72 research outputs found
Toxicity Associated with Stavudine Dose Reduction from 40 to 30 mg in First-Line Antiretroviral Therapy
To compare the incidence and timing of toxicity associated with the use of a reduced dose of stavudine from 40 to 30 mg in first-line antiretroviral therapy (ART) for HIV treatment and to investigate associated risk factors
SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia.
An enhanced requirement for nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a dependency in this disease. We demonstrate that SLC5A3 is essential to support a myo-inositol auxotrophy in AML. The commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1, which encodes the rate limiting enzyme for myo-inositol biosynthesis, inositol-3-phosphate synthase 1. We use gain- and loss-of-function experiments to reveal a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hyper-methylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with IDH1/IDH2 and CEBPA mutations. Our findings reveal myo-inositol as a nutrient dependency in AML caused by the aberrant silencing of a biosynthetic enzyme
Transcriptional dynamics during cell wall removal and regeneration reveals key genes involved in cell wall development in rice
Efficient and cost-effective conversion of plant biomass to usable forms of energy requires a thorough understanding of cell wall biosynthesis, modification and degradation. To elucidate these processes, we assessed the expression dynamics during enzymatic removal and regeneration of rice cell walls in suspension cells over time. In total, 928 genes exhibited significant up-regulation during cell wall removal, whereas, 79 genes were up-regulated during cell wall regeneration. Both gene sets are enriched for kinases, transcription factors and genes predicted to be involved in cell wall-related functions. Integration of the gene expression datasets with a catalog of known and/or predicted biochemical pathways from rice, revealed metabolic and hormonal pathways involved in cell wall degradation and regeneration. Rice lines carrying Tos17 mutations in genes up-regulated during cell wall removal exhibit dwarf phenotypes. Many of the genes up-regulated during cell wall development are also up-regulated in response to infection and environmental perturbations indicating a coordinated response to diverse types of stress
Differential sensitivity of thick and thin fibers to HIV and therapy-induced neuropathy
The study assessed HIV-related and anti-retroviral therapy-induced
neuropathy in myelinated and unmyelinated nerve fibers. One hundred
consecutive HIV patients were examined clinically and standard nerve
conduction velocities were measured. In addition, electrically induced
sympathetic skin response (SSR) was assessed in the palms and soles. The
difference in delay of SSR in palms and soles (Delta SSR) was calculated
as an indirect measure of C-fiber conduction velocity. Thick fiber
conduction velocities significantly decreased with age and increasing
stage of the disease, whereas no effect of stage was found for Delta SSR
(p=0.6). In contrast, medication of at least one of the most known
neurotoxic drugs zalcitabine, stavudine, or didanosine did not result in
significantly lower conduction velocities in thick fibers (51.29 +/- 3.4
m/s vs. 50.86 +/- 3.5 m/s), but was related to an increased Delta SSR.
Delta SSR allows an indirect measurement of C-fiber conduction velocity.
In HIV this measure of unmyelinated sympathetic fibers was most
sensitive to anti-viral treatment whereas conduction velocity of
myelinated somatic fibers was more sensitive to disease-related
neuropathy. The results suggest that HIV neuropathy preferably affects
myelinated and anti-retroviral therapy unmyelinated fibers. (c) 2007
Elsevier B.V. All rights reserved
PGP 9.5 neuronal marker may differentiate immunohistochemically HIV-related from Mediterranean and immunosuppression-associated Kaposi's sarcoma
Mediterranean Kaposi's sarcoma (MKS), HIVrelated KS (HIV-KS) and immunosuppression-associated KS (IS-KS), caused by human herpes virus 8 (HHV-8), share similar histological features. The aim of this study was to investigate differences in epidermal nerve fibers (ENFs) between the three KS types and controls. Skin biopsies from 23 HIV-KS, 16 MKS, 28 IS-KS patients and 18 controls, age-gender matched, were immunostained with PGP 9.5; ENFs in upper epidermal layer (EL) and penetrating the basement membrane were measured. The mean number of nerve fibers penetrating ENFs was significantly lower in HIV-KS (p<0.001) compared to all other groups. MKS and IS-KS had comparable ENFs but lower than controls (p<0.00 1). In the upper EL all groups had comparable ENFs and lower than controls. In conclusion, HIV-KS can be distinguished histologically from other types, by counting ENFs. Moreover, KS is associated with decreased ENFs, which may be a histological reflection of nerve damage. This is even more pronounced in HIV-KS patients and could be explained by a neurotoxic action of HHV-8, HIV, and their co-existence. © Springer-Verlag Berlin Heidelberg 2013
Aspects of the association between leishmaniasis and malignant disorders
Given the prevalence of leishmaniasis and cancer, the co-existence of
these two diseases may be merely coincidental. However, a number of
epidemiological, experimental and Laboratory studies suggest that an
association between these two entities does exist. The aim of this
review is to summarise the occurrence of leishmaniasis as an
opportunistic infection associated with malignant disorders and to
present the available literature potentially linking this infection with
the development of cancerous lesions. We searched electronic databases
and evaluated 37 studies involving 44 patients. Four different types of
association between leishmaniasis and cancer were established:
leishmaniasis mimicking a malignant disorder, such as lymphoma;
leishmaniasis arising as a difficult to diagnose and treat infection
among patients receiving chemotherapy for various malignant disorders;
simultaneous diagnosis of leishmaniasis and a neoplastic disorder in the
same tissue samples of immunocompromised patients; and direct
involvement of Leishmania spp. in the pathogenesis/occurrence of
malignant lesions, especially of the skin and mucous membranes. The main
conclusion of this review is that leishmaniasis can directly or
indirectly affect the presentation, diagnosis and course of various
malignant disorders and it should be considered in the differential.
diagnosis of malignancies in geographic areas where it is endemic and/or
in patients with travel history to these areas. (C) 2007 Royal Society
of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights
reserved
An unusual case of brucellar spondylitis involving both the cervical and lumbar spine
We report an unusual case of brucellar spondylitis, involving both the
cervical and lumbar spine. Diagnosis was established using magnetic
resonance imaging (MRI). An initial plain radiograph of the lumbar
spine, showing mild degenerative lesions, was misleading. Therefore,
institution of a proper treatment was delayed. (C) 2001 Elsevier Science
Inc. All rights reserved
Chemotherapy ± cetuximab modulates peripheral immune responses in metastatic colorectal cancer
Objective: To identify changes in peripheral immune responses in patients with metastatic colorectal cancer (mCRC) treated with irinotecan/5-fluorouracil/ leucovorin (IFL) alone or in combination with cetuximab (C-IFL). Methods: Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (n = 20) and patients with mCRC receiving treatment with either IFL (n = 30) or C-IFL (n = 30) were tested for cytokine production upon polyclonal stimulation with anti-CD3 monoclonal antibody, T cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR) and T regulatory cell (Treg) frequency. The respective results were evaluated over two treatment cycles and further assessed in relation to response to treatment. Results: PBMCs prior to treatment exhibited significantly lower production of IL-2, IFN-γ, IL-12 and IL-18 cytokines and lower auto-MLR responses, whereas Treg frequency, IL-4, IL-10 cytokines were increased compared to healthy donors. During treatment, IL-2, IFN-γ, IL-12, IL-18 and auto-MLR responses increased, while Treg frequency and IL-10 secretion decreased significantly compared to the baseline. Responders to treatment exhibited a significantly higher increase in IL-2, IFN-γ, IL-12 and IL-18 production and auto-MLR responses, and higher decrease in IL-4, IL-10 secretion and Treg frequency. Among all patient subgroups analysed, responders to C-IFL demonstrated significantly higher increase in auto-MLR responses, IL-12 and IL-18 secretion and higher decrease in Treg frequency. Conclusion: The disturbed immune parameters observed in patients with mCRC at presentation can be significantly improved during treatment with IFL and this effect can be potentiated by the addition of cetuximab. Monitoring of the peripheral immune system function could be used as surrogate marker in predicting treatment-related outcome. Copyright © 2013 S. Karger AG, Basel
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