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2.
Exp Mol Pathol ; 113: 104364, 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31881200

RESUMO

Colorectal cancer (CRC) is the third most common carcinoma worldwide. Despite the progress in screening and treatment, CRC remains a leading cause of cancer-related mortality. Alterations to normal nucleic acid processing may drive neoplastic transformation of colorectal epithelium. DNA repair machinery performs an essential function in the protection of genome by reducing the number of genetic polymorphisms/variations that may drive carcinogenicity. Four essential DNA repair systems are known which include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strand break repair (DSBR). Polymorphisms of DNA repair genes have been shown to influence the risk of cancer development as well as outcomes of treatment. Several studies demonstrated the association between genetic polymorphism of DNA repair genes and increased risk of CRC in different populations. In this review, we have summarized the impact of DNA repair gene polymorphisms on risk of CRC development and treatment outcomes. Advancements of the current understanding for the impact of DNA repair gene polymorphisms on the risk and treatment of CRC may support diagnostic and predictive roles in patients with CRC.

3.
J Comput Aided Mol Des ; 33(9): 799-815, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31630312

RESUMO

The glyoxalase-I (GLO-I) enzyme, which is the initial enzyme of the glyoxalase system that is responsible for the detoxification of cytotoxic α-ketoaldehydes, such as methylglyoxal, has been approved as a valid target in cancer therapy. Overexpression of GLO-I has been observed in several types of carcinomas, including breast, colorectal, prostate, and bladder cancer. In this work we aimed to identify potential GLO-I inhibitors via employing different structure-based drug design techniques including structure-based poly-pharmacophore modelling, virtual screening, and molecular docking. Poly-pharmacophore modelling was applied in this study in order to thoroughly explore the binding site of the target enzyme, thereby, revealing hits that could bind in a nonconventional way which can pave the way for designing more potent and selective ligands with novel chemotypes. The modelling phase has resulted in the selection of 31 compounds that were biologically evaluated against human GLO-I enzyme. Among the tested set, seven compounds showed excellent inhibitory activities with IC50 values ranging from 0.34 to 30.57 µM. The most active compound (ST018515) showed an IC50 of 0.34 ± 0.03 µM, which, compared to reported GLO-I inhibitors, can be considered a potent inhibitor, making it a good candidate for further optimization towards designing more potent GLO-I inhibitors.

4.
Int J Nanomedicine ; 14: 7643-7663, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571869

RESUMO

Angiogenesis is the formation of new blood vessels from pre-existing vessels. It is a highly regulated process as determined by the interplay between pro-angiogenic and anti-angiogenic factors. Under certain conditions the balance between angiogenesis stimulators and inhibitors is altered, which results in a shift from physiological to pathological angiogenesis. Therefore, the goal of therapeutic targeting of angiogenic process is to normalize vasculature in target tissues by enhancing angiogenesis in disease conditions of reduced vascularity and blood flow, such as tissue ischemia, or alternatively to inhibit excessive and abnormal angiogenesis in disorders like cancer. Gold nanoparticles (AuNPs) are special particles that are generated by nanotechnology and composed of an inorganic core containing gold which is encircled by an organic monolayer. The ability of AuNPs to alter vasculature has captured recent attention in medical literature as potential therapeutic agents for the management of pathologic angiogenesis. This review provides an overview of the effects of AuNPs on angiogenesis and the molecular mechanisms and biomedical applications associated with their effects. In addition, the main synthesis methods, physical properties, uptake mechanisms, and toxicity of AuNPs are briefly summarized.


Assuntos
Tecnologia Biomédica/métodos , Ouro/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Endocitose , Ouro/toxicidade , Humanos , Nanopartículas Metálicas/toxicidade
5.
Brain Sci ; 9(8)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366021

RESUMO

Management of sickle cell pain in adolescent and pediatric patients is inadequate, and the employment of proper management guidelines and practices are highly variable among different regions and populations. APPT, the multidimensional adolescent pediatric pain tool, promotes optimal pain management and introduces best practical guidelines for pain management. The goal of this study is to assess pain and pain management among young patients diagnosed with sickle cell disease (SCD) by introducing the APPT as a tool for pain management, and analyze factors contributing to pain management. Information relevant to demographic data, SCD characteristics, APPT assessment, and satisfaction of patients regarding pain management were collected using a structured questionnaire. Results showed that SCD is highly associated with gender (p = 0.022), consanguinity (p = 0.012), and number of surgeries (p = 0.013). Most patients (58.9%) indicated the involvement of more than six body areas affected during pain crisis. Severe pain was described by more than half the patients (55.6%), while moderate pain was reported by 31.1%. Most patients described their pain by sensory, affective, and temporal words. The number of painful areas, pain intensity, and use of descriptive pain words was correlated and interpreted by age, BMI, school absence, and number of surgeries. Results of this study could provide guidance to healthcare providers to improve current practices for SCD pain management in order to improve health outcomes and patients' satisfaction.

6.
J Empir Res Hum Res Ethics ; 14(4): 372-382, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31169072

RESUMO

Human research at Jordanian universities is increasing. This descriptive cross-sectional survey assessed knowledge, attitudes, and practices concerning the procedures and review process of research ethics committees (RECs) among faculty in health sciences in two major Jordanian universities. Most faculty reported having no training in research ethics in their current institutions. Although knowledge of RECs' roles and functions was adequate, deficiencies were found regarding the advisory and monitoring roles for RECs raised in this survey. Faculty expressed concerns about levels of ethical training for members of RECs and potential conflicts of interest and bias in review process. RECs should provide ethics training for faculty, and future research should examine the functioning of the RECs in Jordan and other Middle Eastern countries.

7.
Cancers (Basel) ; 11(5)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072015

RESUMO

Breast cancer (BC) recurrence represents a challenge for survivors who have had their primary tumors surgically excised, and/or have completed radiation, neoadjuvant, or adjuvant therapeutic regimens. Current BC treatments mostly lack the ability to reduce the risk of disease recurrence. About 70% of BC patients will subsequently suffer disease relapse, manifesting as local, regional, or distant tumor recurrence, which clearly underscores the urgent need to discover novel recurrence inhibitors. (-)-Oleocanthal (OC) is a natural phenolic, found so far exclusively in extra-virgin olive oil (EVOO). OC exerts documented bioactivities against diverse cancer types, inflammation, and neurodegenerative diseases. Herein we report the novel activity of daily oral treatment with OC (10 mg/kg) in preventing BC locoregional recurrence in a nude mouse xenograft model generated by orthotopic inoculation with BT-474 cells as a luminal type B model. We further report inhibition of tumor recurrence by OC after completion of a lapatinib neoadjuvant regimen. However, in a recurrence model of triple-negative breast cancer (TNBC), OC treatment (10 mg/kg) did not effectively prevent tumor recurrence, but rather, was seen to significantly reduce the growth of recurrent tumors as compared to vehicle control-treated animals. Inhibition of tumor recurrence was associated with significant serum level reductions of the human BC recurrence marker CA 15-3 at the study end in animals treated with OC. OC treatment upregulated the expression of the epithelial marker E-cadherin and downregulated the levels of the mesenchymal marker vimentin in recurrent tumors vs. untreated control animals. OC treatment also reduced the activation of MET and HER2 receptors, as indicated by reduced phosphorylation levels of these proteins in recurrent tumors vs. controls. Collectively, the results of our studies provide the first evidence for suppression of BC tumor recurrence by oral OC treatment in an animal model for such recurrence, and furthermore, highlight favorable prospects for this natural product to emerge as a first-in-class BC recurrence inhibitor.

8.
J Obes ; 2019: 3820759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019808

RESUMO

Purpose: To investigate the association between obesity and breast cancer clinicopathologic characteristics at presentation along with prognostic impact among Jordanian breast cancer patients. Such data are lacking in Arabian countries. Methods: In this retrospective study, 348 breast cancer patients were included. Analyses were conducted for associations between body mass index (BMI) and age at diagnosis, tumor clinicopathologic characteristics, and molecular subtypes. Eight prognostic factors were considered, and total prognostic scores were calculated. The analysis was stratified by menopausal status. Multivariate logistic stepwise regression analysis was conducted to identify predictors for breast cancer recurrence and death. Results: Mean age at diagnosis was 50.98 ± 10.96 years. Mean BMI at diagnosis was 29.52 ± 5.32 kg/m2. Mean age at diagnosis was significantly higher for overweight and obese patients compared to underweight/normal patients (P < 0.001). A significant positive correlation was observed between patient age and BMI at diagnosis (r = 0.251, P < 0.001). Grade of carcinoma was significantly correlated with BMI in the whole population examined (P=0.003). Obese breast cancer patients had significantly higher prognostic scores compared to nonobese cases, indicating worse prognostic features at presentation (P=0.034). Stratification of data analysis based on menopausal status revealed significant associations between obesity and each of tumor stage and grade among postmenopausal but not premenopausal patients (P=0.019 and P=0.031, respectively). Similarly, postmenopausal obese patients had significantly higher prognostic scores compared to nonobese counterparts (P=0.007), indicating worse prognosis, a finding which was also absent among premenopausal breast cancer patients. No significant association between BMI with expression status of hormone receptors, HER2, lymphovascular invasion, and molecular subtypes was found among patients. BMI was a significant predictor for disease recurrence in which obese breast cancer patients had greater odds (2-fold) to develop locoregional and distant recurrence compared to nonobese cases (P=0.011). Conclusions: Obesity was associated with advanced stage and grade of breast carcinoma at diagnosis. The impact of BMI on clinicopathologic characteristics and prognosis was confined to postmenopausal cases. Jordanian obese breast cancer patients are at greater risk of breast cancer recurrence and reduced survival compared to their nonobese counterparts.

9.
Asian Pac J Cancer Prev ; 20(3): 929-934, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30912417

RESUMO

Objectives: There is no consensus regarding the surgical or immunosuppressive treatment of idiopathic granulomatous mastitis (IGM). This study aimed to introduce a clinical classification system for IGM that might facilitate its treatment and predict recurrence. Methods: We analyzed the management of 68 patients with IGM at (Princess Basma Teaching Hospital and King Abdulla University Hospital (1994-2016) to find out if distinct patterns of presentation exist according to the following parameters: presence of a painful or painless breast mass, local inflammation, abscess formation, communication to the skin, and extra-mammary manifestation. Results: We identified four distinct patterns of IGM: A: (13.23 %) A hard, painless breast mass. B: (52.94 %) A hard, painful breast mass with gross inflammation. C: (26.47 %) A breast abscess-like presentation. D: (7. 35 %) A subacute presentation with ulceration, sinus, or fistula formation. Erythema nodosum might complicate any of these patterns. Wide local excision in pattern A was curative with zero recurrence rate. The recurrence rates in patterns B and C were 22.20 % and 50.00 %. Patterns B, C, and D were treated by a combination of surgery and prednisolone. In keeping with this, recent literature is in favor of a wider use of immunosuppression especially in the presence of pus and extra-mammary findings. Conclusion: IGM could be classified into 4 distinct patterns according to the presenting signs and symptoms. These patterns correlated with treatment, recurrence rate, and the gross operative findings. This is the first step toward a classification for IGM. Multicenter and Meta-analysis studies are essential for a comprehensive prognostic classification. Treatment of IGM in any institution should be the responsibility of a multidisciplinary team.


Assuntos
Mastite Granulomatosa/classificação , Mastite Granulomatosa/patologia , Recidiva Local de Neoplasia/patologia , Adolescente , Adulto , Criança , Feminino , Seguimentos , Mastite Granulomatosa/cirurgia , Humanos , Mamografia , Mastectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Adulto Jovem
10.
Nutrients ; 11(2)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30781364

RESUMO

Dysregulation of epidermal growth factor receptor (EGFR)/human epidermal growth factor-2 (HER2) family is a hallmark of aggressive breast cancer. Small-molecule tyrosine kinase inhibitors are among the most effective cancer targeted treatments. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid lead from extra-virgin olive oil with documented anti-cancer activities via targeting mesenchymal epithelial transition factor (c-Met). Dysregulation of c-Met promotes aggressiveness to breast cancer-targeted therapies. Lapatinib (LP) is an FDA-approved dual EGFR/HER2 inhibitor for HER2-amplified breast cancer. HER2-Positive tumor cells can escape targeted therapies like LP effects by overexpressing c-Met. Combined OC-LP treatment is hypothesized to be mechanistically synergistic against HER2-overexpressing breast cancer. Combined sub-effective treatments of OC-LP resulted in synergistic anti-proliferative effects against the HER2-positive BT-474 and SK-BR-3 breast cancer cell lines, compared to OC or LP monotherapy. Antibody array and Western blot analysis showed that combined OC-LP treatment significantly inhibited EGFR, HER2, and c-Met receptor activation, as well as multiple downstream signaling proteins, compared to individual OC or LP treatment. OC-LP Combination significantly inhibited invasion and migration of breast cancer cells through reduced activation of focal adhesion kinase (FAK) and paxillin. Combined treatment of OC-10 mg/kg with LP-12.5 mg/kg suppressed more than 90% of BT-474 tumor cells growth in a nude mouse xenograft model, compared to individual OC or LP treatment. Activated c-Met, EGFR, HER2, and protein kinase B (AKT) were significantly suppressed in combination-treated mice tumors, compared to OC or LP monotherapy. This study reveals the OC future potential as combination therapy to sensitize HER2-overexpressing breast cancers and significantly reduce required doses of targeted HER family therapeutics.


Assuntos
Aldeídos/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Lapatinib/administração & dosagem , Fenóis/administração & dosagem , Receptor ErbB-2/efeitos dos fármacos , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Quimioterapia Combinada , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptores ErbB/efeitos dos fármacos , Feminino , Humanos , Camundongos , Receptor ErbB-2/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-30697064

RESUMO

Cancer immunotherapy has evolved dramatically with improved understanding of immune microenvironment and immunosurveillance. The immunogenicity of breast cancer is rather heterogeneous. Specific subtypes of breast cancer such as estrogen receptor (ER)-negative, human EGF receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC) have shown evidence of immunogenicity based on tumor-immune interactions. Several preclinical and clinical studies have explored the potential for immunotherapy to improve the clinical outcomes for different subtypes of breast cancer. This review describes the immune microenvironment of HER2-positive breast cancer and summarizes recent clinical advances of immunotherapeutic treatments in this breast cancer subtype. The review provides rationale and ongoing clinical evidence to the use of immune checkpoint inhibitors, therapeutic vaccines, and adoptive T cell immunotherapy in breast cancer. In addition, the present paper describes the most relevant clinical progress of strategies for the combination of immunotherapy with standard treatment modalities in HER2-positive breast cancer including chemotherapy, targeted therapy, and radiotherapy.

12.
Oncotarget ; 9(87): 35752-35761, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30515267

RESUMO

Colorectal cancer (CRC) is a public health problem worldwide and in Jordan. Statins are cholesterol lowering agents. Beyond their effects, statins use has been reported to reduced risk of several malignances, including CRC. This study aimed to assess the effect of statins on CRC by studying cellular infiltration of Regulatory T Lymphocytes (Tregs) into CRC tissues and their effect on Transforming growth factor beta 1 (TGF-ß1) level and on angiogenesis. Fourty seven specimens (25 statins users vs. 22 non-users) were used. Immunohistochemistry was performed to study Tregs infiltration using their marker, fork head transcription factor, and angiogenesis using CD31 as a marker. TGF-ß1 levels were measured using ELISA. Results revealed that statins use was associated with more Tregs infiltration, less angiogenesis but no difference in TGF-ß1 content in tumor tissue. When results were further stratified according to stage of disease, more Tregs infiltration was significantly noticed in advanced disease but not in early disease. In addition, more angiogenesis inhibition was noticed in early disease but not in advanced disease. Same stage-dependence wasn't noticed with TGF-ß1 expression. In early disease, reduction of angiogenesis mediated by statins might lead to reduction of tumor aggressiveness. On the other hand, Tregs infiltration into tumor mediated by statins might reduce cancer aggressiveness in advanced disease. These results suggest that statins might be used in the treatment of CRC.

13.
Mar Drugs ; 16(5)2018 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-29751615

RESUMO

Breast cancer (BC) is a heterogeneous disease with different molecular subtypes. The high conductance calcium-activated potassium channels (BK, Maxi-K channels) play an important role in the survival of some BC phenotypes, via membrane hyperpolarization and regulation of cell cycle. BK channels have been implicated in BC cell proliferation and invasion. Penitrems are indole diterpene alkaloids produced by various terrestrial and marine Penicillium species. Penitrem A (1) is a selective BK channel antagonist with reported antiproliferative and anti-invasive activities against multiple malignancies, including BC. This study reports the high expression of BK channel in different BC subtypes. In silico BK channel binding affinity correlates with the antiproliferative activities of selected penitrem analogs. 1 showed the best binding fitting at multiple BK channel crystal structures, targeting the calcium-sensing aspartic acid moieties at the calcium bowel and calcium binding sites. Further, 1 reduced the levels of BK channel expression and increased expression of TNF-α in different BC cell types. Penitrem A (1) induced G1 cell cycle arrest of BC cells, and induced upregulation of the arrest protein p27. Combination treatment of 1 with targeted anti-HER drugs resulted in synergistic antiproliferative activity, which was associated with reduced EGFR and HER2 receptor activation, as well as reduced active forms of AKT and STAT3. Collectively, the BK channel antagonists represented by penitrem A can be novel sensitizing, chemotherapeutics synergizing, and therapeutic agents for targeted BC therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Alta/antagonistas & inibidores , Micotoxinas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Sítios de Ligação , Cálcio/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Feminino , Fase G1/efeitos dos fármacos , Humanos , Alcaloides Indólicos/farmacologia
14.
Onco Targets Ther ; 10: 4869-4883, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29042798

RESUMO

MET is a receptor tyrosine kinase known for its pleiotropic effects in tumorigenesis. Dysregulations of MET expression and/or signaling have been reported and determined to be associated with inferior outcomes in breast cancer patients rendering MET a versatile candidate for targeted therapeutic intervention. Crizotinib is a multi-targeted small-molecule kinase inhibitor for MET, ALK, and ROS1 kinases. This study evaluated the anti-proliferative, cytotoxic, anti-migratory, and anti-invasive effects of crizotinib in breast cancer cells in vitro. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) colorimetric assay. In vitro wound-healing assay was used to examine the effect of crizotinib on breast cancer cell migration. The expressions of Ki-67, MET, and phospho-MET receptors were characterized using immunofluorescence staining. Results showed that crizotinib has significant anti-proliferative activity on all mammary tumor cells with IC50 values of 5.16, 1.5, and 3.85 µM in MDA-MB-231, MCF-7, and SK-BR-3 cells, respectively. Crizotinib induced cytotoxic effects in all breast cancer cells examined. Combined treatment of small dose of crizotinib with paclitaxel or doxorubicin exhibited a highly synergistic inhibition of growth of MDA-MB-231 and MCF-7 cells with combination index values <1 while no significant effect was observed in SK-BR-3 cells compared with individual compounds. Treatment with crizotinib demonstrated a remarkable reduction in the expression of Ki-67 protein in all 3 tested cell lines. Crizotinib inhibited migration and invasion of MDA-MB-231 cells in a dose-dependent fashion. Crizotinib reduced MET receptor activation in MDA-MB-231 cells when treated at effective concentrations. In conclusion, crizotinib suppressed proliferation, migration, and invasion of breast cancer cells in vitro. The results of this study demonstrated that combined treatment of crizotinib with chemotherapeutic agents resulted in a synergistic growth inhibition of specific breast cancer cell lines.

15.
Eur J Pharmacol ; 810: 100-111, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28625568

RESUMO

Luminal breast cancer represents a therapeutic challenge in terms of aggressive disease and emerging resistance to targeted therapy. (-)-Oleocanthal has demonstrated anticancer activity in multiple human cancers. The goal of this study was to explore the effect of (-)-oleocanthal treatment on growth of luminal breast cancer cells and to examine the effect of combination of (-)-oleocanthal with tamoxifen. Results showed that (-)-oleocanthal inhibited growth of BT-474, MCF-7, and T-47D human breast cancer cells in mitogen-free media with IC50 values of 32.7, 24.07, and 80.93µM, respectively. Similarly, (-)-oleocanthal suppressed growth of BT-474, MCF-7, and T-47D cells in 17ß-estradiol-supplemented media with IC50 values of 22.28, 20.77, and 83.91µM, respectively. Combined (-)-oleocanthal and tamoxifen treatments resulted in a synergistic growth inhibition of BT-474, MCF-7, and T-47D cells with combination index values of 0.65, 0.61, and 0.53 for each cell line, respectively. In-silico docking studies indicated high degree of overlapping for the binding of (-)-oleocanthal and 17ß-estradiol to estrogen receptors, while (-)-oleocanthal and tamoxifen have distinguished binding modes. Treatment with 5mg/kg or 10mg/kg (-)-oleocanthal resulted in 97% inhibition of tumor growth in orthotopic athymic mice bearing BT-474 tumor xenografts compared to vehicle-treated animals. (-)-Oleocanthal treatment reduced total levels of estrogen receptors in BT-474 cells both in vitro and in vivo. Collectively, (-)-oleocanthal showed a potential beneficial effect in suppressing growth of hormone-dependent breast cancer and improving sensitivity to tamoxifen treatment. These findings provide rational for evaluating the effect of (-)-oleocanthal in combination with endocrine treatments in luminal breast cancer.


Assuntos
Aldeídos/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Azeite de Oliva/química , Fenóis/farmacologia , Receptores Estrogênicos/metabolismo , Tamoxifeno/farmacologia , Aldeídos/metabolismo , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Simulação de Acoplamento Molecular , Fenóis/metabolismo , Conformação Proteica , Receptores Estrogênicos/química , Tamoxifeno/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Oncotarget ; 8(14): 24009-24030, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28177923

RESUMO

Cancer patients often experience weight loss caused by protein calorie malnutrition (PCM) during the course of the disease or treatment. PCM is expressed as severe if the patient has two or more of the following characteristics: obvious significant muscle wasting, loss of subcutaneous fat; nutritional intake of <50% of recommended intake for 2 weeks or more; bedridden or otherwise significantly reduced functional capacity; weight loss of >2% in 1 week, 5% in 1 month, or 7.5% in 3 months. Cancer anorexia-cachexia syndrome (CACS) is a multifactorial condition of advanced PCM associated with underlying illness (in this case cancer) and is characterized by loss of muscle with or without loss of fat mass. Cachexia is defined as weight loss of more than 5% of body weight in 12 months or less in the presence of chronic disease. Hence with a chronic illness on board even a small amount of weight loss can open the door to cachexia. These nutritional challenges can lead to severe morbidity and mortality in cancer patients. In the clinic, the application of personalized medicine and the ability to withstand the toxic effects of anti-cancer therapies can be optimized when the patient is in nutritional homeostasis and is free of anorexia and cachexia. Routine assessment of nutritional status and appropriate intervention are essential components of the effort to alleviate effects of malnutrition on quality of life and survival of patients.


Assuntos
Neoplasias/metabolismo , Neoplasias/terapia , Medicina de Precisão/métodos , Desnutrição Proteico-Calórica/terapia , Animais , Anorexia/etiologia , Anorexia/terapia , Caquexia/etiologia , Caquexia/terapia , Metabolismo Energético , Humanos , Estado Nutricional , Desnutrição Proteico-Calórica/etiologia
17.
Oncotarget ; 7(41): 67551-67573, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27563824

RESUMO

Hodgkin lymphoma (HL) is a lymphoid malignancy that is typically derived from germinal-center B cells. EBV infection, mutations in NF-κB pathway genes, and genetic susceptibility are known risk factors for developing HL. CD30 and NF-κB have been identified as potential biomarkers in pediatric HL patients, and these molecules may represent therapeutic targets. Although current risk adapted and response based treatment approaches yield overall survival rates of >95%, treatment of relapse or refractory patients remains challenging. Targeted HL therapy with the antibody-drug conjugate Brentuximab vedotin (Bv) has proven to be superior to conventional salvage chemotherapy and clinical trials are being conducted to incorporate Bv into frontline therapy that substitutes Bv for alkylating agents to minimize secondary malignancies. The appearance of secondary malignancies has been a concern in pediatric HL, as these patients are at highest risk among all childhood cancer survivors. The risk of developing secondary leukemia following childhood HL treatment is 10.4 to 174.8 times greater than the risk in the general pediatric population and the prognosis is significantly poorer than the other hematological malignancies with a mortality rate of nearly 100%. Therefore, identifying clinically valuable biomarkers is of utmost importance to stratify and select patients who may or may not need intensive regimens to maintain optimal balance between maximal survival rates and averting late effects. Here we discuss epidemiology, risk factors, staging, molecular and genetic prognostic biomarkers, treatment for low and high-risk patients, and the late occurrence of secondary malignancies in pediatric HL.


Assuntos
Doença de Hodgkin , Adolescente , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pesquisa Médica Translacional
18.
Oncotarget ; 7(30): 48692-48731, 2016 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-27119356

RESUMO

Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL.


Assuntos
Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/terapia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/terapia , Medicina de Precisão/métodos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Progressão da Doença , Humanos , Imunoterapia/métodos , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Medicina de Precisão/tendências , Prognóstico , Radioterapia/métodos , Transdução de Sinais/efeitos dos fármacos , Taxa de Sobrevida , Microambiente Tumoral
19.
Biomed Rep ; 4(5): 642-648, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27123261

RESUMO

Cluster of differentiation 36 (CD36) is involved in the development of atherosclerosis by enhancing macrophage endocytosis of oxidized low-density lipoproteins and foam cell formation. Soluble CD36 (sCD36) was found to be elevated in type 2 diabetic patients and possibly acted as a marker of insulin resistance and atherosclerosis. In young subjects, sCD36 was associated with cardiovascular risk factors including obesity and hypertriglyceridemia. The present study was conducted to further investigate the association between plasma sCD36 and cardiovascular risk factors among middle-aged patients with metabolic syndrome (MetS) and healthy controls. sCD36 concentrations were determined by enzyme-linked immunosorbent assays (ELISA) for 41 patients with MetS and 36 healthy controls. Data for other variables were obtained from patient medical records. sCD36 concentrations were relatively low compared to the majority of other studies and were not significantly different between the MetS group and controls (P=0.17). sCD36 was also not correlated with age, body mass index, glucose, lipid profile, serum electrolytes and blood counts. sCD36 was not significantly different between subjects with obesity, hyperglycemia, dyslipidemia, hypertension or cardiovascular disease, and those without these abnormalities (P>0.05). The inconsistency between results reported in the present study and other studies may be unique to the study population or be a result of the lack of a reliable standardized method for determining absolute sCD36 concentrations. However, further investigations are required to assess CD36 tissue expression in the study population and to assess the accuracy of various commercially available sCD36 ELISA kits. Thus, the availability of a standardized simple sCD36 ELISA that could be performed in any basic laboratory would be more favorable to the specialized flow cytometry methods that detect CD36+ microparticles if it was to be used as a biomarker.

20.
Oncotarget ; 7(28): 44735-44762, 2016 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-27007053

RESUMO

Fibroblast growth factor (FGF) signaling is essential for normal and cancer biology. Mammalian FGF family members participate in multiple signaling pathways by binding to heparan sulfate and FGF receptors (FGFR) with varying affinities. FGF2 is the prototype member of the FGF family and interacts with its receptor to mediate receptor dimerization, phosphorylation, and activation of signaling pathways, such as Ras-MAPK and PI3K pathways. Excessive mitogenic signaling through the FGF/FGFR axis may induce carcinogenic effects by promoting cancer progression and increasing the angiogenic potential, which can lead to metastatic tumor phenotypes. Dysregulated FGF/FGFR signaling is associated with aggressive cancer phenotypes, enhanced chemotherapy resistance and poor clinical outcomes. In vitro experimental settings have indicated that extracellular FGF2 affects proliferation, drug sensitivity, and apoptosis of cancer cells. Therapeutically targeting FGF2 and FGFR has been extensively assessed in multiple preclinical studies and numerous drugs and treatment options have been tested in clinical trials. Diagnostic assays are used to quantify FGF2, FGFRs, and downstream signaling molecules to better select a target patient population for higher efficacy of cancer therapies. This review focuses on the prognostic significance of FGF2 in cancer with emphasis on therapeutic intervention strategies for solid and hematological malignancies.


Assuntos
Fator 2 de Crescimento de Fibroblastos/metabolismo , Neoplasias Hematológicas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Medicina de Precisão/métodos , Animais , Antineoplásicos/uso terapêutico , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Terapia de Alvo Molecular/métodos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos
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