31 research outputs found
Neurofilament light chain as a potential biomarker for monitoring neurodegeneration in X-linked adrenoleukodystrophy
X-linked adrenoleukodystrophy (X-ALD), the most frequent monogenetic disorder of brain white matter, is highly variable, ranging from slowly progressive adrenomyeloneuropathy (AMN) to life-threatening inflammatory brain demyelination (CALD). In this study involving 94 X-ALD patients and 55 controls, we tested whether plasma/serum neurofilament light chain protein (NfL) constitutes an early distinguishing biomarker. In AMN, we found moderately elevated NfL with increased levels reflecting higher grading of myelopathy-related disability. Intriguingly, NfL was a significant predictor to discriminate non-converting AMN from cohorts later developing CALD. In CALD, markedly amplified NfL levels reflected brain lesion severity. In rare cases, atypically low NfL revealed a previously unrecognized smoldering CALD disease course with slowly progressive myelin destruction. Upon halt of brain demyelination by hematopoietic stem cell transplantation, NfL gradually normalized. Together, our study reveals that blood NfL reflects inflammatory activity and progression in CALD patients, thus constituting a potential surrogate biomarker that may facilitate clinical decisions and therapeutic development
Brain metastases in gastro-oesophageal adenocarcinoma: Insights into the role of the human epidermal growth factor receptor 2 (HER2)
Background: Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown.Patients and Methods: A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC. Results: One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54-68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6-46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5-15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0-20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%. Conclusions: The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively
Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.
BACKGROUND:
In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.
METHODS:
We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.
RESULTS:
A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.
CONCLUSIONS:
Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety
Adult autologous mesenchymal stem cells for the treatment of suspected non-infectious inflammatory diseases of the canine central nervous system: safety, feasibility and preliminary clinical findings
Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke.
We sought to investigate the relationship between blood–brain barrier (BBB) permeability and microstructural white
matter integrity, and their potential impact on long-term functional outcomes in patients with acute ischemic stroke (AIS).
We studied 184 AIS subjects with perfusion-weighted MRI (PWI) performed <9 h from last known well time. White matter
hyperintensity (WMH), acute infarct, and PWI-derived mean transit time lesion volumes were calculated. Mean BBB
leakage rates (K2 coefficient) and mean diffusivity values were measured in contralesional normal-appearing white
matter (NAWM). Plasma matrix metalloproteinase-2 (MMP-2) levels were studied at baseline and 48 h. Admission
stroke severity was evaluated using the NIH Stroke Scale (NIHSS). Modified Rankin Scale (mRS) was obtained at
90-days post-stroke. We found that higher mean K2 and diffusivity values correlated with age, elevated baseline MMP-2
levels, greater NIHSS and worse 90-day mRS (all p < 0.05). In multivariable analysis, WMH volume was associated with
mean K2 (p ¼ 0.0007) and diffusivity (p ¼ 0.006) values in contralesional NAWM. In summary, WMH severity measured
on brain MRI of AIS patients is associated with metrics of increased BBB permeability and abnormal white matter
microstructural integrity. In future studies, these MRI markers of diffuse cerebral microvascular dysfunction may improve
prediction of cerebral tissue infarction and functional post-stroke outcome
Rat bone marrow stromal cells and oligonucleotides in pain research
In the last years, significant progress has been made in the medical treatment of pain. However, pathological pains, such us neuropathic pain, remain refractory to the currently available analgesics. Therefore, new therapeutic strategies are being evaluated. We have recently shown that both bone marrow stromal cells (MSCs) and the oligonucleotide IMT504 can prevent the development of mechanical and thermal allodynia when they are administered to rats subjected to a sciatic nerve crush. This chapter summarizes the laboratory techniques used to isolate and culture MSCs, administer both MSCs and IMT504, perform the nerve injury and determine mechanical and thermal sensitivities.Fil: Coronel, Maria Florencia. Universidad Austral. Facultad de Ciencias Biomedicas; ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Villar, Marcelo Jose. Universidad Austral. Facultad de Ciencias Biomedicas; Argentin
Prevalence of BRCA1 and BRCA2 gene mutations in families with medium and high risk of breast and ovarian cancer in Brazil
Of all malignant neoplasias affecting women, breast cancer has the highest incidence rate in Brazil. The objective of the present study was to determine the frequency of genetic modifications in families with medium and high risk for breast and ovarian cancer from different regions of Brazil. An exploratory, descriptive study was carried out on the prevalence of the BRCA1 and BRCA2 mutations in case series of high-risk families for breast and/or ovarian cancer. After heredogram construction, a blood sample was taken and DNA extraction was performed in all index cases. The protein truncation test was used to screen for truncated mutations in exon 11 of the BRCA1 gene and in exons 10 and 11 of the BRCA2 gene. Of the 612 individuals submitted to genetic testing, 21 (3.4%), 19 women and 2 men, had mutations in the BRCA1 or BRCA2 genes. Of the 19 BRCA1 mutations found in the 18 participants, 7 consisted of ins6kb mutations, 4 were 5382insC, 3 were 2156delGinsCC, 2 were 185delAG, 1 was C1201G, 1 was C3522T, and 1 was 3450del4. With respect to the BRCA2 gene, 3 mutations were found: 5878del10, 5036delA and 4232insA (one case each). The prevalence of germline mutations in the BRCA1 and BRCA2 genes found in the present study was lower than reported by other studies on high-risk Brazilian populations. The inclusion of individuals with medium risk may have contributed to the lower prevalence observed
Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice
<p>Abstract</p> <p>Background</p> <p>Cardiac inflammation and generation of oxidative stress are known to contribute to trastuzumab (herceptin) induced cardiac toxicity. Toll-like receptors (TLRs) are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signaling, we investigated whether or not TLR4 is involved in trastuzumab induced cardiotoxicity.</p> <p>Methods</p> <p>Seven days after a single injection of herceptin (2 mg/kg; i.p.), left ventricular pressure volume loops were measured in HeN compotent (TLR4<sup>+/+</sup>) and HeJ mutant (TLR4<sup>-/-</sup>) treated with trastuzumab and control mice. Immunofluorescent staining for monocyte infiltration and analyses of plasma by (ELISAs) for different chemokines including: MCP-1and tumor necrosis factor-α (TNF-α), Western immunoblotting assay for ICAM-1, and used troponin I for cardiac injury marker.</p> <p>Results</p> <p>Trastuzumab injection resulted in an impairment of left ventricular function in TLR-4 competent (HeN), in contrast TLR4<sup>-</sup>/<sup>- </sup>trastuzumab mice showed improved left ventricular function EF%, CO; p < 0.05, attenuation of mononuclear cell infiltration in TLR4 <sup>-/-</sup>; p < 0.05 vs.TLR-4 competent (HeN), reduced level of cytokines TNF-α, MCP-1 and ICAM-1 expression in TLR4<sup>-/-</sup>, marked reduction of myocardial troponin-I levels in TLR4-deficient mice. Data are presented as means ± SE; n = 8 in each group p < 0.05 vs.TLR-4 competent (HeN).</p> <p>Conclusions</p> <p>Treatment with trastuzumab induces an inflammatory response that contributes to myocardial tissue TLR4 mediates chemokine expression (TNF-α, MCP-1and ICAM-1), so in experimental animals TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in trastuzumab induced cardiomyopathy.</p