Publications by authors named "Ana Maria Hernández"

27 Publications

  • Page 1 of 1

Mapping for adult-plant resistance against Septoria tritici blotch in a common wheat line Murga.

Phytopathology 2020 Nov 3. Epub 2020 Nov 3.

CIMMYT, 61619, Global Wheat Program, Texcoco, Mexico;

Septoria tritici blotch (STB) is a major foliar disease globally, which is notorious in the fast development of fungicide resistance, making host resistance an indispensable component in mitigating STB. CIMMYT wheat line Murga is well known for its high, durable, and broad-spectrum resistance against STB infection, and the purpose of this study was to investigate its resistance mechanism to facilitate its utilization in breeding. A recombinant inbred line population was derived from a cross between Murga and a STB susceptible line Huirivis#1, comprising 297 progenies. The population was evaluated for adult-plant STB resistance in Toluca, Mexico (from 2017 to 2019), and in La Estanzuela, Uruguay (from 2016 to 2018). Genotyping was performed with the DArTSeq platform. QTL mapping indicated a major and stable QTL on chromosome 3DL, explaining a phenotypic variation for STB of 41.2-62.5% in Mexico and 27.5-40.3% in Uruguay. This QTL was regarded as Stb16 based on comparison of its physical position, the possible origin from synthetic wheat, and its broad-spectrum resistance. Additional QTL with minor effects were identified on chromosomes 2B, 2D, 3A, 3B, and 5B. The one on 5BS was significant in four out of the six environments and must be new. Murga was the resistant donor for all QTL, except for those on 2B and 3A. Being an elite breeding line, the Stb16 carrier Murga could be used as a promising STB resistance donor. The rational employment of Stb16 could contribute to STB management yet avoid the rapid emergence of Stb16-virulent isolates.
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http://dx.doi.org/10.1094/PHYTO-05-20-0172-RDOI Listing
November 2020

Limited sampling strategy to predict the area under the curve of tacrolimus in Mexican renal transplant pediatric patients receiving Prograf or non-innovator formulations.

Pediatr Transplant 2019 12 1;23(8):e13595. Epub 2019 Oct 1.

Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico.

TDM of tacrolimus is usually performed with trough levels (C ). However, in pediatric patients, C may not be an adequate marker. The AUC is considered a more suitable indicator of drug exposure. As several blood samples are needed for the estimation of AUC, and LSS for predicting tacrolimus AUC and optimizing the dose adjustment have been proposed. Moreover, in emerging countries such as Mexico, non-innovator formulations, which bioequivalence has not been demonstrated, are frequently used. Hence, the aim of this study was to develop and validate a LSS to predict the tacrolimus AUC in Mexican pediatric kidney transplant recipients who received either Prograf or non-innovator tacrolimus formulations. A total of 56 pharmacokinetic profiles were randomized into two groups: model development (n = 28) and model validation (n = 28). The limited sampling equations were obtained after a stepwise multiple regression using AUC as the dependent variable and tacrolimus blood concentrations, quantified by CMIA, at different time points as the independent variables. The final equation included observed concentrations at 1 hour (C ) and 4 hours (C ) after dose administration. The predictive performance of the model was adequate in terms of both, bias and precision. Results strongly suggest that the clinical use of this LSS could provide an ethical, cost-, and time-effective method in the TDM of tacrolimus in pediatric patients with kidney transplant. The model proved to be adequate with either Prograf or non-innovator tacrolimus formulations of dubious bioequivalence.
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http://dx.doi.org/10.1111/petr.13595DOI Listing
December 2019

Swallowing Analyses of Neonates and Infants in Breastfeeding and Bottle-feeding: Impact on Videofluoroscopy Swallow Studies.

Int Arch Otorhinolaryngol 2019 Jul 28;23(3):e343-e353. Epub 2019 May 28.

Post Graduation Program in Speech, Language and Hearing Sciences (PEPG), Pontifícia Universidade Católica de São Paulo, São Paulo, SP, Brazil.

 Dysphagia, when left untreated, can result in an increase in morbidity and mortality rates, especially among infants with history of life-threatening neonatal diseases. The videofluoroscopy swallowing study (VFSS) is considered the gold standard for the diagnosis of dysphagia. There are few imaging studies of infant swallowing based on videofluoroscopy, none of which were performed during breast-feeding.  To analyze the similarities and differences in infant swallowing function -regarding the feeding method - breast or bottle - and the impact on videofluoroscopy findings.  A retrospective study of 25 VFSSs of breastfeeding and bottle-feeding infants was performed. The studied variables were: oral capture and control; tongue versus mandible movement coordination; sucking pattern; mandible excursion; liquid flow; bolus retention; laryngeal penetration; tracheal aspiration; clearing of material collected in the pharynx; and gastroesophageal reflux (GER).  The study showed a statistically significant association between nipple/areole capture; oral control; sucking pattern; mandibular excursion; liquid flow and feeding method. The velar sealing deficit, the place that trigger the pharyngeal swallow, food retention in the pharyngeal recesses, laryngeal penetration and GER were also factors associated with the feeding method.  The analysis of the swallowing characteristics of both feeding methods revealed significant differences between them, with an impact on the diagnosis in the VFSSs, especially regarding velar function.
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http://dx.doi.org/10.1055/s-0039-1677753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660293PMC
July 2019

The Psychopathology of Delusion of Control According to Subjective Experience.

Rev Colomb Psiquiatr 2018 Oct - Dec;47(4):221-228. Epub 2017 Apr 1.

York University, Toronto, Canadá.

Background: Delusion of control, including thought insertion, occurs in 20% of patients with schizophrenia. However little is known of its psychopathology, and studies involving patients are scarce.

Aims: To explore the subjective experience of patients with delusion of control and to propose a psychopathological explanation based on empirical evidence.

Methods: Qualitative exploratory study of 7 patients (6 with schizophrenia and 1 with schizophreniform disorder). A phenomenologically-oriented semi-structured interview was used.

Results: Delusion of control is not an isolated and pure symptom; it is always immersed in the context of a persecutory delusion and other psychiatric symptoms. The patient experiences partial control, i.e. the control is never complete. In all cases, it is possible to trace the history of the narrative formation of delusion of control from its origins in persecutory delusions and other concomitant symptoms.

Conclusions: The delusion of control is a narrative resulting from the joint presence of a persecutory delusion and other psychiatric symptoms. For the patient, the delusion of control is the narrative of the elaborate expression of the meaning of the anomalous experience. Delusion of control is a narrative variety of persecutory delusion.
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http://dx.doi.org/10.1016/j.rcp.2017.02.004DOI Listing
December 2018

Sticholysin II-mediated cytotoxicity involves the activation of regulated intracellular responses that anticipates cell death.

Biochimie 2018 May 13;148:18-35. Epub 2018 Feb 13.

Center for Protein Studies, Biology Faculty, University of Havana, CP10400, Cuba. Electronic address:

Sticholysin II (StII) is a pore-forming toxin of biomedical interest that belongs to the actinoporin protein family. Sticholysins are currently under examination as an active immunomodulating component of a vaccinal platform against tumoral cells and as a key element of a nucleic acids delivery system to cell cytosol. These proteins form pores in the plasma membrane leading to ion imbalance and cell lysis. However, the intracellular mechanisms triggered by actinoporins upon binding to membranes and its consequences for cell death are barely understood. Here, we have examined the cytotoxicity and intracellular responses induced by StII upon binding to human B-cell lymphoma Raji in vitro. StII cytotoxicity involves a functional actin cytoskeleton, induces cellular swelling, lysis and the concomitant release of cytosol content. In addition, StII induces calcium release mainly from the Endoplasmic Reticulum, activates Mitogen-Activated Protein Kinase ERK and impairs mitochondrial membrane potential. Furthermore, StII stimulates the expression of receptor interacting protein kinase 1 (RIP1), normally related to different forms of regulated cell death such as apoptosis and necroptosis. In correspondence, necrostatin-1, an inhibitor of this kinase, reduces StII cytotoxicity. However, the mechanism of cell death activated by StII does not involve caspases activation, typical molecular features of apoptosis and pyroptosis. Our results suggest that, beyond pore-formation and cell lysis, StII-induced cytotoxicity could involve other regulated intracellular mechanisms connected to RIP1-MEK1/2 -ERK1/2- pathways. This opens new perspectives and challenges the general point of view that these toxins induce a completely unregulated mechanism of necrotic cell death. This study contributes to a better understanding of the molecular mechanisms involved in toxin-cell interaction and the implications for cell functioning, with connotation for the exploitations of these toxins in clinical settings.
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http://dx.doi.org/10.1016/j.biochi.2018.02.006DOI Listing
May 2018

Editorial: Natural Antibodies in Health and Disease.

Front Immunol 2017 13;8:1795. Epub 2017 Dec 13.

Department of Biomedical Sciences, Center for Immunobiology, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, United States.

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http://dx.doi.org/10.3389/fimmu.2017.01795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733483PMC
December 2017

Defining Natural Antibodies.

Front Immunol 2017 26;8:872. Epub 2017 Jul 26.

Natural Antibodies Group, Tumor Immunology Division, Center of Molecular Immunology, Havana, Cuba.

The traditional definition of natural antibodies (NAbs) states that these antibodies are present prior to the body encountering cognate antigen, providing a first line of defense against infection thereby, allowing time for a specific antibody response to be mounted. The literature has a seemingly common definition of NAbs; however, as our knowledge of antibodies and B cells is refined, re-evaluation of the common definition of Nabs may be required. Defining Nabs becomes important as the function of NAb production is used to define B cell subsets (1) and as these important molecules are shown to play numerous roles in the immune system (Figure 1). Herein, we aim to briefly summarize our current knowledge of NAbs in the context of initiating a discussion within the field of how such an important and multifaceted group of molecules should be defined.
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http://dx.doi.org/10.3389/fimmu.2017.00872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526850PMC
July 2017

Detection of Naturally Occurring Human Antibodies Against Gangliosides by ELISA.

Methods Mol Biol 2017 ;1643:179-186

Center for Molecular Immunology, 11600, Havana, Cuba.

Gangliosides are sialic acid-containing glycolipids that have been considered attractive targets for cancer immunotherapy, based on the qualitative and quantitative changes they suffer during malignant transformation and due to their importance for tumor biology. Natural antibodies against gangliosides have been detected not only in cancer patients but also in healthy donors. The presence of these antibodies can be used as diagnostic or prognostic factor. However, these responses are difficult to detect because anti-ganglioside antibodies are usually of IgM isotype and low affinity. Enzyme Linked Immunosorbent Assay (ELISA) is an immunoassay based on the specific binding of antibodies to antigens bound to a solid phase. These antigens can be glycolipids like gangliosides. An enzyme linked to the last reactant allows the detection of specific binding through the development of color after the addition of a suitable substrate. ELISA combines the specificity of antibodies with the sensitivity of enzyme reactions. The ELISA method described herein can be used to detect antibody responses against gangliosides not only related to cancer but also to autoimmune diseases and infections, both in healthy donors, and patients, untreated or receiving specific immunotherapy.
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http://dx.doi.org/10.1007/978-1-4939-7180-0_14DOI Listing
March 2018

B-CD8 T Cell Interactions in the Anti-Idiotypic Response against a Self-Antibody.

J Immunol Res 2017 9;2017:2860867. Epub 2017 Apr 9.

Tumor Immunology Direction, Center of Molecular Immunology, Havana, Cuba.

P3 is a murine, germline, IgM mAb that recognizes -glycolylated gangliosides and other self-antigens. This antibody is able to induce an anti-idiotypic IgG response and B-T idiotypic cascade, even in the absence of any adjuvant or carrier protein. P3 mAb immunization induces the expression of activation markers in a significant percentage of B-1a cells in vivo. Interestingly, transfer of both B-1a and B-2 to BALB/Xid mice was required to recover anti-P3 IgG response in this model. In fact, P3 mAb activated B-2 cells, in vitro, inducing secretion of IFN-γ and IL-4, although this activation was not detected ex vivo. Interestingly, naïve CD8 T cells increased the expression of activation markers and IFN-γ secretion in the presence of B-1a cells isolated from P3 mAb-immunized mice, even without in vitro restimulation. In contrast, B-2 cells were able to stimulate CD8 T cells only if P3 was added in vitro. Using bioinformatics, a MHC class I-binding peptide from P3 V region was identified. P3 mAb was able to induce a specific CTL response in vivo against cells presenting this peptide. Both humoral and CTL anti-idiotypic responses could be mechanisms to protect against the self-reactive antibody, contributing to keeping the tolerance to self-antigens.
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http://dx.doi.org/10.1155/2017/2860867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401753PMC
February 2018

Are Tacrolimus Pharmacokinetics Affected by Nephrotic Stage?

Ther Drug Monit 2016 06;38(3):288-92

*Laboratorio de Investigacion en Nefrologia, Hospital Infantil de Mexico Federico Gomez; †Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México; ‡Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico; §Department of Pediatrics, Children's Hospital, London Health Science Centre; ¶Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry; ‖Department of Medicine, London Health Science Centre, University of Western Ontario, London, Ontario, Canada.

Background: Although tacrolimus therapy is not the first-line therapy for childhood nephrotic syndrome, it is often used instead of cyclosporine to ameliorate the side effects. The pharmacokinetics (PK) of tacrolimus (Tac) can be influenced by many conditions, and it has a high plasma protein binding. The Tac PK during relapse and remission of childhood nephrotic syndrome has not been well described.

Methods: We performed 14 PK profiles (with measurements before intake and 0.5, 1, 2, 4, and 12 hours postintake) in 7 children with steroid-resistant nephrotic syndrome at week 1 (all nephrotic) and week 16 after Tac therapy (all in remission). These data were compared with historical PK data of 161 PK profiles in 87 pediatric renal transplant recipients with measurements before intake and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postintake. Tac levels were measured using the Abbott Tacro II assay. We used descriptive statistics to generate percentiles and compared these with those of patients with steroid-resistant nephrotic syndrome.

Results: The median age of patients with nephrotic syndrome was 3.2 years (range 2.5, 17.2), male gender 71.4%, significantly younger than the control group. Median Tac dose was similar during both PK profiles (0.11 mg·kg·d at week 1 versus 0.13 mg·kg·d at week 16, P = 0.81). There were no statistically significant differences in median dose-normalized area-under-the-time-concentration profiles, peak concentration, time to reach peak concentration, and Tac trough levels. Individual dose-normalized Tac levels for each time point during the PK profile were also not different (P = 0.81).

Conclusions: We conclude that Tac PK profiles are unaltered during relapse of nephrotic syndrome.
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http://dx.doi.org/10.1097/FTD.0000000000000285DOI Listing
June 2016

Distinctions among Circulating Antibody-Secreting Cell Populations, Including B-1 Cells, in Human Adult Peripheral Blood.

J Immunol 2016 Feb 6;196(3):1060-9. Epub 2016 Jan 6.

Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY 11030;

Human Ab-secreting cell (ASC) populations in circulation are not well studied. In addition to B-1 (CD20(+)CD27(+)CD38(lo/int)CD43(+)) cell and conventional plasmablast (PB) (CD20-CD27(hi)CD38(hi)) cell populations, in this study, we identified a novel B cell population termed 20(+)38(hi) B cells (CD20(+)CD27(hi)CD38(hi)) that spontaneously secretes Ab. At steady-state, 20(+)38(hi) B cells are distinct from PBs on the basis of CD20 expression, amount of Ab production, frequency of mutation, and diversity of BCR repertoire. However, cytokine treatment of 20(+)38(hi) B cells induces loss of CD20 and acquisition of CD138, suggesting that 20(+)38(hi) B cells are precursors to PBs or pre-PBs. We then evaluated similarities and differences among CD20(+)CD27(+)CD38(lo/int)CD43(+) B-1 cells, CD20(+)CD27(hi)CD38(hi) 20(+)38(hi) B cells, CD20(-)CD27(hi)CD38(hi) PBs, and CD20(+)CD27(+)CD38(lo/int)CD43(-) memory B cells. We found that B-1 cells differ from 20(+)38(hi) B cells and PBs in a number of ways, including Ag expression, morphological appearance, transcriptional profiling, Ab skewing, Ab repertoire, and secretory response to stimulation. In terms of gene expression, B-1 cells align more closely with memory B cells than with 20(+)38(hi) B cells or PBs, but differ in that memory B cells do not express Ab secretion-related genes. We found that B-1 cell Abs use Vh4-34, which is often associated with autoreactivity, 3- to 6-fold more often than other B cell populations. Along with selective production of IgM anti-phosphoryl choline, these data suggest that human B-1 cells might be preferentially selected for autoreactivity/natural specificity. In summary, our results indicate that human healthy adult peripheral blood at steady-state consists of three distinct ASC populations.
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http://dx.doi.org/10.4049/jimmunol.1501843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351554PMC
February 2016

Immunolocalization of hyperpolarization-activated cationic HCN1 and HCN3 channels in the rat nephron: regulation of HCN3 by potassium diets.

Histochem Cell Biol 2016 Jan 29;145(1):25-40. Epub 2015 Oct 29.

Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico, DF, México.

Hyperpolarization-activated cationic and cyclic nucleotide-gated channels (HCN) comprise four homologous subunits (HCN1-HCN4). HCN channels are found in excitable and non-excitable tissues in mammals. We have previously shown that HCN2 may transport ammonium (NH4 (+)), besides sodium (Na(+)), in the rat distal nephron. In the present work, we identified HCN1 and HCN3 in the proximal tubule (PT) and HCN3 in the thick ascending limb of Henle (TALH) of the rat kidney. Immunoblot assays detected HCN1 (130 kDa) and HCN3 (90 KDa) and their truncated proteins C-terminal HCN1 (93 KDa) and N-terminal HCN3 (65 KDa) in enriched plasma membranes from cortex (CX) and outer medulla (OM), as well as in brush-border membrane vesicles. Immunofluorescence assays confirmed apical localization of HCN1 and HCN3 in the PT. HCN3 was also found at the basolateral membrane of TALH. We evaluated chronic changes in mineral dietary on HCN3 protein abundance. Animals were fed with three different diets: sodium-deficient (SD) diet, potassium-deficient (KD) diet, and high-potassium (HK) diet. Up-regulation of HCN3 was observed in OM by KD and in CX and OM by HK; the opposite effect occurred with the N-terminal truncated HCN3 in CX (KD) and OM (HK). SD diet did not produce any change. Since HCN channels activate with membrane hyperpolarization, our results suggest that HCN channels may play a role in the Na(+)-K(+)-ATPase activity, contributing to Na(+), K(+), and acid-base homeostasis in the rat kidney.
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http://dx.doi.org/10.1007/s00418-015-1375-6DOI Listing
January 2016

Anti-NeuGcGM3 reactivity: a possible role of natural antibodies and B-1 cells in tumor immunosurveillance.

Ann N Y Acad Sci 2015 Dec 27;1362:224-38. Epub 2015 Jul 27.

Natural Antibodies Group, Tumor Immunology Division, Center of Molecular Immunology, Havana, Cuba.

While not naturally expressed in normal human tissues, N-glycolylated (NeuGc) gangliosides are overexpressed in several tumors and have immunosuppressive capacity, which contributes to cancer progression. Naturally occurring antibodies against NeuGcGM3 exist in healthy donors that specifically recognize and kill tumor cells expressing the antigen by complement-dependent and -independent mechanisms, the latter resembling an oncotic necrosis-type of cell death. Both the levels of anti-NeuGcGM3 antibodies in the sera of healthy donors and the percentage of donors with these natural antibodies decrease with age. Our work has shown that anti-NeuGcGM3 antibodies are not detected in the sera of non-small cell lung cancer (NSCLC) patients, compared to age- and sex-matched healthy donors, which have anti-NeuGcGM3. Interestingly, the level of serum total IgM, but not IgG, was significantly lower in cancer patients than in healthy donors. Screening of immortalized mouse splenic and peritoneal-derived hybridomas showed that peritoneal B-1 cells secrete anti-NeuGcGM3 with tumor cytotoxic capacity. Defects in the natural surveillance against tumor antigens could increase the risk of elderly donors developing cancer and affect the capacity of cancer patients to effectively fight against tumor cells.
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http://dx.doi.org/10.1111/nyas.12827DOI Listing
December 2015

Racotumomab-alum vaccine for the treatment of non-small-cell lung cancer.

Expert Rev Vaccines 2015 Jan 25;14(1):9-20. Epub 2014 Nov 25.

Center for Molecular Immunology - Tumor Biology, 15th Ave and 217 Street, Atabey, Playa, Habana, Cuba.

Racotumomab-alum vaccine is an anti-idiotypic vaccine able to mimic the tumor-associated antigen NeuGcGM3. Different Phase I clinical trials and compassionate use studies demonstrated its low toxicity and capacity to induce a strong anti-NeuGcGM3 response, able to bind and directly kill tumor cells expressing the antigen. A Phase II/III randomized double-blind clinical trial in advanced non-small cell lung cancer patients showed a significant improvement in overall survival and progression-free survival for racotumomab-alum versus placebo. Patients who developed anti-NeuGcGM3 antibodies capable of binding and killing NeuGcGM3 expressing tumor cells showed significantly longer median survival times. The impact of using racotumomab-alum as switch maintenance followed by second-line therapy is currently being explored in a new randomized, multinational Phase III study.
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http://dx.doi.org/10.1586/14760584.2015.984691DOI Listing
January 2015

A randomized, multicenter, placebo-controlled clinical trial of racotumomab-alum vaccine as switch maintenance therapy in advanced non-small cell lung cancer patients.

Clin Cancer Res 2014 Jul 1;20(14):3660-71. Epub 2014 May 1.

Center of Molecular Immunology;

Purpose: Racotumomab-alum is an anti-idiotype vaccine targeting the NeuGcGM3 tumor-associated ganglioside. This clinical trial was conducted to provide a preliminary estimate of efficacy and safety of racotumomab as switch maintenance for patients with advanced non-small cell lung cancer (NSCLC).

Experimental Design: Patients with stage IIIb/IV NSCLC who have at least stable disease after first-line chemotherapy were randomized 1:1 to racotumomab-alum (5 immunizations every 2 weeks and re-immunizations every 4 weeks) or placebo. Treatment was administered beyond progressive disease, until severe performance status worsening or toxicity. At progression, only five patients per group received further anticancer therapy. The primary endpoint was overall survival (OS).

Results: One-hundred and seventy-six patients were randomized to racotumomab-alum (n = 87) and placebo (n = 89). Median OS was 8.23 and 6.80 months, respectively [HR, 0.63; 95% confidence interval (CI), 0.46-0.87; P = 0.004]. Median progression-free survival (PFS) in vaccinated patients was 5.33 versus 3.90 months for placebo (HR, 0.73; 95% CI 0.53-0.99; P = 0.039). The most common adverse events in the racotumomab-alum arm were burning and pain at the injection site, bone pain, and asthenia. A high antibody response of IgM and IgG isotype against the NeuGcGM3 ganglioside was obtained. Hyperimmune sera were able to specifically recognize and kill the NeuGcGM3-expressing L1210 cell line. Patients who developed anti-NeuGcGM3 antibodies capable to bind and kill ≥30% L1210 cells showed longer median survival times.

Conclusions: Switch maintenance with racotumomab-alum is an effective and a well-tolerated treatment option for patients with advanced NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1674DOI Listing
July 2014

Urinary MCP-1/creatinine in Henoch-Schönlein purpura and its relationship with nephritis.

Pediatr Nephrol 2014 Jun 12;29(6):1047-52. Epub 2014 Jan 12.

Laboratorio de Investigación en Nefrología, Hospital Infantil de México Federico Gómez, Calle Dr. Márquez 162, Col. Doctores, Deleg. Cuauhtémoc, C. P. 06720, México, D. F., México,

Background: Monocyte chemotactic protein-1 (MCP-1) plays a direct role in the infiltration of macrophages and monocytes during the early stages of Henoch-Schönlein purpura (HSP) nephritis. The aim of this study was to compare the urinary MCP-1/creatinine levels in children with and without HSP nephritis and determine if they are associated with the severity of renal lesions.

Methods: We included 77 patients with HSP and 25 healthy control children. Levels of serum creatinine, urinalysis, and 12-h proteinuria assessments were performed. Urinary MCP-1 levels were determined by ELISA.

Results: Fifty-seven patients had nephritis (74 %). Urinary MCP-1/creatinine levels were significantly higher in patients with HSP nephritis (median, 653 pg/mg) compared to those with HSP without nephritis (median, 269 pg/mg) or healthy children (191 pg/mg). In addition, higher MCP-1/creatinine levels were observed in HSP patients who had renal biopsy (median, 1,412 pg/mg) in comparison to HSP patients without renal biopsy (median, 302 pg/mg). The urinary MCP-1 cut-off value of 530 pg/mg could be used to distinguish patients who undergo renal biopsy with a sensitivity of 81 % and specificity of 77 %.

Conclusions: Urinary MCP-1/creatinine levels are elevated in the early stages of severe HSP nephritis and can be used as a biomarker for HSP nephritis.
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http://dx.doi.org/10.1007/s00467-013-2740-0DOI Listing
June 2014

Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila.

PLoS Genet 2013 Nov 7;9(11):e1003941. Epub 2013 Nov 7.

Department of Ecology and Evolutionary Biology, Brown University, Providence, Rhode Island, United States of America.

Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling.
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http://dx.doi.org/10.1371/journal.pgen.1003941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820802PMC
November 2013

Human antibodies reactive to NeuGcGM3 ganglioside have cytotoxic antitumor properties.

Eur J Immunol 2013 Mar 8;43(3):826-37. Epub 2013 Feb 8.

Tumor Immunology Direction, Center of Molecular Immunology, Havana, Cuba.

N-glycolylated gangliosides are not naturally expressed in healthy human tissues but are overexpressed in several tumors. We demonstrate the existence of antibodies that bind (N-glycolylneuraminyl)-lactosylceramide (NeuGcGM3) and are detectable in the sera of 65 from the 100 donors (65%) tested by ELISA. From those 65 NeuGcGM3 antibody-positive donors, 35 had antibodies that were able to recognize and kill NeuGcGM3-expressing tumor cells by a complement-mediated mechanism. After complement inactivation, 11 of the 35 positive sera showed a direct cytotoxic effect on the tumor cells. This complement-independent cytotoxicity was dependent on the presence of antigen on the membrane and resembles an oncotic necrosis cell death. Both the levels of anti-NeuGcGM3 antibodies in the sera as well as the percentage of healthy donors with this immunity decreased with the age of the donor. In contrast to age and gender-matched healthy donors, we could only detect low reactivity against NeuGcGM3 in the sera of six out of 53 non-small cell lung cancer patients. These results suggest the existence of antibodies against NeuGcGM3 with antitumor immune surveillance functions, reinforcing the importance of N-glycolylated gangliosides as antitumor targets.
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http://dx.doi.org/10.1002/eji.201242693DOI Listing
March 2013

P3 mAb: An Immunogenic Anti-NeuGcGM3 Antibody with Unusual Immunoregulatory Properties.

Front Immunol 2012 26;3:94. Epub 2012 Apr 26.

Tumor Immunology Direction, Center of Molecular Immunology Havana, Cuba.

P3 is a murine IgM mAb that recognize N-glycosylated gangliosides, sulfatides, and antigens expressed in melanoma, breast, and lung human tumors. This antibody has the ability to trigger an IgG antibody response in the syngeneic BALB/c model, even when it is administered in the absence of adjuvant or carrier protein. The mechanism by which the P3 mAb, a self-immunoglobulin, induce this immune response in the absence of co-stimulatory or classical danger signals is still unknown. In the present paper we show that the high immunogenicity of P3 mAb depends not only on CD4 but also on CD8(+) T cells, since the depletion of CD8(+) or CD4(+) T cells led to the loss of P3 mAb immunogenicity in the syngeneic model. Furthermore, the immunization with P3 mAb enhanced the recovery of the CD8(+) T cell population in mice treated with an anti-CD8a antibody. Additionally, the immunization with P3 mAb restored the capacity of immunosuppressed mice to reject allogeneic tumors, a mechanism mediated by the action of CD8(+) T cells. Finally, in mice with cyclophosphamide induced lymphopenia, the administration of P3 mAb accelerated the recovery of both CD4(+) and CD8(+) T cells. These results show new possibilities for B and CD8(+) T cells interactions during the immune response elicited by a self-protein. Furthermore they point to P3 mAb as a potential interesting candidate for the treatment of immunosuppressed patients.
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http://dx.doi.org/10.3389/fimmu.2012.00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342266PMC
August 2012

Immunopharmacology 2011: an updated report of clinical achievements and perspectives.

Expert Rev Clin Pharmacol 2011 Nov;4(6):693-5

Finlay Institute, Avenida 27, No 19805, CP 11600, La Lisa, La Habana, Cuba.

On 26-30 June 2011 the Cuban Society of Pharmacology organized the Second International Congress on Immunopharmacology (Immunopharmacology 2011), held at the beautiful Convention Centre 'Plaza América' and the Meliá Varadero Hotel, in Varadero beach, Cuba. The main topics of the congress were immunopharmacology (including inflammation, cancer immunotherapy and immunomodulation), neuroimmunology, and the pharmacology of cytochrome P450 and transporters, among other relevant and updated related topics. Immunopharmacology 2011 offered an outstanding scientific program with the active contribution of 90 speakers from 23 foreign countries, as well as more than 170 Cuban researchers from the most important local institutions devoted to the development of immunology and pharmacology sciences.
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http://dx.doi.org/10.1586/ecp.11.61DOI Listing
November 2011

Anti-NeuGcGM3 antibodies, actively elicited by idiotypic vaccination in nonsmall cell lung cancer patients, induce tumor cell death by an oncosis-like mechanism.

J Immunol 2011 Mar 7;186(6):3735-44. Epub 2011 Feb 7.

Department of Antibody Engineering, Center of Molecular Immunology, Havana 11600, Cuba.

1E10 is a murine anti-idiotypic mAb specific for an idiotypic mAb that reacts with NeuGc-containing gangliosides, sulfatides, and Ags expressed in some human tumors. In melanoma, breast, and lung cancer patients, this anti-idiotypic Ab was able to induce a specific Ab response against N-glycosylated gangliosides, attractive targets for cancer immunotherapy as these glycolipids are not naturally expressed in humans. A clinical study with nonsmall cell lung cancer patients showed encouraging clinical benefits. Immunological studies performed in 20 of these patients suggested a correlation between the induction of Abs against NeuGcGM3 and longer survival times. The induced anti-NeuGcGM3 Abs recognized and directly killed tumor cells expressing the Ag, by a mechanism independent of complement activation. In the present work, we show that this cytotoxicity differs from apoptosis because it is temperature independent, no chromatin condensation or caspase 3 induction are detected, and the DNA fragmentation induced has a different pattern than the one characteristic for apoptosis. It is a very quick process and involves cytosqeleton reorganization. The Abs induce cellular swelling and the formation of big membrane lesions that allow the leakage of cytoplasm and the loss of the cell membrane integrity. All of these characteristics resemble a process of oncotic necrosis. To our knowledge, this is the first report of the active induction in cancer patients of NeuGcGM3-specific Abs able to induce complement independent oncotic necrosis to tumor cells. These results contribute to reinforcing the therapeutic potential of anti-idiotypic vaccines and the importance of NeuGcGM3 ganglioside as antitumor target.
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http://dx.doi.org/10.4049/jimmunol.1000609DOI Listing
March 2011

Characterization of the antibody response against NeuGcGM3 ganglioside elicited in non-small cell lung cancer patients immunized with an anti-idiotype antibody.

J Immunol 2008 Nov;181(9):6625-34

Department of Antibody Engineering, Center of Molecular Immunology, Havana, Cuba.

1E10 mAb is an anti-Id murine mAb (Ab2 mAb) specific for an Ab1 mAb that reacts with NeuGc-containing gangliosides, sulfatides, and Ags expressed in some human tumors. In preclinical studies, this Ab2 Ab was able to mimic NeuGc-containing gangliosides only in animals lacking expression of these Ags in normal tissues. In this study, we report on the immune responses elicited in 20 non-small cell lung cancer patients treated with 1 mg of aluminum hydroxide-precipitated 1E10 mAb. In the hyperimmune sera from 16 of 20 patients, a strong specific Ab response of both IgM and IgG isotypes against NeuGcGM3 ganglioside was observed. Patient immune sera were able to induce complement-independent cell death of NeuGcGM3-expressing X63 murine myeloma target cells. Significant immunoreactivity to NeuGcGM3 was still detected after the complete abrogation of the reactivity against 1E10 mAb by the adsorption of patient sera with this Ab. We hypothesize that Id(-)Ag(+) Abs could reflect the activation of an autologous idiotypic cascade into the patients. Both Id(+)Ag(+) and Id(-)Ag(+) fractions were separated by affinity chromatography and characterized. Although IgG isotype Abs were found in both fractions, IgM isotype Abs were found only in the Id(-)Ag(+) fraction. Both Id(+)Ag(+) and Id(-)Ag(+) Abs were able to specifically recognize and induce cell death in NeuGcGM3-expressing X63 myeloma target cells. Patients that developed IgG and/or IgM Abs against NeuGcGM3 showed longer median survival times.
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http://dx.doi.org/10.4049/jimmunol.181.9.6625DOI Listing
November 2008

Perlecan, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway.

Mol Cancer 2006 Mar 1;5. Epub 2006 Mar 1.

Department of Pathology, Emory University, Atlanta, GA 30322, USA.

Background: Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers. We have identified HSPG2 (Perlecan) as a candidate gene for CAPB. Previously we have linked Perlecan to Hedgehog signaling in Drosophila. More recently, we have demonstrated the importance of Hedgehog signaling in humans for advanced prostate cancer.

Results: Here we demonstrate Perlecan expression in prostate cancer, and its function in prostate cancer cell growth through interaction and modulation of Sonic Hedgehog (SHH) signaling. Perlecan expression in prostate cancer tissues correlates with a high Gleason score and rapid cell proliferation. Perlecan is highly expressed in prostate cancer cell lines, including androgen insensitive cell lines and cell lines selected for metastatic properties. Inhibition of Perlecan expression in these cell lines decreases cell growth. Simultaneous blockade of Perlecan expression and androgen signaling in the androgen-sensitive cell line LNCaP was additive, indicating the independence of these two pathways. Perlecan expression correlates with SHH in tumor tissue microarrays and increased tumor cell proliferation based on Ki-67 immunohistochemistry. Inhibition of Perlecan expression by siRNA in prostate cancer cell lines decreases SHH signaling while expression of the downstream SHH effector GLI1 rescues the proliferation defect. Perlecan forms complexes with increasing amounts of SHH that correlate with increasing metastatic potential of the prostate cancer cell line. SHH signaling also increases in the more metastatic cell lines. Metastatic prostate cancer cell lines grown under serum-starved conditions (low androgen and growth factors) resulted in maintenance of Perlecan expression. Under low androgen, low growth factor conditions, Perlecan expression level correlates with the ability of the cells to maintain SHH signaling.

Conclusion: We have demonstrated that Perlecan, a candidate gene for the CAPB locus, is a new component of the SHH pathway in prostate tumors and works independently of androgen signaling. In metastatic tumor cells increased SHH signaling correlates with the maintenance of Perlecan expression and more Perlecan-SHH complexes. Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions. This proteoglycan represents an important central regulator of SHH activity and presents an ideal drug target for blocking SHH effects.
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http://dx.doi.org/10.1186/1476-4598-5-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1421430PMC
March 2006

Generation of anti-Neu-glycolyl-ganglioside antibodies by immunization with an anti-idiotype monoclonal antibody: A self versus non-self-matter.

Immunobiology 2005 ;210(1):11-21

Department of Antibody Engineering, Center of Molecular Immunology, P.O. Box 16040, Havana 11600, Cuba.

We have previously generated a murine anti-idiotype (Ab2) monoclonal antibody (mAb) to a murine Ab1 mAb, named P3, which selectively binds Neu-glycolyl (NeuGc)-sialic acid on several monosialo- and disialogangliosides, and also reacts with sulfatides and antigens expressed in human melanoma and breast tumors. This Ab2 mAb, designated as 1E10, induced anti-anti-idiotype antibodies (Ab3) in mice and cancer patients. These Ab3 generated by 1E10 mAb were characterized by bearing P3 mAb idiotopes (Ab3, Id +). But when the specificity of these Ab3 antibodies was tested, no specific humoral response against NeuGc-containing gangliosides was detected in sera from immunized mice. However, hyperimmune sera from melanoma and breast cancer patients vaccinated with this Ab2 mAb were able to react specifically with these gangliosides. The different expression of NeuGc-containing gangliosides in the normal tissues of mice and humans could explain these results. In order to demonstrate these findings in other animal species with a different NeuGc-sialic acid expression, we performed similar studies in monkeys and chickens. In monkeys, as in most mammals, NeuGc-containing gangliosides are self-antigens. In contrast, chickens, like humans, lack the expression of these antigens in normal tissues. Here we report that the antibody response against NeuGc-containing gangliosides induced by immunization with 1E10 mAb was completely different in both species. No specific antibody response against these gangliosides was detected in hyperimmune monkey sera. In contrast, a strong and specific Ab3 response against GM3(NeuGc) and GM2(NeuGc) gangliosides (Ab3, Ag+) was generated in chickens due to the administration of 1E10 mAb.
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http://dx.doi.org/10.1016/j.imbio.2005.02.002DOI Listing
September 2005

Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling.

Proc Natl Acad Sci U S A 2004 Aug 16;101(34):12561-6. Epub 2004 Aug 16.

Skirball Institute and Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.

Prostate cancer is the most common solid tumor in men, and it shares with all cancers the hallmark of elevated, nonhomeostatic cell proliferation. Here we have tested the hypothesis that the SONIC HEDGEHOG (SHH)-GLI signaling pathway is implicated in prostate cancer. We report expression of SHH-GLI pathway components in adult human prostate cancer, often with enhanced levels in tumors versus normal prostatic epithelia. Blocking the pathway with cyclopamine or anti-SHH antibodies inhibits the proliferation of GLI1+/PSA+ primary prostate tumor cultures. Inversely, SHH can potentiate tumor cell proliferation, suggesting that autocrine signaling may often sustain tumor growth. In addition, pathway blockade in three metastatic prostate cancer cell lines with cyclopamine or through GLI1 RNA interference leads to inhibition of cell proliferation, suggesting cell-autonomous pathway activation at different levels and showing an essential role for GLI1 in human cells. Our data demonstrate the dependence of prostate cancer on SHH-GLI function and suggest a novel therapeutic approach.
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http://dx.doi.org/10.1073/pnas.0404956101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC514658PMC
August 2004

An anti-idiotype vaccine elicits a specific response to N-glycolyl sialic acid residues of glycoconjugates in melanoma patients.

J Immunol 2002 Mar;168(5):2523-9

Department of Antibody Engineering, Center of Molecular Immunology, P.O. Box 16040, Havana 11600, Cuba.

We generated the 1E10 gamma-type anti-idiotype mAb (Ab2) specific to an Ab1 mAb able to react specifically with N-glycolyl-containing gangliosides and with Ags expressed on human melanoma and breast carcinoma cells. This Ab2 mAb induced an Ab response in animal models sharing immunochemically defined idiotopes with the Ab1. The treatment of tumor-bearing mice with 1E10 mAb induced a strong antitumor activity. A clinical trial was conducted in 20 patients with advanced malignant melanoma. Patients were treated with six intradermal injections of aluminum hydroxide-precipitated 1E10 anti-Id mAb given at 2-wk intervals. Sixteen of the 17 patients who received at least four doses of the anti-Id vaccine develop Ab3 Abs capable of inhibiting Ab2 binding to Ab1 (Ab3Id+). In contrast to the incapacity of 1E10 mAb to generate Ab3 Abs with the same antigenic specificity as the Ab1 mAb in mice, a very specific and strong Ab3 response against N-glycolyl-containing gangliosides was induced in 16 patients (Ab3Ag+). No evidence of serious or unexpected adverse effects has been observed in this clinical trial. 1E10 anti-Id vaccine was safe, well tolerated, and immunologically effective, with most patients being able to generate a specific immune response against 1E10 and Neu-glycolyl-GM(3) ganglioside.
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http://dx.doi.org/10.4049/jimmunol.168.5.2523DOI Listing
March 2002