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1.
Br J Cancer ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32025027

RESUMO

BACKGROUND: Ibrutinib is a Bruton's tyrosine kinase (BTK) and interleukin-2-inducible kinase (ITK) inhibitor used for treating chronic lymphocytic leukaemia (CLL) and other cancers. Although ibrutinib is known to inhibit the growth of breast cancer cell growth in vitro, its impact on the treatment and metastasis of breast cancer is unclear. METHODS: Using an orthotopic mouse breast cancer model, we show that ibrutinib inhibits the progression and metastasis of breast cancer. RESULTS: Ibrutinib inhibited proliferation of cancer cells in vitro, and Ibrutinib-treated mice displayed significantly lower tumour burdens and metastasis compared to controls. Furthermore, the spleens and tumours from Ibrutinib-treated mice contained more mature DCs and lower numbers of myeloid-derived suppressor cells (MDSCs), which promote disease progression and are linked to poor prognosis. We also confirmed that ex vivo treatment of MDSCs with ibrutinib switched their phenotype to mature DCs and significantly enhanced MHCII expression. Further, ibrutinib treatment promoted T cell proliferation and effector functions leading to the induction of antitumour TH1 and CTL immune responses. CONCLUSIONS: Ibrutinib inhibits tumour development and metastasis in breast cancer by promoting the development of mature DCs from MDSCs and hence could be a novel therapeutic agent for the treatment of breast cancer.

2.
Parasite Immunol ; 41(11): e12669, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31494954

RESUMO

CD8+ T-cell function is compromised in chronic diseases such as visceral leishmaniasis (VL). However, little is known about the changes in gene expression that cause CD8+ T-cell dysfunction during VL. We used targeted transcriptional profiling of peripheral blood CD8+ T cells from VL patients pre- and post-anti-parasitic drug treatment, and compared them with the same cell population from healthy endemic controls to assess their activation, differentiation and functional status during disease. We found a predominance of downregulated immune genes in CD8+ T cells from VL patients. However, genes encoding several notable immune checkpoint molecules, including LAG-3, TIM-3 and CTLA-4, cytolytic molecules, such as granzymes A, B and H and perforin, as well as SOCS3, STAT1, JAK2 and JAK3 cytokine signalling genes were found to be increasingly expressed by VL patient CD8+ T cells. Additional studies confirmed increased expression of the inhibitory receptors LAG3 and TIM3 on VL patient CD8+ T cells, thereby identifying these molecules as potential targets to improve antigen-specific CD8+ T-cell responses during disease.

3.
Future Med Chem ; 11(15): 1999-2018, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31390889

RESUMO

Parasitic infections are responsible for significant morbidity and mortality throughout the world. Management strategies rely primarily on antiparasitic drugs that have side effects and risk of drug resistance. Therefore, novel strategies are needed for treatment of parasitic infections. Host-directed therapy (HDT) is a viable alternative, which targets host pathways responsible for parasite invasion/survival/pathogenicity. Recent innovative combinations of genomics, proteomics and computational biology approaches have led to discovery of several host pathways that could be promising targets for HDT for treating parasitic infections. Herein, we review major advances in HDT for parasitic disease with regard to core regulatory pathways and their interactions.

4.
PLoS Negl Trop Dis ; 13(8): e0007673, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31419223

RESUMO

Amphotericin B provides improved therapy for visceral leishmaniasis (VL) caused by Leishmania donovani, with single dose liposomal-encapsulated Ambisome providing the best cure rates. The VL elimination program aims to reduce the incidence rate in the Indian subcontinent to <1/10,000 population/year. Ability to predict which asymptomatic individuals (e.g. anti-leishmanial IgG and/or Leishmania-specific modified Quantiferon positive) will progress to clinical VL would help in monitoring disease outbreaks. Here we examined whole blood transcriptional profiles associated with asymptomatic infection, active disease, and in treated cases. Two independent microarray experiments were performed, with analysis focussed primarily on differentially expressed genes (DEGs) concordant across both experiments. No DEGs were identified for IgG or Quantiferon positive asymptomatic groups compared to negative healthy endemic controls. We therefore concentrated on comparing concordant DEGs from active cases with all healthy controls, and in examining differences in the transcriptome following different regimens of drug treatment. In these comparisons 6 major themes emerged: (i) expression of genes and enrichment of gene sets associated with erythrocyte function in active cases; (ii) strong evidence for enrichment of gene sets involved in cell cycle in comparing active cases with healthy controls; (iii) identification of IFNG encoding interferon-γ as the major hub gene in concordant gene expression patterns across experiments comparing active cases with healthy controls or with treated cases; (iv) enrichment for interleukin signalling (IL-1/3/4/6/7/8) and a prominent role for CXCL10/9/11 and chemokine signalling pathways in comparing active cases with treated cases; (v) the novel identification of Aryl Hydrocarbon Receptor signalling as a significant canonical pathway when comparing active cases with healthy controls or with treated cases; and (vi) global expression profiling support for more effective cure at day 30 post-treatment with a single dose of liposomal encapsulated amphotericin B compared to multi-dose non-liposomal amphotericin B treatment over 30 days. (296 words; 300 words allowed).


Assuntos
Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Biomarcadores/sangue , Células Sanguíneas , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/patologia , Transcriptoma , Adolescente , Adulto , Idoso , Doenças Assintomáticas , Criança , Feminino , Perfilação da Expressão Gênica , Humanos , Índia , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Adulto Jovem
5.
Infect Immun ; 87(8)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31182615

RESUMO

CD4+ T helper 1 (Th1) cells producing interferon gamma (IFN-γ) are critical for the resolution of visceral leishmaniasis (VL). MicroRNA 155 (miR155) promotes CD4+ Th1 responses and IFN-γ production by targeting suppressor of cytokine signaling-1 (SOCS1) and Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP-1) and therefore could play a role in the resolution of VL. To determine the role of miR155 in VL, we monitored the course of Leishmania donovani infection in miR155 knockout (miR155KO) and wild-type (WT) C57BL/6 mice. miR155KO mice displayed significantly higher liver and spleen parasite loads than WT controls and showed impaired hepatic granuloma formation. However, parasite growth eventually declined in miR155KO mice, suggesting the induction of a compensatory miR155-independent antileishmanial pathway. Leishmania antigen-stimulated splenocytes from miR155KO mice produced significantly lower levels of Th1-associated IFN-γ than controls. Interestingly, at later time points, levels of Th2-associated interleukin-4 (IL-4) and IL-10 were also lower in miR155KO splenocyte supernatants than in WT mice. On the other hand, miR155KO mice displayed significantly higher levels of IFN-γ, iNOS, and TNF-α gene transcripts in their livers than WT mice, indicating that distinct organ-specific antiparasitic mechanisms were involved in control of L. donovani infection in miR155KO mice. Throughout the course of infection, organs of miR155KO mice showed significantly more PDL1-expressing Ly6Chi inflammatory monocytes than WT mice. Conversely, blockade of Ly6Chi inflammatory monocyte recruitment in miR155KO mice significantly reduced parasitic loads, indicating that these cells contributed to disease susceptibility. In conclusion, we found that miR155 contributes to the control of L. donovani but is not essential for infection resolution.


Assuntos
Leishmania donovani , Leishmaniose Visceral/imunologia , MicroRNAs/fisiologia , Animais , Granuloma/etiologia , Interferon gama/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/fisiologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/fisiologia
6.
Expert Opin Drug Metab Toxicol ; 15(7): 595-612, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31174439

RESUMO

Introduction: Being on the top list of neglected tropical diseases, leishmaniasis has been marked for elimination by 2020. In the light of small armamentarium of drugs and their associated drawbacks, the understanding of pharmacodynamics and/or pharmacokinetics becomes a priority to achieve and sustain disease elimination. Areas covered: The authors have looked into pharmacological aspects of existing and emerging drugs for treatment of leishmaniasis. An in-depth understanding of pharmacodynamics and pharmacokinetics (PKPD) provides a rationale for drug designing and optimizing the treatment strategies. It forms a key to prevent drug resistance and avoid drug-associated adverse effects. The authors have compiled the researches on the PKPD of different anti-leishmanial formulations that have the potential for improved and/or effective disease intervention. Expert opinion: Understanding the pharmacological aspects of drugs forms the basis for the clinical application of novel drugs. Tailoring drug dosage and individualized treatment can avoid the adverse events and bridge gap between the in vitro models and their clinical application. An integrated approach, with pragmatic use of technological advances can improve phenotypic screening and physiochemical properties of novel drugs. Concomitantly, this can serve to improve clinical efficacies, reduce the incidence of relapse and accelerate the drug discovery/development process for leishmaniasis elimination.


Assuntos
Antiprotozoários/administração & dosagem , Desenvolvimento de Medicamentos/métodos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/farmacocinética , Antiprotozoários/farmacologia , Relação Dose-Resposta a Droga , Desenho de Drogas , Descoberta de Drogas/métodos , Resistência a Medicamentos , Humanos , Leishmaniose/parasitologia
7.
Circ Res ; 125(3): 328-340, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31159652

RESUMO

RATIONALE: Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long noncoding RNAs (lncRNAs), are proposed novel biomarkers of myocardial injury. Their release kinetics have not been explored without confounding by heparin nor has their relationship to myocardial protein biomarkers. OBJECTIVE: To compare ncRNA types in heparinase-treated samples with established and emerging protein biomarkers for myocardial injury. METHODS AND RESULTS: Screening of 158 circRNAs and 21 lncRNAs in human cardiac tissue identified 12 circRNAs and 11 lncRNAs as potential biomarkers with cardiac origin. Eleven miRNAs were included. At low spike-in concentrations of myocardial tissue, significantly higher regression coefficients were observed across ncRNA types compared with cardiac troponins and cMyBP-C (cardiac myosin-binding protein C). Heparinase treatment of serial plasma and serum samples of patients undergoing transcoronary ablation of septal hypertrophy removed spurious correlations between miRNAs in non-heparinase-treated samples. After transcoronary ablation of septal hypertrophy, muscle-enriched miRNAs (miR-1 and miR-133a) showed a steeper and earlier increase than cardiac-enriched miRNAs (miR-499 and miR-208b). Putative cardiac lncRNAs, including LIPCAR (long intergenic noncoding RNA predicting cardiac remodeling and survival), did not rise, refuting a predominant cardiac origin. Cardiac circRNAs remained largely undetectable. In a validation cohort of acute myocardial infarction, receiver operating characteristic curve analysis revealed noninferiority of cardiac-enriched miRNAs, but miRNAs failed to identify cases presenting with low troponin values. cMyBP-C was validated as a biomarker with highly sensitive properties, and the combination of muscle-enriched miRNAs with high-sensitive cardiac troponin T and cMyBP-C returned the highest area under the curve values. CONCLUSIONS: In a comparative assessment of ncRNAs and protein biomarkers for myocardial injury, cMyBP-C showed properties as the most sensitive cardiac biomarker while miRNAs emerged as promising candidates to integrate ncRNAs with protein biomarkers. Sensitivity of current miRNA detection is inferior to cardiac proteins but a multibiomarker combination of muscle-enriched miRNAs with cMyBP-C and cardiac troponins could open a new path of integrating complementary characteristics of different biomarker types.

8.
PLoS Negl Trop Dis ; 13(3): e0007216, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30917114

RESUMO

BACKGROUND: Asymptomatic Leishmania donovani infections outnumber clinical presentations, however the predictors for development of active disease are not well known. We aimed to identify serological, immunological and genetic markers for progression from L. donovani infection to clinical Visceral Leishmaniasis (VL). METHODS: We enrolled all residents >2 years of age in 27 VL endemic villages in Bihar (India). Blood samples collected on filter paper on two occasions 6-12 months apart, were tested for antibodies against L. donovani with rK39-ELISA and DAT. Sero converters, (negative for both tests in the first round but positive on either of the two during the second round) and controls (negative on both tests on both occasions) were followed for three years. At the start of follow-up venous blood was collected for the following tests: DAT, rK39- ELISA, Quantiferon assay, SNP/HLA genotyping and L.donovani specific quantitative PCR. RESULTS: Among 1,606 subjects enrolled,17 (8/476 seroconverters and 9/1,130 controls) developed VL (OR 3.1; 95% CI 1.1-8.3). High DAT and rK39 ELISA antibody titers as well as positive qPCR were strongly and significantly associated with progression from seroconversion to VL with odds ratios of 19.1, 30.3 and 20.9 respectively. Most VL cases arose early (median 5 months) during follow-up. CONCLUSION: We confirmed the strong association between high DAT and/or rK39 titers and progression to disease among asymptomatic subjects and identified qPCR as an additional predictor. Low predictive values do not warrant prophylactic treatment but as most progressed to VL early during follow-up, careful oberservation of these subjects for at least 6 months is indicated.


Assuntos
Anticorpos Antiprotozoários/sangue , Doenças Endêmicas , Leishmania donovani/imunologia , Leishmaniose Visceral/epidemiologia , Infecções Assintomáticas/epidemiologia , Estudos de Coortes , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Índia/epidemiologia , Lactente , Leishmania donovani/genética , Leishmania donovani/isolamento & purificação , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/patologia , Masculino , Soroconversão
9.
Am J Trop Med Hyg ; 100(4): 816-821, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30793688

RESUMO

B-cells have a spectrum of functions ranging from antibody production to antigen presentation and have additional vital roles in immune mechanisms. There is rudimentary knowledge about the role of B-cells in intracellular infections with contradictory findings. We explored the role of B-cell dysfunctions in visceral leishmaniasis (VL) pathogenesis in terms of the phenotypic and functional properties of B-cells during the course of disease. This study was performed on blood and splenic aspirates (SA) of VL cases pre- and post-treatment. Whole blood was used for flow cytometric studies for determining the profiles of B-cells at different time-points of treatment. Peripheral blood mononuclear cells were used for magnetic purification of B-cells, for transcriptional studies by real-time polymerase chain reaction (RT-PCR). Serum/plasma was used for direct agglutination test for determining parasite-specific antibodies and SA were used for scoring the presence of parasite by microscopic examination. Flow cytometric studies depicted decreased B-cell percentages during the entire course of disease and attainment of exhaustive phenotype with tissue-like memory cell markers, indicative of B-cell dysfunctions in VL. In addition, B-cells had compromised abilities of antigen processing and presentation and altered levels of B-lymphocyte-induced maturation protein-1 (Blimp-1). Blimp-1 expression goes hand in hand with B-cell maturation antigen and transmembrane activator and calcium modulator (TACI) and cyclophilin ligand interactor, suggestive of its role in promoting plasma cell survival and antibody production. Elevated level of VL-specific antibody titre was directly correlated with exhausted phenotype and also with disease severity during VL. This study indicated for impaired B-cell functions during chronic infection which may lead to pathological consequences in human VL.


Assuntos
Subpopulações de Linfócitos B/imunologia , Imunidade Humoral , Leishmaniose Visceral/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Apresentação do Antígeno , Humanos , Índia
10.
J Infect Dis ; 220(1): 163-173, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-30796820

RESUMO

Control of visceral leishmaniasis (VL) caused by Leishmania donovani requires interferon-γ production by CD4+ T cells. In VL patients, antiparasitic CD4+ T-cell responses are ineffective for unknown reasons. In this study, we measured the expression of genes associated with various immune functions in these cells from VL patients and compared them to CD4+ T cells from the same patients after drug treatment and from endemic controls. We found reduced GATA3, RORC, and FOXP3 gene expression in CD4+ T cells of VL patients, associated with reduced Th2, Th17, and FOXP3+CD4+ T regulatory cell frequencies in VL patient blood. Interleukin 2 (IL-2) was an important upstream regulator of CD4+ T cells from VL patients, and functional studies demonstrated the therapeutic potential of IL-2 for improving antiparasitic immunity. Together, these results provide new insights into the characteristics of CD4+ T cells from VL patients that can be used to improve antiparasitic immune responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-2/imunologia , Leishmaniose Visceral/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Animais , Feminino , Humanos , Interferon gama/imunologia , Leishmania donovani/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th17/imunologia , Células Th2/imunologia
11.
Parasite Immunol ; 41(1): e12601, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30402883

RESUMO

AIM: Iron is key ingredient for immunosurveillance and host-pathogen interaction. Intracellular pathogen steals the iron from the host, but how parasite orchestrates iron acquisition and affects immune responses remains controversial. We aimed to study the iron homoeostasis in visceral leishmaniasis (VL) and its influence on immune machinery. METHODS AND RESULTS: This study was performed on purified monocytes and T cells, peripheral blood mononuclear cells and splenic aspirates for transcriptional analyses of iron homoeostasis (hepcidin, DMT1, transferrin receptor, ferroportin) and immune modulations (IFN-γ, HLA-DR, IL-10, iNOS, IL-6). Serum/plasma was used for determination of iron, total/transferrin iron-binding capacity and anti-leishmania antibody titres in cases. We report that VL-induced perturbation in iron homoeostasis may cause immune dysfunctions. VL cases had decreased iron uptake by transferrin-dependent and transferrin-independent routes while elevated hepcidin, degraded sole iron exporter ferroportin. Therefore, it appears that perturbation in iron homoeostasis has essential role in HLA-DR mediated antigen presentation and innate armoury by downregulating iNOS as well as altering IFN-γ, IL-6 and IL-10 profiles. CONCLUSION: The iron homoeostasis by hepcidin can serve as one of the crucial determinants for regulating immune cell signalling; therefore, targeting iron metabolism, specifically hepcidin alone or in combination with agonists, can serve to clear infection.


Assuntos
Hepcidinas/imunologia , Homeostase , Ferro/metabolismo , Leishmaniose Visceral/imunologia , Adulto , Apresentação do Antígeno , Proteínas de Transporte de Cátions/metabolismo , Feminino , Hepcidinas/genética , Humanos , Interleucina-10/metabolismo , Leishmania , Leishmaniose Visceral/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Monócitos/metabolismo , Baço/metabolismo , Transcrição Genética
12.
Immunology ; 156(2): 174-186, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30403401

RESUMO

Genetic variation at HLA-DRB1 is a risk factor for visceral leishmaniasis (VL) caused by Leishmania donovani. The single nucleotide polymorphism rs9271252 upstream of the DRB1 gene provides a perfect tag for protective versus risk HLA-DRB1 four-digit alleles. In addition to the traditional role of the membrane-distal region of HLA class II molecules in antigen presentation and CD4 T-cell activation, the membrane-proximal region mediates 'non-traditional' multi-functional activation, differentiation, or death signals, including in DR-expressing T cells. To understand how HLA-DR contributes to disease pathogenesis, we examined expression at the protein level in circulating myeloid (CD14+ , CD16+ ) and lymphoid (CD4+ , CD8+ , CD19+ ) cells of VL patients (pre- and post-treatment) compared with endemic healthy controls (EHC). Although DR expression is reduced in circulating myeloid cells in active disease relative to EHC and post-treatment groups, expression is enhanced on CD4+  DR+ and CD8+  DR+ T cells consistent with T-cell activation. Cells of all myeloid and lymphoid populations from active cases were refractory to stimulation of DR expression with interferon-γ (IFN-γ). In contrast, all populations except CD19+ B cells from healthy blood bank controls showed enhanced DR expression following IFN-γ stimulation. The rs9271252 genotype did not impact significantly on IFN-γ-activated DR expression in myeloid, B or CD8+ T cells, but CD4+ T cells from healthy individuals homozygous for the risk allele were particularly refractory to activated DR expression. Further analysis of DR expression on subsets of CD4+ T cells regulating VL disease could uncover additional ways in which pleiotropy at HLA DRB1 contributes to disease pathogenesis.


Assuntos
Regulação da Expressão Gênica , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Leishmaniose Visceral/genética , Linfócitos , Células Mieloides , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alelos , Antígenos CD/genética , Antígenos CD/imunologia , Criança , Pré-Escolar , Feminino , Cadeias HLA-DRB1/imunologia , Homozigoto , Humanos , Lactente , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/patologia , Masculino , Fatores de Risco
13.
Expert Opin Ther Targets ; 22(6): 467-486, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29718739

RESUMO

INTRODUCTION: Parasitic diseases that pose a threat to human life include leishmaniasis - caused by protozoan parasite Leishmania species. Existing drugs have limitations due to deleterious side effects like teratogenicity, high cost and drug resistance. This calls for the need to have an insight into therapeutic aspects of disease. Areas covered: We have identified different drug targets via. molecular, imuunological, metabolic as well as by system biology approaches. We bring these promising drug targets into light so that they can be explored to their maximum. In an effort to bridge the gaps between existing knowledge and prospects of drug discovery, we have compiled interesting studies on drug targets, thereby paving the way for establishment of better therapeutic aspects. Expert opinion: Advancements in technology shed light on many unexplored pathways. Further probing of well established pathways led to the discovery of new drug targets. This review is a comprehensive report on current and emerging drug targets, with emphasis on several metabolic targets, organellar biochemistry, salvage pathways, epigenetics, kinome and more. Identification of new targets can contribute significantly towards strengthening the pipeline for disease elimination.


Assuntos
Antiprotozoários/farmacologia , Descoberta de Drogas/métodos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/efeitos adversos , Desenho de Drogas , Humanos , Leishmania/efeitos dos fármacos , Leishmania/isolamento & purificação , Leishmaniose/parasitologia , Terapia de Alvo Molecular
14.
Expert Rev Proteomics ; 15(5): 371-390, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29717934

RESUMO

INTRODUCTION: Leishmania spp. are causative agents of leishmaniasis, a broad-spectrum neglected vector-borne disease. Genomic and transcriptional studies are not capable of solving intricate biological mysteries, leading to the emergence of proteomics, which can provide insights into the field of parasite biology and its interactions with the host. Areas covered: The combination of genomics and informatics with high throughput proteomics may improve our understanding of parasite biology and pathogenesis. This review analyses the roles of diverse proteomic technologies that facilitate our understanding of global protein profiles and definition of parasite development, survival, virulence and drug resistance mechanisms for disease intervention. Additionally, recent innovations in proteomics have provided insights concerning the drawbacks associated with conventional chemotherapeutic approaches and Leishmania biology, host-parasite interactions and the development of new therapeutic approaches. Expert commentary: With progressive breakthroughs in the foreseeable future, proteome profiles could provide target molecules for vaccine development and therapeutic intervention. Furthermore, proteomics, in combination with genomics and informatics, could facilitate the elimination of several diseases. Taken together, this review provides an outlook on developments in Leishmania proteomics and their clinical implications.


Assuntos
Leishmania/metabolismo , Parasitos/metabolismo , Proteômica/métodos , Animais , Humanos , Leishmania/citologia , Leishmania/crescimento & desenvolvimento , Parasitos/citologia , Parasitos/crescimento & desenvolvimento , Proteoma/metabolismo , Proteínas de Protozoários/metabolismo , Biologia de Sistemas
15.
Chem Commun (Camb) ; 53(91): 12337-12340, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29098225

RESUMO

p-Selective (sp2)-C-H functionalization of electron rich arenes has been achieved for acylation and alkylation reactions, respectively, with acyl/alkylselenides by organic photoredox catalysis involving an interesting mechanistic pathway.

16.
J Biomed Opt ; 22(4): 46008, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28447102

RESUMO

Diffuse optical tomography (DOT) is emerging as a noninvasive functional imaging method for breast cancer diagnosis and neoadjuvant chemotherapy monitoring. In particular, the multimodal approach of combining DOT with x-ray digital breast tomosynthesis (DBT) is especially synergistic as DBT prior information can be used to enhance the DOT reconstruction. DOT, in turn, provides a functional information overlay onto the mammographic images, increasing sensitivity and specificity to cancer pathology. We describe a dynamic DOT apparatus designed for tight integration with commercial DBT scanners and providing a fast (up to 1 Hz) image acquisition rate to enable tracking hemodynamic changes induced by the mammographic breast compression. The system integrates 96 continuous-wave and 24 frequency-domain source locations as well as 32 continuous wave and 20 frequency-domain detection locations into low-profile plastic plates that can easily mate to the DBT compression paddle and x-ray detector cover, respectively. We demonstrate system performance using static and dynamic tissue-like phantoms as well as in vivo images acquired from the pool of patients recalled for breast biopsies at the Massachusetts General Hospital Breast Imaging Division.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mamografia/métodos , Imagem Multimodal/métodos , Mama/diagnóstico por imagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Pessoa de Meia-Idade , Distribuição Normal , Óptica e Fotônica , Imagens de Fantasmas , Ondas de Rádio , Tomografia Óptica
17.
Biomed Opt Express ; 8(2): 555-569, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28270967

RESUMO

We characterize novel breast cancer imaging biomarkers for monitoring neoadjuvant chemotherapy (NACT) and predicting outcome. Specifically, we recruited 30 patients for a pilot study in which NACT patients were imaged using dynamic tomographic optical breast imaging (DTOBI) to quantify the hemodynamic changes due to partial mammographic compression. DTOBI scans were obtained pre-treatment (referred to as day 0), as well as 7 and 30 days into therapy on female patients undergoing NACT. We present data for the 13 patients who participated in both day 0 and 7 measurements and had evaluable data, of which 7 also returned for day 30 measurements. We acquired optical images over 2 minutes following 4-8 lbs (18-36 N) of compression. The timecourses of tissue-volume averaged total hemoglobin (HbT), as well as hemoglobin oxygen saturation (SO2) in the tumor vs. surrounding tissues were compared. Outcome prediction metrics based on the differential behavior in tumor vs. normal areas for responders (>50% reduction in maximum diameter) vs. non-responders were analyzed for statistical significance. At baseline, all patients exhibit an initial decrease followed by delayed recovery in HbT, and SO2 in the tumor area, in contrast to almost immediate recovery in surrounding tissue. At day 7 and 30, this contrast is maintained in non-responders; however, in responders, the contrast in hemodynamic time-courses between tumor and normal tissue starts decreasing at day 7 and substantially disappears at day 30. At day 30 into NACT, responding tumors demonstrate "normalization" of compression induced hemodynamics vs. surrounding normal tissue whereas non-responding tumors did not. This data suggests that DTOBI imaging biomarkers, which are governed by the interplay between tissue biomechanics and oxygen metabolism, may be suitable for guiding NACT by offering early predictions of treatment outcome.

18.
Indian J Med Res ; 143(Supplement): S52-S58, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27748278

RESUMO

BACKGROUND & OBJECTIVES: The proto-oncogene HER2/neu has been extensively studied in breast cancer patients. Serum levels of HER2/neu by ELISA in breast cancer patients were compared with tissue HER2/neu expression and with other clinicopathological parameters with the aim to investigate whether the serum assay could replace the established tests (IHC/FISH) for HER-2 status. METHODS: Blood and Tru-cut biopsy samples were collected for determining HER2/neu status in 64 breast cancer patients. The tissue specimens were processed routinely and immunohistochemistry (IHC) for HER2/ER/PR (oestrogen/progesterone receptors) performed. Fluorescence in-situ hybridization (FISH) was performed on all HER2/neu 2 positive cases. Sixty age matched healthy females and females with benign breast disease were taken as controls for ELISA. RESULTS: Of the 64 breast cancer cases, 25 (39.1%) had elevated serum HER2/neu levels accompanied with increased tissue expression of HER2/neu receptors. On IHC, HER2/neu score was 3+ in 24 (37.5%) cases, 2+ in three (4.6%), 1+ in 18 (28.1%); while 19 cases (29.7%) showed no HER2/neu expression. o0 f the three 2+ cases on IHC, two showed amplification on FISH. Twenty one (32.8%) patients were ER positive and 17 (26.6%) were PR positive. There was a significant correlation (P<0.001) of serum HER2 concentration with tumour size, lymph node involvement, stage of disease and histological grade. Serum HER2/neu levels showed a negative correlation with ER status (P=0.047) but no correlation with PR status. INTERPRETATION & CONCLUSIONS: The results suggest that elevated serum HER2 level was associated with a clinicopathological aggressive phenotype of breast carcinoma and was related to tissue HER2 overexpression. Therefore, serum HER2 may be useful for monitoring the course of the disease and response to treatment.


Assuntos
Neoplasias da Mama/genética , Proteínas Oncogênicas/genética , Receptor ErbB-2/genética , Adulto , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Oncogênicas/biossíntese , Receptor ErbB-2/sangue , Receptores Estrogênicos/sangue , Receptores de Progesterona/sangue
19.
Infect Dis Poverty ; 5: 19, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26951132

RESUMO

Visceral leishmaniasis (VL) is a serious parasitic disease causing considerable mortality and major disability in the Indian subcontinent. It is most neglected tropical disease, particularly in terms of new drug development for the lack of financial returns. An elimination campaign has been running in India since 2005 that aim to reduce the incidence of VL to below 1 per 10,000 people at sub-district level. One of the major components in this endeavor is reducing transmission through early case detection followed by complete treatment. Substantial progress has been made during the recent years in the area of VL treatment, and the VL elimination initiatives have already saved many lives by deploying them effectively in the endemic areas. However, many challenges remain to be overcome including availability of drugs, cost of treatment (drugs and hospitalization), efficacy, adverse effects, and growing parasite resistance. Therefore, better emphasis on implementation research is urgently needed to determine how best to deliver existing interventions with available anti-leishmanial drugs. It is essential that the new treatment options become truly accessible, not simply available in endemic areas so that they may promote healing and save lives. In this review, we highlight the recent advancement and challenges in current treatment options for VL in disease endemic area, and discuss the possible strategies to improve the therapeutic outcome.


Assuntos
Antiprotozoários/administração & dosagem , Leishmaniose Visceral/tratamento farmacológico , Animais , Humanos , Índia/epidemiologia , Leishmania/efeitos dos fármacos , Leishmania/genética , Leishmania/fisiologia , Leishmaniose Visceral/epidemiologia , Saúde Pública
20.
Microbes Infect ; 18(5): 369-72, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26774334

RESUMO

Lipid phosphatase, PTEN is amongst the host gene actively involved in determining disease susceptibility. Expression of pten and other genes in vicinity egr1 &4e-bp1 were evaluated in splenic tissue before and after treatment in visceral leishmaniasis patients. Lower expression of egr1 in correlation with pten suppressed 4e-bp1 gene in active cases. The higher levels of pten mRNA expression post treatment confirmed its role in effective clearance of Leishmania. Therefore, it is hypothesized that lower mRNA expression of pten is due to suppression of egr1 activates PI3K signaling bestowing host the ability to cope up infection and continue its normal metabolic machinery.


Assuntos
Regulação para Baixo , Expressão Gênica , Evasão da Resposta Imune , Leishmania donovani/patogenicidade , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/patologia , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Humanos
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