Iceberg lettuce cultivated in different systems of planting and sources of fertilizer / Alface americana cultivada em diferentes sistemas de plantio e fontes de fertilizantes

Organic fertilization is a cheaper and highly effective option for profitability and consequent improvement of the soil's physical, chemical, and biological structure. Thus, the objective of this work was to evaluate different types of fertilization: organic (poultry shed litter), mineral, and leaf path on yield parameters of lettuce grown in various types of planting. The treatments consisted of using two planting systems (P1 - Line and P2 - quincunxes) and mineral and organic fertilizers (A1 - mineral fertilization; A2 - mineral fertilization + leaf fertilization; A3 - organic fertilization with poultry shed litter and A4 - fertilization organic + mineral). The experimental units consisted of 36 and 52 plants, respectively, for treatments P1 and P2, and all central plants of the experimental unit were evaluated. Heart height, fresh mass, and leaf number were observed. The mineral and mineral + leaf treatments did not differentiate, either in line or in quincunxes. The treatment that stood out about the analyzed variables was the organic fertilization and quincunxes planting system, reflecting a more significant number of lettuce plants and better use of the area.

A adubação orgânica é uma opção mais barata e de grande eficácia em relação à rentabilidade e consequente melhoria da estrutura física, química e biológica do solo. Desta forma, o objetivo deste trabalho foi avaliar diferentes tipos de adubação: orgânica (cama de frango), mineral e via foliar sobre parâmetros de produtividade de alface cultivada em diferentes tipos de plantio. Os tratamentos consistiram na utilização de dois sistemas de plantio (P1 - Linha e P2 - Quincôncio) e adubações minerais e orgânicas (A1 - adubação mineral; A2 - adubação mineral + adubação foliar; A3 - adubação orgânica com cama de aviário e A4 - adubação orgânica + mineral). As unidades experimentais foram compostas por 36 e 52 plantas, respectivamente, para os tratamentos em linha e em quincôncio, sendo avaliadas todas as plantas centrais da unidade experimental. Foram observados a altura do coração, massa fresca e número de folhas. Os tratamentos mineral e mineral + foliar não diferenciaram entre si, tanto em linha quanto em quincôncio. O tratamento que se destacou em relação às variáveis analisadas foi aquele baseado na adubação orgânica e sistema de plantio em quincôncio, refletindo em maior número de pés de alface e melhor aproveitamento da área.

Iceberg lettuce cultivated in different systems of planting and sources of fertilizer

Abstract Organic fertilization is a cheaper and highly effective option for profitability and consequent improvement of the soil's physical, chemical, and biological structure. Thus, the objective of this work was to evaluate different types of fertilization: organic (poultry shed litter), mineral, and leaf path on yield parameters of lettuce grown in various types of planting. The treatments consisted of using two planting systems (P1 - Line and P2 - quincunxes) and mineral and organic fertilizers (A1 - mineral fertilization; A2 - mineral fertilization + leaf fertilization; A3 - organic fertilization with poultry shed litter and A4 - fertilization organic + mineral). The experimental units consisted of 36 and 52 plants, respectively, for treatments P1 and P2, and all central plants of the experimental unit were evaluated. Heart height, fresh mass, and leaf number were observed. The mineral and mineral + leaf treatments did not differentiate, either in line or in quincunxes. The treatment that stood out about the analyzed variables was the organic fertilization and quincunxes planting system, reflecting a more significant number of lettuce plants and better use of the area.

Resumo A adubação orgânica é uma opção mais barata e de grande eficácia em relação à rentabilidade e consequente melhoria da estrutura física, química e biológica do solo. Desta forma, o objetivo deste trabalho foi avaliar diferentes tipos de adubação: orgânica (cama de frango), mineral e via foliar sobre parâmetros de produtividade de alface cultivada em diferentes tipos de plantio. Os tratamentos consistiram na utilização de dois sistemas de plantio (P1 - Linha e P2 - Quincôncio) e adubações minerais e orgânicas (A1 - adubação mineral; A2 - adubação mineral + adubação foliar; A3 - adubação orgânica com cama de aviário e A4 - adubação orgânica + mineral). As unidades experimentais foram compostas por 36 e 52 plantas, respectivamente, para os tratamentos em linha e em quincôncio, sendo avaliadas todas as plantas centrais da unidade experimental. Foram observados a altura do coração, massa fresca e número de folhas. Os tratamentos mineral e mineral + foliar não diferenciaram entre si, tanto em linha quanto em quincôncio. O tratamento que se destacou em relação às variáveis analisadas foi aquele baseado na adubação orgânica e sistema de plantio em quincôncio, refletindo em maior número de pés de alface e melhor aproveitamento da área.

Injectable hydrogels for the delivery of nanomaterials for cancer combinatorial photothermal therapy.

Progress in the nanotechnology field has led to the development of a new class of materials capable of producing a temperature increase triggered by near infrared light. These photothermal nanostructures have been extensively explored in the ablation of cancer cells. Nevertheless, the available data in the literature have exposed that systemically administered nanomaterials have a poor tumor-homing capacity, hindering their full therapeutic potential. This paradigm shift has propelled the development of new injectable hydrogels for the local delivery of nanomaterials aimed at cancer photothermal therapy. These hydrogels can be assembled at the tumor site after injection (in situ forming) or can undergo a gel-sol-gel transition during injection (shear-thinning/self-healing). Besides incorporating photothermal nanostructures, these injectable hydrogels can also incorporate or be combined with other agents, paving the way for an improved therapeutic outcome. This review analyses the application of injectable hydrogels for the local delivery of nanomaterials aimed at cancer photothermal therapy as well as their combination with photodynamic-, chemo-, immuno- and radio-therapies.

Development of Thiol-Maleimide hydrogels incorporating graphene-based nanomaterials for cancer chemo-photothermal therapy.

Nano-sized materials have been widely explored in the biomedicine field, especially due to their ability to encapsulate drugs intended to be delivered to cancer cells. However, systemically administered nanomaterials face several barriers that can hinder their tumor-homing capacity. In this way, researchers are now focusing their efforts in developing technologies that can deliver the nanoparticles directly into the tumor tissue. Particularly, hydrogels assembled using Thiol-Maleimide Michael type additions are emerging for this purpose due to their capacity to incorporate high nanoparticles' doses in a compact 3D structure as well as good chemical selectivity, biocompatibility, and straightforward preparation. Nevertheless, such hydrogels have been mostly prepared using synthetic polymers, which is not ideal due to their poor biodegradability. In this work, a novel natural polymer-based Thiol-Maleimide hydrogel was produced for application in breast cancer chemo-photothermal therapy. To obtain natural polymers compatible with this crosslinking chemistry, Hyaluronic acid was endowed with Thiol groups and deacetylated Chitosan was grafted with Maleimide groups. Parallelly, Doxorubicin loaded Dopamine-reduced graphene oxide (DOX/DOPA-rGO) was prepared for attaining Near Infrared (NIR) light responsive chemo-photothermal nanoagents. By simply mixing Hyaluronic Acid-Thiol, deacetylated Chitosan-Maleimide and DOX/DOPA-rGO, Thiol-Maleimide crosslinked hydrogels incorporating this nanomaterial could be assembled (DOX/DOPA-rGO@TMgel). When breast cancer cells were incubated with DOPA-rGO@TMgel and exposed to NIR light (photothermal therapy), their viability was reduced to about 59 %. On the other hand, DOX/DOPA-rGO@TMgel (chemotherapy) reduced cancer cells' viability to 50 %. In stark contrast, the combined action of DOX/DOPA-rGO@TMgel and NIR light decreased breast cancer cells' viability to just 21 %, highlighting its chemo-photothermal potential.

Simple preparation of POxylated nanomaterials for cancer chemo-PDT/PTT.

Near infrared (NIR) light-responsive nanomaterials hold potential to mediate combinatorial therapies targeting several cancer hallmarks. When irradiated, these nanomaterials produce reactive oxygen species (photodynamic therapy) and/or a temperature increase (photothermal therapy). These events can damage cancer cells and trigger the release of drugs from the nanomaterials' core. However, engineering nanomaterials for cancer chemo-photodynamic/photothermal therapy is a complex process. First, nanomaterials with photothermal capacity are synthesized, being then loaded with photosensitizers plus chemotherapeutics, and, finally functionalized with polymers for achieving suitable biological properties. To overcome this limitation, in this work, a novel straightforward approach to attain NIR light-responsive nanosystems for cancer chemo-photodynamic/photothermal therapy was established. Such was accomplished by synthesizing poly(2-ethyl-2-oxazoline)-IR780 amphiphilic conjugates, which can be assembled into nanoparticles with photodynamic/photothermal capabilities that simultaneously encapsulate Doxorubicin (DOX/PEtOx-IR NPs). The DOX/PEtOx-IR NPs presented a suitable size and surface charge for cancer-related applications. When irradiated with NIR light, the DOX/PEtOx-IR NPs produced singlet oxygen as well as a smaller thermic effect that boosted the release of DOX by 1.7-times. In the in vitro studies, the combination of DOX/PEtOx-IR NPs and NIR light could completely ablate breast cancer cells (viability ≈ 4 %), demonstrating the enhanced outcome arising from the nanomaterials' chemo-photodynamic/photothermal therapy.

Iceberg lettuce cultivated in different systems of planting and sources of fertilizer.

Organic fertilization is a cheaper and highly effective option for profitability and consequent improvement of the soil's physical, chemical, and biological structure. Thus, the objective of this work was to evaluate different types of fertilization: organic (poultry shed litter), mineral, and leaf path on yield parameters of lettuce grown in various types of planting. The treatments consisted of using two planting systems (P1 - Line and P2 - quincunxes) and mineral and organic fertilizers (A1 - mineral fertilization; A2 - mineral fertilization + leaf fertilization; A3 - organic fertilization with poultry shed litter and A4 - fertilization organic + mineral). The experimental units consisted of 36 and 52 plants, respectively, for treatments P1 and P2, and all central plants of the experimental unit were evaluated. Heart height, fresh mass, and leaf number were observed. The mineral and mineral + leaf treatments did not differentiate, either in line or in quincunxes. The treatment that stood out about the analyzed variables was the organic fertilization and quincunxes planting system, reflecting a more significant number of lettuce plants and better use of the area.

A reaction-diffusion network model predicts a dual role of Cactus/IκB to regulate Dorsal/NFκB nuclear translocation in Drosophila.

Dorsal-ventral patterning of the Drosophila embryo depends on the NFκB superfamily transcription factor Dorsal (Dl). Toll receptor activation signals for degradation of the IκB inhibitor Cactus (Cact), leading to a ventral-to-dorsal nuclear Dl gradient. Cact is critical for Dl nuclear import, as it binds to and prevents Dl from entering the nuclei. Quantitative analysis of cact mutants revealed an additional Cact function to promote Dl nuclear translocation in ventral regions of the embryo. To investigate this dual Cact role, we developed a predictive model based on a reaction-diffusion regulatory network. This network distinguishes non-uniform Toll-dependent Dl nuclear import and Cact degradation, from the Toll-independent processes of Cact degradation and reversible nuclear-cytoplasmic Dl flow. In addition, it incorporates translational control of Cact levels by Dl. Our model successfully reproduces wild-type data and emulates the Dl nuclear gradient in mutant dl and cact allelic combinations. Our results indicate that the dual role of Cact depends on the dynamics of Dl-Cact trimers along the dorsal-ventral axis: In the absence of Toll activation, free Dl-Cact trimers retain Dl in the cytoplasm, limiting the flow of Dl into the nucleus; in ventral-lateral regions, Dl-Cact trimers are recruited by Toll activation into predominant signaling complexes and promote Dl nuclear translocation. Simulations suggest that the balance between Toll-dependent and Toll-independent processes are key to this dynamics and reproduce the full assortment of Cact effects. Considering the high evolutionary conservation of these pathways, our analysis should contribute to understanding NFκB/c-Rel activation in other contexts such as in the vertebrate immune system and disease.

Behavior Patterns of Antisocial Teenagers Interacting with Parents and Peers: A Longitudinal Study.

Antisocial behavior may begin during childhood and if maintained during adolescence, is likely to continue and escalate during adulthood. During adolescence, in particular, it has been established that antisocial behavior may be reinforced and shaped by exchanges between the teenager and his parents and peers, although the molecular process of these relations is as yet unknown. This paper explores the patterns of social interaction established by adolescents with and without the risk of engaging in antisocial behavior in order to understand the exchanges of them with their most important social groups, during 2 years. The study involved a sample of 70 adolescents classified into these two groups (with risk of antisocial behavior and control group). They were video-recorded interacting with one of their parents and one of their peers, independently. The interaction was done about the negotiation of conflictive conversational topics. Those video-records were registered by pairs of trained observers, using an observational catalog with nineteen behavioral categories, to know about the molecular interactional patterns characteristics. Thirty participants were evaluated only once, 30 were evaluated two times, and the other 10 were evaluated three times, the evaluations were performed annually. It was found that a higher occurrence of eye contact and use of open questions and elaborate answers appears to act as a protective factor for engaging in antisocial behavior.

Cytomegalovirus (CMV) genotype in allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Based on sequence variation in the UL55 gene that encodes glycoprotein B (gB), human cytomegalovirus (CMV) can be classified into four gB genotypes. Previous studies have suggested an association between CMV gB genotype and clinical outcome in patients who underwent an allogeneic hematopoietic stem cell transplant (HSCT). The goals of this study were identify patients with active infection caused by CMV in recipients of HSCT; determine the prevalence of CMV genotypes in the study group; correlate genotype with CMV disease, acute GVHD and overall survival. METHODS: The diagnosis of active CMV infection after allogeneic HSCT was detected by antigenemia (AGM) and/or nested-PCR (N-PCR). Positive samples from patients with active CMV infection were submitted to genotyping using N-PCR to amplify a region of UL55, followed by restriction analysis based on HinfI and RsaI digestion. Real-time PCR (qPCR) was used to determine the viral load during active CMV infection and antiviral treatment. RESULTS: Sixty-three allogeneic HSCT recipients were prospectively evaluated; 49/63 (78%) patients were infected with CMV genotypes - gB1 19/49 (39%), gB2 17/49 (35%), gB3 3/49 (6%), gB4 7/49 (14%) - and 3 (6%) had mixed CMV genotypes (gB1 + gB3, gB1 + gB4 and gB2 + gB4). Characterized by gastrointestinal disease, CMV disease occurred in 3/49 (6.1%) patients, who had CMV gB3 genotype. These gB3 genotype patients presented an increasing AGM number, mean 125 (± 250) (P = 0.70), and qPCR copies/ml, mean 37938 (SD ± 50542) (P = 0.03), during antiviral treatment, when compared with other CMV genotypes. According to CMV genotypes, stratified overall survival was 55% for gB1, 43% for gB2; 0% for gB3 and 57% for gB4 (P = 0.03). CONCLUSIONS: One of the restrictions of the presented study was the low number of CMV gB sub-cohorts). However, we demonstrated that the frequency of active CMV infection in this HSCT population was high, and the most prevalent genotype in these patients with active CMV infection was gB1 and gB2 genotype (74%). In Brazil, HSCT recipients seem to carry mainly gB1 and gB2 CMV genotype.

The role of Bicoid cooperative binding in the patterning of sharp borders in Drosophila melanogaster.

In Drosophila embryonic development, the Bicoid (Bcd) protein establishes positional information of downstream developmental genes like hunchback (hb), which has a strong anterior expression and a sharp on-off boundary in the mid-embryo. The role of Bcd cooperative binding in the positioning of the Hb pattern has been previously demonstrated. However, there are discrepancies in the reported results about the role of this mechanism in the sharp Hb border. Here, we determined the Hill coefficient (nH) required for Bcd to generate the sharp border of Hb in wild-type (WT) embryos. We found that an n(H) of approximately 6.3 (s.d. 1.4) and 10.8 (s.d. 4.0) is required to account for Hb sharpness at early and late cycle 14A, respectively. Additional mechanisms are possibly required because the high nH is likely unachievable for Bcd binding to the hb promoter. To test this idea, we determined the nH required to pattern the Hb profile of 15 embryos expressing an hb14F allele that is defective in self-activation and found nH to be 3.0 (s.d. 1.0). This result indicates that in WT embryos, the hb self-activation is important for Hb sharpness. Corroborating our results, we also found a progressive increase in the required value of n(H) spanning from 4.0 to 9.2 by determining this coefficient from averaged profiles of eight temporal classes at cycle 14A (T1 to T8). Our results indicate that there is a transition in the mechanisms responsible for the sharp Hb border during cycle 14A: in early stages of this cycle, Bcd cooperative binding is primarily responsible for Hb sharpness; in late cycle 14A, hb self-activation becomes the dominant mechanism.

Measuring gene expression noise in early Drosophila embryos: nucleus-to-nucleus variability.

In recent years the analysis of noise in gene expression has widely attracted the attention of experimentalists and theoreticians. Experimentally, the approaches based on in vivo fluorescent reporters in single cells appear to be straightforward and effective tools for bacteria and yeast. However, transferring these approaches to multicellular organisms presents many methodological problems. Here we describe our approach to measure between-nucleus variability (noise) in the primary morphogenetic gradient of Bicoid (Bcd) in the precellular blastoderm stage of fruit fly (Drosophila) embryos. The approach is based on the comparison of results for fixed immunostained embryos with observations of live embryos carrying fluorescent Bcd (Bcd-GFP). We measure the noise using two-dimensional Singular Spectrum Analysis (2D SSA). We have found that the nucleus-to-nucleus noise in Bcd intensity, both for live (Bcd-GFP) and for fixed immunstained embryos, tends to be signal-independent. In addition, the character of the noise is sensitive to the nuclear masking technique used to extract quantitative intensities. Further, the method of decomposing the raw quantitative expression data into a signal (expression surface) and residual noise affects the character of the residual noise. We find that careful masking of confocal images and use of appropriate computational tools to decompose raw expression data into trend and noise makes it possible to extract and study the biological noise of gene expression.

Nitric oxide modulates metalloproteinase-2, collagen deposition and adhesion rate after polypropylene mesh implantation in the intra-abdominal wall.

Prosthetic meshes are commonly used to correct abdominal wall defects. However, the inflammatory reaction induced by these devices in the peritoneum is not completely understood. We hypothesized that nitric oxide (NO), produced by nitric oxide synthase 2 (NOS2) may modulate the response induced by mesh implants in the abdominal wall and, consequently, affect the outcome of the surgical procedure. Polypropylene meshes were implanted in the peritoneal side of the abdominal wall in wild-type and NOS2-deficient (NOS2(-/-)) mice. After 15 days tissues around the mesh implant were collected, and inflammatory markers (the cytokine interleukin 1ß (IL-1ß) and NO) and tissue remodeling (collagen and metalloproteinases (MMP) 2 and 9) were analyzed. The lack of NOS2-derived NO induced a higher incidence of visceral adhesions at the mesh implantation site compared with wild-type mice that underwent the same procedure (P<0.05). Additionally, higher levels of IL-1ß were present in the mesh-implanted NOS2(-/-) animals compared with control and wild-type mice. Mesh implantation induced collagen I and III deposition, but in smaller amounts in NOS2(-/-) mice. MMP-9 activity after the surgical procedure was similarly increased in both groups. Conversely, MMP-2 activity was unchanged in mesh-implanted wild-type mice, but was significantly increased in NOS2(-/-) mice (P<0.01), due to decreased S-nitrosylation of the enzyme in these animals. We conclude that NOS2-derived NO is crucial for an adequate response to and integration of polypropylene mesh implants in the peritoneum. NO deficiency results in a prolonged inflammatory reaction to the mesh implant, and reduced collagen deposition may contribute to an increased incidence of visceral adhesions.

Time-course of sFlt-1 and VEGF-A release in neutropenic patients with sepsis and septic shock: a prospective study.

BACKGROUND: Septic shock is the most feared complication of chemotherapy-induced febrile neutropenia. So far, there are no robust biomarkers that can stratify patients to the risk of sepsis complications. The VEGF-A axis is involved in the control of microvascular permeability and has been involved in the pathogenesis of conditions associated with endothelial barrier disruption such as sepsis. sFlt-1 is a soluble variant of the VEGF-A receptor VEGFR-1 that acts as a decoy receptor down-regulating the effects of VEGF-A. In animal models of sepsis, sFlt-1 was capable to block the barrier-breaking negative effects of VEGF-A and to significantly decrease mortality. In non-neutropenic patients, sFlt-1 has been shown to be a promising biomarker for sepsis severity. METHODS: We prospectively evaluated concentrations of sFlt-1 and VEGF-A at different time-points during febrile neutropenia, and evaluated the association of these levels with sepsis severity and septic shock development. RESULTS: Neutropenic patients that evolved with septic shock (n = 10) presented higher levels of sFlt-1 and VEGF-A measured 48 hours after fever onset than patients with non-complicated sepsis (n = 31) and levels of these biomarkers correlated with sepsis severity scores. Estimation of the diagnostic accuracy of sFlt-1 levels for the discrimination of patients that evolved to septic shock yielded promising results in our study population. DISCUSSION: Our data suggest that sFlt-1 and VEGF-A could be useful biomarkers for sepsis severity in patients with febrile neutropenia. In addition, the kinetics of sFlt-1 release in patients that evolve to septic shock suggest that the sFlt-1 could be a salvage compensatory mechanism in patients with septic shock, but that the magnitude of the sFlt-1 release observed in human sepsis is not sufficient to reproduce the beneficial anti-VEGF-A effects observed in animal models of sepsis.

Gene expression noise in spatial patterning: hunchback promoter structure affects noise amplitude and distribution in Drosophila segmentation.

Positional information in developing embryos is specified by spatial gradients of transcriptional regulators. One of the classic systems for studying this is the activation of the hunchback (hb) gene in early fruit fly (Drosophila) segmentation by the maternally-derived gradient of the Bicoid (Bcd) protein. Gene regulation is subject to intrinsic noise which can produce variable expression. This variability must be constrained in the highly reproducible and coordinated events of development. We identify means by which noise is controlled during gene expression by characterizing the dependence of hb mRNA and protein output noise on hb promoter structure and transcriptional dynamics. We use a stochastic model of the hb promoter in which the number and strength of Bcd and Hb (self-regulatory) binding sites can be varied. Model parameters are fit to data from WT embryos, the self-regulation mutant hb(14F), and lacZ reporter constructs using different portions of the hb promoter. We have corroborated model noise predictions experimentally. The results indicate that WT (self-regulatory) Hb output noise is predominantly dependent on the transcription and translation dynamics of its own expression, rather than on Bcd fluctuations. The constructs and mutant, which lack self-regulation, indicate that the multiple Bcd binding sites in the hb promoter (and their strengths) also play a role in buffering noise. The model is robust to the variation in Bcd binding site number across a number of fly species. This study identifies particular ways in which promoter structure and regulatory dynamics reduce hb output noise. Insofar as many of these are common features of genes (e.g. multiple regulatory sites, cooperativity, self-feedback), the current results contribute to the general understanding of the reproducibility and determinacy of spatial patterning in early development.

Surveillance of active human cytomegalovirus infection in hematopoietic stem cell transplantation (HLA sibling identical donor): search for optimal cutoff value by real-time PCR.

BACKGROUND: Human cytomegalovirus (CMV) infection still causes significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, it is extremely important to diagnosis and monitor active CMV infection in HSCT patients, defining the CMV DNA levels of virus replication that warrant intervention with antiviral agents in order to accurately prevent CMV disease and further related complications. METHODS: During the first 150 days after allogeneic HSTC, thirty patients were monitored weekly for active CMV infection by pp65 antigenemia, nested-PCR and real-time PCR assays. Receiver operating characteristic (ROC) plot analysis was performed to determine a threshold value of the CMV DNA load by real-time PCR. RESULTS: Using ROC curves, the optimal cutoff value by real-time PCR was 418.4 copies/104 PBL (sensitivity, 71.4%; specificity, 89.7%). Twenty seven (90%) of the 30 analyzed patients had active CMV infection and two (6.7%) developed CMV disease. Eleven (40.7%) of these 27 patients had acute GVHD, 18 (66.7%) had opportunistic infection, 5 (18.5%) had chronic rejection and 11 (40.7%) died - one died of CMV disease associated with GVHD and bacterial infection. CONCLUSIONS: The low incidence of CMV disease in HSCT recipients in our study attests to the efficacy of CMV surveillance based on clinical routine assay. The quantification of CMV DNA load using real-time PCR appears to be applicable to the clinical practice and an optimal cutoff value for guiding timely preemptive therapy should be clinically validated in future studies.

Brazilian experience using high-dose sequential chemotherapy followed by autologous hematopoietic stem cell transplantation for relapsed or refractory Hodgkin lymphoma.

PURPOSE: We evaluate the effectiveness and toxicity of high-dose sequential chemotherapy (HDS) as salvage therapy in patients with advanced-stage Hodgkin lymphoma. PATIENTS AND METHODS: We performed a retrospective analysis on 77 patients receiving HDS between 1998 and 2006. Patients enrolled were in disease progression or relapsed disease, or did not achieve a complete remission after first-line treatment. HDS consisted of the sequential administration of cyclophosphamide and granulocyte colony-stimulating factor with stem cell harvesting, followed by methotrexate plus vincristine and etoposide. RESULTS: The majority of patients had stage III/IV (64%) and B symptoms (71.4%). Disease status improvement after HDS was observed in 24 of 57 patients (42%) previously in disease progression or relapse. HDS-related deaths occurred in 8 of 77 patients (10.4%). Four patients (5.2%) developed acute myeloid leukemia/myelodysplastic syndrome. Overall, disease-free and progression-free survival was 27%, 57%, and 25%, respectively. CONCLUSION: Despite the treatment-related mortality, HDS is feasible, with satisfactory response rates, even in patients with poor prognosis.

Brazilian experience using high-dose sequential therapy (HDS) followed by autologous hematopoietic stem cell transplantation (ASCT) for malignant lymphomas / Experiência brasileira utilizando terapia sequencial de alta dose seguido de transplante autólogo de célula-tronco hematopoética para linfomas malignos

Using the overall survival (OS), disease free survival (DFS) and progression free survival (PFS), as well as associated toxicity, the purpose of this work was to evaluate the effectiveness of HDS followed by ASCT as salvage therapy. A retrospective analysis was performed of 106 patients with high grade non-Hodgkin lymphoma receiving HDS followed by ASCT, between 1998 and 2006. Median age was 45 years (Range: 8-65), with 66 (62 percent) men. Histopathological classification was: 78 percent DLBCL patients, 12 percent T and anaplastic and 9 percent Mantle cell lymphomas; 87 percent had B cell and 12 percent T cell lymphomas; 83 percent were stage III-IV (Ann Arbor Staging), 63 percent had B symptoms, 32 percent had bone marrow involvement, 62 percent bulky disease and 42 percent high-intermediate or high risk IPI. After HDCY, 9 patients died, 7 from toxicity and 2 from sepsis. Eighty patients underwent ASCT, 47 percent were in complete remission (CR) and 15 percent died, all from toxicity. Their OS was 45 percent over 8 years. During the follow-up, another 35 patients died [4 CR, 1 partial response (PR), 2 relapsed disease (RD) and 28 disease progression (DP)], 11 (31 percent) had not performed ASCT. OS was 37 percent; DFS was 49 percent and PFS 28 percent. OS by diagnosis was 42 percent for DLBCL, 40 percent for T-cell (8 y) and 20 percent for Mantle Cell (6 y) (P=NS). OS by B symptom patients was 22 percent vs. 58 percent (P=0.002) and PFS was 23 percent vs. 37 percent (P=0.03). Patients who achieved CR after HDCY (38) had significantly better OS and PFS (38 percent and 17 percent) than patients who remained in DP (P<0.0001). Cox Regression demonstrated therapeutic lines before HDCY (Relative risk - RR = 1.41; CI 95 percent: 1.04-1.90; P= 0.02) and PD both before (RR = 2.70; CI 95 percent: 1.49-4.91, P<0.001) and after HDCY (RR = 5.38; 95 percent CI: 2.93-9.87; P<0.0001). Conclusions: Our study suggests HDS is an efficient treatment to ...

A proposta deste trabalho foi avaliar a eficácia da HDS seguida do transplante autólogo como terapia de salvamento através da sobrevida global, livre de doença e livre de progressão bem como sua toxicidade. Realizou-se estudo retrospectivo com 106 pacientes com LNH de alto grau de malignidade entre 1998 e 2006. A mediana de idade foi 45 anos (8-65); 62 por cento homens; DLBCL, 78 por cento; 12 por cento, T e anaplásico e 9 por cento, linfoma da zona do manto; 87 por cento, células B; 83 por cento estádios III-IV; 63 por cento com sintomas B; 32 por cento com infiltração da medula óssea ao diagnóstico; 62 por cento com grande massa e 42 por cento com IPI de alto risco ou intermediário. Após alta dose de ciclofosfamida (HDCY), nove pacientes faleceram. Oitenta pacientes realizaram o transplante, sendo que 47 por cento estavam em RC e 15 por cento faleceram devido à toxicidade. A sobrevida global foi de 45 por cento em oito anos para estes pacientes. Trinta e cinco pacientes não realizaram o transplante por causas diversas. Sobrevida global para todos os pacientes foi de 42 por cento, DLBCL, 40 por cento; T-cell, 40 por cento e zona do manto, 20 por cento (P=NS). Pacientes que obtiveram RC após HDCY tiveram melhor sobrevida global e livre de progressão (38 por cento e 17 por cento, respectivamente) do que os que permaneceram em PD (P<0.0001). O modelo de Cox resultou que o número de linhas terapêuticas antes da HDCY (RR 1.41 IC 95 por cento: 1.04-1.90, P=0.02) e PD antes da HDCY (RR 2.70, IC 95 por cento: 1.49-4.91, P<0.001) e após HDCY (RR 5.38, IC 95 por cento: 2.93-9.87, P<0.0001). Nosso estudo sugere que HDS é um método eficiente de tratamento para melhorar o status e reduzir a massa tumoral. Em relação à toxicidade, é factível, especialmente em pacientes de prognóstico ruim

Correlation of IL-6 and IL-10 production following bone marrow transplantation with donor cytokine gene polymorphisms / Correlação da produção de IL-6 e IL-10 seguindo o transplante de medula óssea com os polimorfismos de genes de citocinas do doador

Several candidate gene studies have demonstrated that genetic polymorphisms in cytokine genes contribute to variations in the levels of cytokines produced and this variation may influence the occurrence and severity of complications after stem cell transplantation (HSCT). In this work we compared the serum concentrations of TNF-α, IFN-γ, IL-6, IL-10, and TGF-β1 in 13 recipients following HSCT with the TNF-308, IFNG+874, IL6-174, IL10-1082,-819,-592, and TGFB1+869,+915 polymorphisms. Serum cytokine levels were assessed using commercial ELISA kits for TNF-α, IFN-γ, IL-6, IL-10, and TGF-β1 (BioSource®, Nivelles, Belgium, Europe). Donor/recipient genotypes for these cytokine polymorphisms were analyzed by polymerase chain reaction-sequence-specific primer (PCR-SSP) with the Cytokine Genotyping Primers Kit (One Lambda , Canoga Park, CA, USA). We found correlation between the levels of IL-6 and IL-10 concentrations following HSCT and the IL6-174 and IL10-1082,-819,-592 polymorphisms, but not for other cytokines investigated in this study. Those with genotypes associated with low production of IL-6 and IL-10 produced lower levels of these cytokines than those with genotypes associated with high or intermediate production of these cytokines (P < 0.05).

Estudos de vários genes candidatos têm demonstrado que polimorfismos genéticos em genes de citocinas contribuem com variações nos níveis de citocinas produzidas e esta variação pode influenciar a ocorrência e gravidade de complicações após o transplante de células-tronco hematopoéticas (TCTH). Neste trabalho comparamos as concentrações séricas de TNF-α, IFN-γ, IL-6, IL-10 e TGF-β 1 em 13 receptores seguindo o TCTH com os polimorfismos TNF-308, IFNG+874, IL6-174, IL10-1082,-819,-592 e TGFB1+869,+915. Os níveis séricos de citocinas foram medidos usando-se kits comerciais de ELISA para TNF-α, IFN-γ, IL-6, IL-10 e TGF-β 1 (BioSource®, Nivelles, Belgium, Europe). Os genótipos de doadores/receptores para estes polimorfismos de citocinas foram analisados pela reação em cadeia da polimerase com sequências específicas de primer (PCR-SSP) com o kit Cytokine Genotyping Primers (One Lambda, Canoga Park, CA, USA). Encontramos correlação entre os níveis de IL-6 e IL-10 seguindo o TCTH e os polimorfismos IL6-174 e IL10-1082,-819,-592, mas não para outras citocinas investigadas neste estudo. Aqueles com genótipos relativos à baixa produção de IL-6 e IL-10 produziram mais baixos níveis destas citocinas que aqueles com genótipos relativos à produção alta e/ou intermediária destas citocinas (P < 0,05).

Spatial bistability generates hunchback expression sharpness in the Drosophila embryo.

During embryonic development, the positional information provided by concentration gradients of maternal factors directs pattern formation by providing spatially dependent cues for gene expression. In the fruit fly, Drosophila melanogaster, a classic example of this is the sharp on-off activation of the hunchback (hb) gene at midembryo, in response to local concentrations of the smooth anterior-posterior Bicoid (Bcd) gradient. The regulatory region for hb contains multiple binding sites for the Bcd protein as well as multiple binding sites for the Hb protein. Some previous studies have suggested that Bcd is sufficient for properly sharpened Hb expression, yet other evidence suggests a need for additional regulation. We experimentally quantified the dynamics of hb gene expression in flies that were wild-type, were mutant for hb self-regulation or Bcd binding, or contained an artificial promoter construct consisting of six Bcd and two Hb sites. In addition to these experiments, we developed a reaction-diffusion model of hb transcription, with Bcd cooperative binding and hb self-regulation, and used Zero Eigenvalue Analysis to look for multiple stationary states in the reaction network. Our model reproduces the hb developmental dynamics and correctly predicts the mutant patterns. Analysis of our model indicates that the Hb sharpness can be produced by spatial bistability, in which hb self-regulation produces two stable levels of expression. In the absence of self-regulation, the bistable behavior vanishes and Hb sharpness is disrupted. Bcd cooperative binding affects the position where bistability occurs but is not itself sufficient for a sharp Hb pattern. Our results show that the control of Hb sharpness and positioning, by hb self-regulation and Bcd cooperativity, respectively, are separate processes that can be altered independently. Our model, which matches the changes in Hb position and sharpness observed in different experiments, provides a theoretical framework for understanding the data and in particular indicates that spatial bistability can play a central role in threshold-dependent reading mechanisms of positional information.

Leucemia Mielóide Crônica: transplante de medula óssea / Cronic Myeloid Leukemia: bone marrow transplantation

A única terapia curativa para Leucemia Mielóide Crônica ainda é o transplante de células hematopoéticas progenitoras (TCHP); os atuais resultados com uso do imatinibe são suficientes para indicarmos o TCHP como um tratamento de segunda ou terceira linha. A decisão de realizar TCHP existe em uma variedade de momentos: falha em se conseguir remissão hemtológica, citogenética ou molecular, ou quando se perde a melhor resposta conseguida ou por progressão da doença para uma fase avançada. Há decisão também de como transplantar. Nesta revisão apontamos algumas destas decisões e as atuais controvérsias.

Although the only curative therapy for chronic myeloid leukemia remains allogeneic stem cell transplantation (allo-SCT), the results of imatinib in newly diagnosed patients are sufficiently impressive to have displaced allo-SCT to second or third-line treatment. Patients now arrive at a decision for transplantation in a variety of disease situations: failing to achieve certain hematological, cytogenetic and molecular remission by some pre-determined timepoint, having lost a previous best response or due to progression to an advanced phase. The decision is also how to transplant. In this review article, the evidence supporting some of these decisions and current controversies are discussed.