389 research outputs found
Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis: A Randomized Clinical Trial.
Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome.
iskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the
gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor
cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of
autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral
vector encoding functional WASP to genetically correct HSPCs from three WAS patients and
reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed
stable engraftment of WASP-expressing cells and improvements in platelet counts, immune
functions, and clinical scores. Vector integration analyses revealed highly polyclonal and
multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy
did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was
observed after 20 to 32 months. Although extended clinical observation is required to establish
long-term safety, lentiviral gene therapy represents a promising treatment for WAS
Stage at presentation of breast cancer in Luanda, Angola - a retrospective study
Background: It is expected that, by 2020, 15 million new cases of cancer will occur every year in the world, one
million of them in Africa. Knowledge of cancer trends in African countries is far from adequate, and improvements in cancer prevention efforts are urgently needed. The aim of this study was to characterize breast cancer clinically and pathologically at presentation in Luanda, Angola; we additionally provide quality information that will be useful for breast cancer care planning in the country.
Methods:
Data on breast cancer cases were retrieved from the Angolan Institute of Cancer Control, from 2006 to 2014. For women diagnosed in 2009 (5-years of follow-up), demographic, clinical and pathological information, at presentation, was collected, namely age at diagnosis, parity, methods used for pathological diagnoses, tumor
pathological characteristics, stage of disease and treatment. Descriptive statistics were performed.
Results:
The median age of women diagnosed with breast cancer in 2009 was 47 years old (range 25–89). The most frequent clinical presentation was breast swelling with axillary lymph nodes metastasis (44.9 %), followed by a mass
larger than 5 cm (14.2 %) and lump (12.9 %). Invasive ductal carcinoma was the main histologic type (81.8 %). Only 10.1 % of cancer cases had a well differentiated histological grade. Cancers were diagnosed mostly at advanced stages
(66.7 % in stage III and 11.1 % in stage IV).
Discussion:
In this study, breast cancer was diagnosed at a very advanced stage. Although it reports data from a single cancer center in Luanda, Angola it reinforces the need for early diagnosis and increasing awareness. According to the
main challenges related to breast cancer diagnosis and treatment herein presented, we propose a realistic framework that would allow for the implementation of a breast cancer care program, built under a strong network based on cooperation, teaching, audit, good practices and the organization of health services.
Conclusion:
Angola needs urgently a program for early diagnosis of breast cancer.We thank Susana Santos for correction of the article in English language, and a Cancer Registry Staff from IACC, particularly Pedro Luis Hernandez Gonzalez, Paulo Ernesto Alves, Xacu Parica and Alberto Sivi Lutumba for their support in data acquisition. We also thank SEMED -Portugal in support for publication
4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells
BACKGROUND: The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a polar metabolite of fenretinide (4-HPR) very effective in killing cancer cells of different histotypes, able to inhibit 4-HPR-resistant cell growth and to act synergistically in combination with the parent drug. Unlike 4-HPR and other retinoids, 4-oxo-4-HPR inhibits tubulin polymerization, leading to multipolar spindle formation and mitotic arrest. Here we investigated whether 4-oxo-4-HPR, like 4-HPR, triggered cell death also via reactive oxygen species (ROS) generation and whether its antimicrotubule activity was related to a ROS-dependent mechanism in ovarian (A2780), breast (T47D), cervical (HeLa) and neuroblastoma (SK-N-BE) cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: We provided evidence that 4-oxo-4-HPR, besides acting as an antimicrotubule agent, induced apoptosis through a signaling cascade starting from ROS generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and upregulation of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Through time-course analysis and inhibition of the ROS-related signaling pathway (upstream by vitamin C and downstream by PLAB silencing), we demonstrated that the antimitotic activity of 4-oxo-4-HPR was independent from the oxidative stress induced by the retinoid. In fact, ROS generation occurred earlier than mitotic arrest (within 30 minutes and 2 hours, respectively) and abrogation of the ROS-related signaling pathway did not prevent the 4-oxo-4-HPR-induced mitotic arrest. CONCLUSIONS/SIGNIFICANCE: These data indicate that 4-oxo-4-HPR anticancer activity is due to at least two independent mechanisms and provide an explanation of the ability of 4-oxo-4-HPR to be more potent than the parent drug and to be effective also in 4-HPR-resistant cell lines. In addition, the double mechanism of action could allow 4-oxo-4-HPR to efficiently target tumour and to eventually counteract the development of drug resistance
The methodology for developing a prospective meta-analysis in the family planning community
<p>Abstract</p> <p>Background</p> <p>Prospective meta-analysis (PMA) is a collaborative research design in which individual sites perform randomized controlled trials (RCTs) and pool the data for meta-analysis. Members of the PMA collaboration agree upon specific research interventions and outcome measures, ideally before initiation but at least prior to any individual trial publishing results. This allows for uniform reporting of primary and secondary outcomes. With this approach, heterogeneity among trials contributing data for the final meta-analysis is minimized while each site maintains the freedom to design a specific trial. This paper describes the process of creating a PMA collaboration to evaluate the impact of misoprostol on ease of intrauterine device (IUD) insertion in nulliparous women.</p> <p>Methods</p> <p>After the principal investigator developed a preliminary PMA protocol, he identified potential collaborating investigators at other sites. One site already had a trial underway and another site was in the planning stages of a trial meeting PMA requirements. Investigators at six sites joined the PMA collaborative. Each site committed to enroll subjects to meet a pre-determined total sample size. A final common research plan and site responsibilities were developed and agreed upon through email and face-to-face meetings. Each site committed to contribute individual patient data to the PMA collaboration, and these data will be analyzed and prepared as a multi-site publication. Individual sites retain the ability to analyze and publish their site's independent findings.</p> <p>Results</p> <p>All six sites have obtained Institutional Review Board approval and each has obtained individual funding to meet the needs of that site's study. Sites have shared resources including study protocols and consents to decrease costs and improve study flow. This PMA protocol is registered with the Cochrane Collaboration and data will be analyzed according to Cochrane standards for meta-analysis.</p> <p>Conclusions</p> <p>PMA is a novel research method that improves meta-analysis by including several study sites, establishing uniform reporting of specific outcomes, and yet allowing some independence on the part of individual sites with respect to the conduct of research. The inclusion of several sites increases statistical power to address important clinical questions. Compared to multi-center trials, PMA methodology encourages collaboration, aids in the development of new investigators, decreases study costs, and decreases time to publication.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00613366">NCT00613366</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00886834">NCT00886834</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT01001897">NCT01001897</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT01147497">NCT01147497</a> and <a href="http://www.clinicaltrials.gov/ct2/show/NCT01307111">NCT01307111</a></p
Two Notch Ligands, Dll1 and Jag1, Are Differently Restricted in Their Range of Action to Control Neurogenesis in the Mammalian Spinal Cord
Notch signalling regulates neuronal differentiation in the vertebrate nervous system. In addition to a widespread function in maintaining neural progenitors, Notch signalling has also been involved in specific neuronal fate decisions. These functions are likely mediated by distinct Notch ligands, which show restricted expression patterns in the developing nervous system. Two ligands, in particular, are expressed in non-overlapping complementary domains of the embryonic spinal cord, with Jag1 being restricted to the V1 and dI6 progenitor domains, while Dll1 is expressed in the remaining domains. However, the specific contribution of different ligands to regulate neurogenesis in vertebrate embryos is still poorly understood.In this work, we investigated the role of Jag1 and Dll1 during spinal cord neurogenesis, using conditional knockout mice where the two genes are deleted in the neuroepithelium, singly or in combination. Our analysis showed that Jag1 deletion leads to a modest increase in V1 interneurons, while dI6 neurogenesis was unaltered. This mild Jag1 phenotype contrasts with the strong neurogenic phenotype detected in Dll1 mutants and led us to hypothesize that neighbouring Dll1-expressing cells signal to V1 and dI6 progenitors and restore neurogenesis in the absence of Jag1. Analysis of double Dll1;Jag1 mutant embryos revealed a stronger increase in V1-derived interneurons and overproduction of dI6 interneurons. In the presence of a functional Dll1 allele, V1 neurogenesis is restored to the levels detected in single Jag1 mutants, while dI6 neurogenesis returns to normal, thereby confirming that Dll1-mediated signalling compensates for Jag1 deletion in V1 and dI6 domains.Our results reveal that Dll1 and Jag1 are functionally equivalent in controlling the rate of neurogenesis within their expression domains. However, Jag1 can only activate Notch signalling within the V1 and dI6 domains, whereas Dll1 can signal to neural progenitors both inside and outside its domains of expression
MASked-unconTrolled hypERtension management based on office BP or on ambulatory blood pressure measurement (MASTER) Study: a randomised controlled trial protocol.
Masked uncontrolled hypertension (MUCH) carries an increased risk of cardiovascular (CV) complications and can be identified through combined use of office (O) and ambulatory (A) blood pressure (BP) monitoring (M) in treated patients. However, it is still debated whether the information carried by ABPM should be considered for MUCH management. Aim of the MASked-unconTrolled hypERtension management based on OBP or on ambulatory blood pressure measurement (MASTER) Study is to assess the impact on outcome of MUCH management based on OBPM or ABPM
Epidemiological and some clinical characteristics of neuroblastoma in Mexican children (1996–2005)
<p>Abstract</p> <p>Background</p> <p>Neuroblastoma (NB) is the principal tumor of the sympathetic nervous system in children under one year of age. The incidence in developed countries is greater than that in developing countries. The aim of this article is to present the epidemiological and some clinical characteristics of Mexican children with NB.</p> <p>Methods</p> <p>A population-based, prolective study, with data obtained from the Childhood Cancer Registry of the Instituto Mexicano de Seguro Social. Statistical analysis: The simple frequencies of the variables of the study and the annual average incidence (per 1,000,000 children/years) by age and sex were obtained. The trend was evaluated by calculating the annual percentage of change. The curves of Kaplan-Meyer were employed for the survival rate and the log-rank test was used to compare the curves.</p> <p>Results</p> <p>Of a total of 2,758 children with cancer registered during the period from 1996–2005, 72 (2.6%) were identified as having Group IV, defined according to the International Classification of Childhood Cancer. The incidence for NB was 3.8 per 1,000,000 children/year; NB was highest in the group of children under one year of age, followed by the group of children between the ages 1–4 years (18.5 and 5.4 per 1,000,000 children/years, respectively). The male/female ratio was 1.1 and there was no trend toward an increase. The time of diagnosis was 26 days (median), but varied according to the stage at diagnosis. Stages III and IV were presented in 88% of the cases. There was no association between the stage, the age at time of diagnosis, or the histological pattern. The overall five-year survival rate was 64%; the patients with stage I, II, III, or IVs did not die; and the five-year survival rate of cases in Stage IV was 40%.</p> <p>Conclusion</p> <p>It is possible that the low incidence of neuroblastoma in Mexican children is due to the difficulty in diagnosing the cases with the best prognosis, some of which could have had spontaneous regression. There was no trend to an increase; the majority of the cases were diagnosed in the advanced stages; and the overall five-years survival rate was similar to that for developed countries.</p
Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study
Background
Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC) gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy.
Methods
We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP) expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462) and EudraCT (number 2009-017346-32).
Findings
Between April 20, 2010, and Feb 26, 2015, nine patients (all male) were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1–12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5–5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8–35·6) before gene therapy to 66·7% (55·7–98·6) at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1–31·0) to 76·6% (53·1–98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44–3·72) per patient-year of observation (PYO) in the year before gene therapy to 0·31 (0·04–1·11) per PYO in the second year after gene therapy and 0·17 (0·00–0·93) per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 109 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20–50 × 109 per L in one patient, 50–100 × 109 per L in five patients, and more than 100 × 109 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%) of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy.
Interpretation
Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available
Role of Sphingomyelin Synthase in Controlling the Antimicrobial Activity of Neutrophils against Cryptococcus neoformans
The key host cellular pathway(s) necessary to control the infection caused by inhalation of the environmental fungal pathogen Cryptococcus neoformans are still largely unknown. Here we have identified that the sphingolipid pathway in neutrophils is required for them to exert their killing activity on the fungus. In particular, using both pharmacological and genetic approaches, we show that inhibition of sphingomyelin synthase (SMS) activity profoundly impairs the killing ability of neutrophils by preventing the extracellular release of an antifungal factor(s). We next found that inhibition of protein kinase D (PKD), which controls vesicular sorting and secretion and is regulated by diacylglycerol (DAG) produced by SMS, totally blocks the extracellular killing activity of neutrophils against C. neoformans. The expression of SMS genes, SMS activity and the levels of the lipids regulated by SMS (namely sphingomyelin (SM) and DAG) are up-regulated during neutrophil differentiation. Finally, tissue imaging of lungs infected with C. neoformans using matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS), revealed that specific SM species are associated with neutrophil infiltration at the site of the infection. This study establishes a key role for SMS in the regulation of the killing activity of neutrophils against C. neoformans through a DAG-PKD dependent mechanism, and provides, for the first time, new insights into the protective role of host sphingolipids against a fungal infection
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