathways. Overexpression of importins and exportins is reported in many malignancies, with implications in cell growth and viability, differentiation, drug resistance, and tumor microenvironment. Given their broad significance across tumors and pathways, much effort is being put to develop specific inhibitors as a novel anticancer therapeutics. Already, selinexor, a specific inhibitor of exportin-1 (XPO1), is approved for clinical use. This review will focus on the role of importins and exportins in hematological malignancies. We will discuss current preclinical and clinical data on importins and exportins, and demonstrate how our growing understanding of their functions has identified new therapeutic targets.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/metabolismo , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Humanos , Carioferinas/antagonistas & inibidores , Carioferinas/metabolismo
5.
Environ Health ; 19(1): 53, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32430062

RESUMO

BACKGROUND: The petrochemical industry is a major source of hazardous and toxic air pollutants that are recognised to have mutagenic and carcinogenic properties. A wealth of occupational epidemiology literature exists around the petrochemical industry, with adverse haematological effects identified in employees exposed to 'low' concentrations of aromatic hydrocarbons (benzene, toluene, ethylbenzene, and xylene). Releases from the petrochemical industry are also thought to increase the risk of cancer incidence in fenceline communities. However, this emerging and at times inconclusive evidence base remains fragmented. The present study's aim was to conduct a systematic review and meta-analysis of epidemiological studies investigating the association between incidences of haematological malignancy and residential exposure to the petrochemical industry. METHODS: Epidemiological studies reporting the risk of haematological malignancies (Leukaemia, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, and Multiple myeloma) were included where the following criteria were met: (i) Cancer incidence is diagnosed by a medical professional and coded in accordance to the International Classification of Diseases; (ii) A clear definition of fenceline communities is provided, indicating the proximity between exposed residents and petrochemical activities; and (iii) Exposure is representative of normal operating conditions, not emergency events. Two investigators independently extracted information on study characteristics and outcomes in accordance with PRISMA and MOOSE guidelines. Relative risks and their 95% confidence intervals were pooled across studies for the four categories of haematological malignancy, using a random effects meta-analysis. RESULTS: The systematic review identified 16 unique studies, which collectively record the incidence of haematological malignancies across 187,585 residents living close to a petrochemical operation. Residents from fenceline communities, less than 5 km from a petrochemical facility (refinery or manufacturer of commercial chemicals), had a 30% higher risk of developing Leukaemia than residents from communities with no petrochemical activity. Meanwhile, the association between exposure and rarer forms of haematological malignancy remains uncertain, with further research required. CONCLUSIONS: The risk of developing Leukaemia appears higher in individuals living near a petrochemical facility. This highlights the need for further policy to regulate the release of carcinogens by industry.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Exposição Ambiental/efeitos adversos , Neoplasias Hematológicas/epidemiologia , Indústria de Petróleo e Gás , Características de Residência/estatística & dados numéricos , Feminino , Neoplasias Hematológicas/etiologia , Humanos , Incidência , Masculino
6.
Ann Hematol ; 99(7): 1543-1550, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32430702

RESUMO

The major sources of the data on the hematological malignancies in the post-Chernobyl period in the regions of Ukraine differing by the levels of the residual contamination with radionuclides have been analyzed. According to the data collected from the primary hematological facilities in Ukraine in 2010-2017, the incidence of lymphoid neoplasms from mature B cells, acute myeloid leukemia, and multiple myeloma in the most contaminated regions was higher than in the less contaminated ones. For the first time, the relative contribution of the several specific types of leukemia in the total diagnosed hematological malignancies has been analyzed throughout 1997-2017 based on the in-house database compiled by the Reference Laboratory of RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, the National Academy of Sciences of Ukraine. In 2011-2017, the Reference Laboratory provided the diagnostic studies in about 26% of all Ukrainian patients with tumors of hematopoietic and lymphoid tissues (34% of patients with different forms of acute and chronic leukemia). The increased proportion of acute myeloid leukemia and chronic lymphocytic leukemia in the total diagnosed cases of overall leukemia in the patients from contaminated regions has been demonstrated following Chernobyl accident.


Assuntos
Acidente Nuclear de Chernobyl , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/etiologia , Neoplasias Induzidas por Radiação/epidemiologia , Bases de Dados Factuais , Feminino , História do Século XX , História do Século XXI , Humanos , Incidência , Leucemia/epidemiologia , Leucemia/etiologia , Linfoma/epidemiologia , Linfoma/etiologia , Masculino , Dados Preliminares , Cinza Radioativa/efeitos adversos , Cinza Radioativa/estatística & dados numéricos , Sistema de Registros , Ucrânia/epidemiologia
7.
Leukemia ; 34(11): 3028-3041, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32366935

RESUMO

Cyclooxygenase (COX)-dependent production of prostaglandins (PGs) is known to play important roles in tumorigenesis. PGD2 has recently emerged as a key regulator of tumor- and inflammation-associated functions. Here we show that mesenchymal stromal cells (MSCs) from patients with acute myeloid leukemia (AML) or normal MSCs overexpressing COX2 promote proliferation of co-cultured hematopoietic stem and progenitor cells (HSPCs), which can be prevented by treatment with COX2 knockdown or TM30089, a specific antagonist of the PGD2 receptor CRTH2. Mechanistically, we demonstrate that PGD2-CRTH2 signaling acts directly on type 2 innate lymphoid cells (ILC2s), potentiating their expansion and driving them to produce Interleukin-5 (IL-5) and IL-13. Furthermore, IL-5 but not IL-13 expands CD4+CD25+IL5Rα+ T regulatory cells (Tregs) and promotes HSPC proliferation. Disruption of the PGD2-activated ILC2-Treg axis by specifically blocking the PGD2 receptor CRTH2 or IL-5 impedes proliferation of normal and malignant HSPCs. Conversely, co-transfer of CD4+CD25+IL5Rα+ Tregs promotes malignant HSPC proliferation and accelerates leukemia development in xenotransplanted mice. Collectively, these results indicate that the mesenchymal source of PGD2 promotes proliferation of normal and malignant HSPCs through activation of the ILC2-Treg axis. These findings also suggest that this novel PGD2-activated ILC2-Treg axis may be a valuable therapeutic target for cancer and inflammation-associated diseases.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Imunidade Inata , Linfócitos/imunologia , Linfócitos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Prostaglandina D2/metabolismo , Biomarcadores , Células Cultivadas , Técnicas de Cocultura , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Interleucina-5/metabolismo , Ativação Linfocitária , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Neoplásicas/patologia , Receptores Imunológicos/genética , Receptores de Prostaglandina/genética , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
10.
Cancer Immunol Immunother ; 69(2): 315-324, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31915854

RESUMO

There is mounting evidence that the immune system can spontaneously clear malignant lesions before they manifest as overt cancer, albeit this activity has been difficult to demonstrate in humans. The calreticulin (CALR) exon 9 mutations are driver mutations in patients with chronic myeloproliferative neoplasms (MPN), which are chronic blood cancers. The CALR mutations generate a neo-antigen that is recognized by patient T cells, and T cells isolated from a patient with a CALR-mutation can recognize and kill autologous CALR-mutant cells. Surprisingly, healthy individuals display frequent and strong T cell responses to the CALR neo-antigens too. Furthermore, healthy individuals display immune responses to all parts of the mutant CALR epitope, and the CALR neo-epitope specific responses are memory T cell responses. These data suggest that although healthy individuals might acquire a CALR mutation, the mutant cells can be eliminated by the immune system. Additionally, a small fraction of healthy individuals harbor a CALR exon 9 mutation. Four healthy individuals carrying CALR mutations underwent a full medical examination including a bone marrow biopsy after a median follow up of 6.2 years. None of these patients displayed any signs of CALR-mutant MPN. Additionally, all healthy individuals displayed strong CALR neo-epitope specific T cell responses suggesting that these healthy individuals retained their CALR-mutant cells in the editing stage for several years. Thus, we suggest that CALR-mutant MPN could be a disease model of cancer immuno-editing, as we have demonstrated that CALR-mutant MPN displays all three stages described in the theory of cancer immuno-editing.


Assuntos
Suscetibilidade a Doenças , Neoplasias Hematológicas/etiologia , Imunomodulação , Evasão Tumoral , Animais , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais , Calreticulina/genética , Calreticulina/metabolismo , Transformação Celular Neoplásica , Modelos Animais de Doenças , Epitopos/imunologia , Neoplasias Hematológicas/metabolismo , Humanos , Imunomodulação/genética , Mutação , Evasão Tumoral/genética
11.
Lupus ; 29(3): 225-235, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31933408

RESUMO

Chronic inflammation has profound tumor-promoting effects. Inflammatory cells are the key players in immunosurveillance against tumors, and immunosuppression is known to increase the risk of tumors. Autoimmune diseases, which manifest as loss of self-tolerance and chronic immune dysregulation, provide a perfect environment for tumor development. Aside from managing the direct inflammatory consequences of autoimmune pathogenesis, cancer risk profiles should be considered as a part of a patient's treatment. In this review, we describe the various associations of malignancies with autoimmune diseases, specifically systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and Sjögren's syndrome, as well as discuss the mechanisms contributing to the pathogenesis of both disorders.


Assuntos
Doenças do Tecido Conjuntivo/complicações , Neoplasias Hematológicas/etiologia , Doenças Autoimunes/complicações , Doenças do Tecido Conjuntivo/fisiopatologia , Neoplasias Hematológicas/fisiopatologia , Humanos , Inflamação/complicações , Inflamação/fisiopatologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/fisiopatologia , Doenças Reumáticas/complicações , Doenças Reumáticas/fisiopatologia , Fatores de Risco , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/fisiopatologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/fisiopatologia
12.
Med. oral patol. oral cir. bucal (Internet) ; 25(1): e21-e28, ene. 2020. graf, tab
Artigo em Inglês | IBECS | ID: ibc-196192

RESUMO

BACKGROUND: Numerous studies have explored the correlation of periodontal disease (PD) with risk of hematopoi-etic and lymphatic cancers, but the findings were inconsistent. Therefore, we did a meta-analysis to ascertain the correlation of PD with risk of incident hematopoietic and lymphatic cancers. MATERIAL AND METHODS: The authors searched relevant studies in databases (PubMed, Web of Science, and MED-LINE). The summary relative risk (RR) along with 95% confidence interval (CI) was calculated by use of random or fixed effects models. RESULTS: Six studies were included in qualitative synthesis. The pooled analysis revealed that PD was significantly associated with an increased risk of hematopoietic and lymphatic cancers (RR = 1.17; 95% CI = 1.07-1.27; P = 0). Stratified analysis showed the association of PD with hematopoietic and lymphatic cancers remained significant in the never smokers (RR = 1.28; 95% CI = 1.07-1.54; P = 0.007), and in the American population (RR = 1.17; 95% CI = 1.05-1.30; P = 0.003), respectively. CONCLUSION: Never smokers population and the American population with PD have a higher risk of developing hematopoietic and lymphatic cancers. PD might be considered as a risk factor for hematopoietic and lymphatic cancers


No disponible


Assuntos
Humanos , Masculino , Feminino , Periodontite/complicações , Linfoma/etiologia , Neoplasias Hematológicas/etiologia , Fatores de Risco , Fumar/efeitos adversos , Medição de Risco
13.
Turk J Haematol ; 37(1): 48-52, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31752482

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare malignancy with skin tropism. The entity was recently defined and the diagnosis is generally made by skin biopsies. It is necessary to apply appropriate immunohistochemistry to recognize this rare entity. There is no consensus on therapy and the survival rates are low. The aim of this study is to describe the clinical and histopathological features of BPDCN. We retrospectively reviewed 8 BPDCN cases of the Cerrahpasa Medical Faculty diagnosed between 2005 and 2019. We documented the clinical findings, histopathologic diagnoses, and outcomes. The mean age of the patients was 58.7 years (range=11-86 years), and 7 patients were male. The patients presented with erythematous or purple papules, plaques, and papulonodular or nodular cutaneous lesions. Two had lymphadenomegaly at presentation. In microscopic evaluations, tumor cells infiltrated the entire dermis with a clear-cut subepidermal Grenz zone in all cases. CD4, CD56, and CD123 were the most frequently expressed immunohistochemical markers. The median follow-up of 7 cases was 14 months, ranging from 6 to 48 months. Three patients died of the disease, while 4 patients were still alive. Out of 7 patients, 5 received chemotherapy. We found that the outcomes of some patients were different from others but we did not link any distinct clinical or histopathological characteristics to these different outcomes.


Assuntos
Células Dendríticas/patologia , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Biópsia , Criança , Células Dendríticas/metabolismo , Feminino , Seguimentos , Neoplasias Hematológicas/etiologia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/diagnóstico , Adulto Jovem
14.
J Natl Cancer Inst ; 112(1): 107-110, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504684

RESUMO

Chemotherapy and radiation therapy are the foundations of adjuvant therapy for early-stage breast cancer. As a complication of cytotoxic regimens, breast cancer patients are at risk for therapy-related myeloid neoplasms (t-MNs). These t-MNs are commonly refractory to antileukemic therapies and result in poor patient outcomes. We previously demonstrated that somatic mutations in leukemia-related genes are present in the tumor-infiltrating leukocytes (TILeuks) of a subset of early breast cancers. Here, we performed genomic analysis of microdissected breast cancer tumor cells and TILeuks from seven breast cancer patients who subsequently developed leukemia. In four patients, mutations present in the leukemia were detected in breast cancer TILeuks. This finding suggests that TILeuks in the primary breast cancer may harbor the ancestor of the future leukemogenic clone. Additional research is warranted to ascertain whether infiltrating mutant TILeuks could constitute a biomarker for the development of t-MN and to determine the functional consequences of mutant TILeuks.


Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Evolução Clonal , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/etiologia , Hematopoese , Leucócitos/patologia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/etiologia , Evolução Clonal/genética , Feminino , Hematopoese/genética , Humanos
15.
Blood Cancer J ; 9(12): 99, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31811114

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, male-predominant hematologic malignancy with poor outcomes and with just one recently approved agent (tagraxofusp). It is characterized by the abnormal proliferation of precursor plasmacytoid dendritic cells (pDCs) with morphologic and molecular similarities to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) in its presentation within the bone marrow and peripheral blood. To identify disease-specific molecular features of BPDCN, we profiled the bone marrow, peripheral blood, and serum samples from primary patient samples using an in-house hematologic malignancy panel ("T300" panel), transcriptome microarray, and serum multiplex immunoassays. TET2 mutations (5/8, 63%) were the most prevalent in our cohort. Using the transcriptome microarray, genes specific to pDCs (LAMP5, CCDC50) were more highly expressed in BPDCN than in AML specimens. Finally, the serum cytokine profile analysis showed significantly elevated levels of eosinophil chemoattractants eotaxin and RANTES in BPDCN as compared with AML. Along with the high levels of PTPRS and dendritic nature of the tumor cells, these findings suggest a possible pre-inflammatory context of this disease, in which BPDCN features nonactivated pDCs.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Suscetibilidade a Doenças/imunologia , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/etiologia , Fenótipo , Idoso , Idoso de 80 Anos ou mais , Alelos , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Análise Serial de Proteínas
16.
Curr Hematol Malig Rep ; 14(6): 515-522, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31853773

RESUMO

PURPOSE OF REVIEW: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive hematologic malignancy that has heterogeneous presentation and can involve the skin, lymph nodes, and bone marrow. Recent advancements in our patho-biologic understanding of the disease have led to the development of new targeted therapies for BPDCN. In this review, we aimed to describe some of the novel treatments that are being put forward for the management of BPDCN. RECENT FINDINGS: Tagraxofusp is the first CD123-targeted therapy approved as the first ever targeted treatment of BPDCN in patients aged 2 years and older. This agent was approved based on a pivotal clinical trial that showed that it was associated with high rates of clinical responses in both treatment-naïve and treatment-experienced patients. The most serious adverse event was occurrence of the capillary leak syndrome. Other targeted therapies are actively being investigated in clinical trials. These include other CD123-targeted approaches, as well as active investigation in targets beyond CD123, such as the BCL-2 inhibitor, venetoclax. BPDCN is a rare hematologic clonal disorder with historically poor outcomes. Newer targeted therapies have been recently introduced, with promising results and novel toxicities that are important to recognize and understand. Stem cell transplantation after achievement of complete remission remains the mainstay of therapy among younger/fit, eligible patients, regardless of treatment modality used.


Assuntos
Células Dendríticas/patologia , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Biomarcadores Tumorais , Tomada de Decisão Clínica , Evolução Clonal , Terapia Combinada , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/mortalidade , Humanos , Terapia de Alvo Molecular , Resultado do Tratamento
17.
Blood Adv ; 3(21): 3461-3472, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714965

RESUMO

Growing evidence suggests that human microbiota likely influence diverse processes including hematopoiesis, chemotherapy metabolism, and efficacy, as well as overall survival in patients with hematologic malignancies and other cancers. Both host genetic susceptibility and host-microbiota interactions may impact cancer risk and response to treatment; however, microbiota have the potential to be uniquely modifiable and accessible targets for treatment. Here, we focus on strategies to modify microbiota composition and function in patients with cancer. First, we evaluate the use of fecal microbiota transplant to restore microbial equilibrium following perturbation by antibiotics and chemotherapy, and as a treatment of complications of hematopoietic stem cell transplantation (HSCT), such as graft-versus-host disease and colonization with multidrug-resistant organisms. We then address the potential use of both probiotics and dietary prebiotic compounds in targeted modulation of the microbiota intended to improve outcomes in hematologic diseases. With each type of therapy, we highlight the role that abnormal, or dysbiotic, microbiota play in disease, treatment efficacy, and toxicity and evaluate their potential promise as emerging strategies for microbiota manipulation in patients with hematologic malignancies and in those undergoing HSCT.


Assuntos
Microbiota , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Tomada de Decisão Clínica , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças , Transplante de Microbiota Fecal , Feminino , Microbioma Gastrointestinal , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Infecções/diagnóstico , Infecções/etiologia , Infecções/terapia , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Probióticos/uso terapêutico , Pesquisa Médica Translacional , Transplante Homólogo
18.
Medicine (Baltimore) ; 98(44): e17735, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689818

RESUMO

BACKGROUND: Several studies have reported the association of Behcet disease (BD) with the risk of diverse kinds of cancers. However, its association is controversial. Therefore, we conducted a bioinformatics-analysis to explore any possible association. METHODS: We obtained relevant findings published before October 2018 through literature survey of the PubMed, EMBASE, and Web of Science databases. STATA 12.0 software was used for statistical analysis. RESULTS: After screening, the meta-analysis comprised 5 studies. We observed a significant positive association between BD and enhanced malignancy risk (pooled relative risk [RR], 1.19; 95% confidence interval [CI]: 1.09-1.30), especially for hematological cancer (pooled RR, 2.58; 95% CI: 1.61-3.55) and thyroid cancer (pooled RR, 1.25; 95% CI: 1.04-1.47). However, high heterogeneity was also observed in the results (I = 81.3%). Subgroup analysis indicated that female BD patients from Korean population are at highest predisposition to overall malignancy. Besides, publication bias was not observed with our choice of surveys. CONCLUSION: We conclude that patients suffering from BD have an overall increased risk for malignancy. Greater numbers of exhaustive temporal studies are essential for definitive inferences.


Assuntos
Síndrome de Behçet/complicações , Neoplasias Hematológicas/etiologia , Neoplasias/etiologia , Neoplasias da Glândula Tireoide/etiologia , Biologia Computacional , Feminino , Humanos , Masculino , Risco , Fatores de Risco
19.
Dis Model Mech ; 12(11)2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771951

RESUMO

The search for oncogenic mutations in haematological malignancies has largely focused on coding sequence variants. These variants have been critical in understanding these complex cancers in greater detail, ultimately leading to better disease monitoring, subtyping and prognostication. In contrast, the search for oncogenic variants in the noncoding genome has proven to be challenging given the vastness of the search space, the intrinsic difficulty in assessing the impact of variants that do not code for functional proteins, and our still primitive understanding of the function harboured by large parts of the noncoding genome. Recent studies have broken ground on this quest, identifying somatically acquired and recurrent mutations in the noncoding genome that activate the expression of proto-oncogenes. In this Review, we explore some of the best-characterised examples of noncoding mutations in haematological malignancies, and highlight how a significant majority of these variants impinge on gene regulation through the formation of aberrant enhancers and promoters. We delve into the challenges faced by those that embark on a search for noncoding driver mutations, and provide a framework distilled from studies that have successfully identified such variants to overcome some of the most salient hurdles. Finally, we discuss the current therapeutic strategies being explored to target the oncogenic mechanism supported by recurrent noncoding variants. We postulate that the continued discovery and functional characterisation of somatic variants in the noncoding genome will not only advance our understanding of haematological malignancies, but offer novel therapeutic avenues and provide important insights into transcriptional regulation on a broader scale.


Assuntos
Neoplasias Hematológicas/genética , Mutação , Regiões não Traduzidas/genética , Animais , Elementos Facilitadores Genéticos , Regulação Neoplásica da Expressão Gênica , Variação Genética , Neoplasias Hematológicas/etiologia , Humanos , Regiões Promotoras Genéticas , Processamento de RNA
20.
Curr Opin Hematol ; 26(6): 427-433, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31577606

RESUMO

PURPOSE OF REVIEW: Although chimeric antigen receptor T (CART)-cell therapy is best recognized for its antitumor effect in relapsed/refractory B-cell hematological cancers, it is still associated with a high relapse rate. RECENT FINDINGS: We firstly analyzed internal immunological and genetic reasons of CD19+ relapse after treatment for R/R B-cell hematological cancers with CART19 cells. The reasons: murine-derived scFv may limit expansion of CART cells. Repeated antigen exposure leads to T-cell exhaustion. Activation of T cells can cause T-cell senescence and high expression of inhibitive receptors, PD-1, CTLA4, TIGIT, LAG-3, CD244, CD160, TIM3, which might be solved by some external pharmacological intervention methods [for instance, the use of FC (Fludarabine, Cyclophosphamide) lymphodepletion regimen, lenalidomide, PD-1 inhibitor, ibrutinib and humanized CD19-CART cells. Secondly, mechanism of CD19 relapse can be attributed to the preexisting of CD19 subclone, the loss or alternative RNA splicing on exon 2 of chromosome 16 on which CD19 gene is located, B-cell transcript factors - paired-box 5 (PAX5) and early B-cell factor 1 (EBF1) are down-regulated to cause lineage-switch from lymphoid to myeloid. SUMMARY: Although different preparation techniques generates various entities of CART 19 cells, these problems could be conquered by novel agents and novel CAR system. VIDEO ABSTRACT: Although Chimeric Antigen Receptor T (CART) cell therapy is best recognized for its antitumor effect in Relapsed/Refractory B-cell hematological cancers, it still shows a high relapse rate. We review mechanisms of failure of CART therapy. http://links.lww.com/COH/A18.


Assuntos
Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Fatores de Confusão Epidemiológicos , Engenharia Genética , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/terapia , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Recidiva , Pesquisa , Fatores de Risco , Falha de Tratamento , Resultado do Tratamento
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