365 research outputs found
Sequencing of folding events in Go-like proteins
We have studied folding mechanisms of three small globular proteins: crambin
(CRN), chymotrypsin inhibitor 2 (CI2) and the fyn Src Homology 3 domain (SH3)
which are modelled by a Go-like Hamiltonian with the Lennard-Jones
interactions. It is shown that folding is dominated by a well-defined
sequencing of events as determined by establishment of particular contacts. The
order of events depends primarily on the geometry of the native state.
Variations in temperature, coupling strengths and viscosity affect the
sequencing scenarios to a rather small extent. The sequencing is strongly
correlated with the distance of the contacting aminoacids along the sequence.
Thus -helices get established first. Crambin is found to behave like a
single-route folder, whereas in CI2 and SH3 the folding trajectories are more
diversified. The folding scenarios for CI2 and SH3 are consistent with
experimental studies of their transition states.Comment: REVTeX, 12 pages, 11 EPS figures, J. Chem. Phys (in press
Spectral-domain optical coherence tomography of conjunctival mucosa-associated lymphoid tissue lymphoma with presumed choroidal involvement
Conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma has been well-described, but rarely do these lesions demonstrate intraocular involvement. We report a case of conjunctival MALT lymphoma with intraocular involvement and novel spectral-domain ocular coherence tomography (SD-OCT) findings.
A 75-year-old woman with biopsy-proven MALT lymphoma of the conjunctiva presented with ipsilateral yellowish diffuse choroidal infiltrates on fundoscopic examination. Choroidal involvement was documented clinically, on ultrasonography, on fluorescein angiography, and by SD-OCT. Treatment consisted of 3Â weeks of oral doxycycline and six cycles of systemic chemotherapy with cyclophosphamide, vincristine, prednisone, and rituximab.
There was no evidence of progression or recurrence of MALT lymphoma after 9Â months of follow-up. Despite complete resolution of clinical findings, ultrasound, and fluorescein angiography, the choroidal lesions remained unchanged on SD-OCT.
Choroidal involvement of conjunctival MALT is rare, and can be successfully treated. Persistence of irregularities on SD-OCT did not influence management in the presence of clinical improvement and resolution on ultrasonography and fluorescein angiography
Coarse grained description of the protein folding
We consider two- and three-dimensional lattice models of proteins which were
characterized previously. We coarse grain their folding dynamics by reducing it
to transitions between effective states. We consider two methods of selection
of the effective states. The first method is based on the steepest descent
mapping of states to underlying local energy minima and the other involves an
additional projection to maximally compact conformations. Both methods generate
connectivity patterns that allow to distinguish between the good and bad
folders. Connectivity graphs corresponding to the folding funnel have few loops
and are thus tree-like. The Arrhenius law for the median folding time of a
16-monomer sequence is established and the corresponding barrier is related to
easily identifiable kinetic trap states.Comment: REVTeX, 9 pages, 15 EPS figures, to appear in Phys. Rev.
Scaling of folding properties in simple models of proteins
Scaling of folding properties of proteins is studied in a toy system -- the
lattice Go model with various two- and three- dimensional geometries of the
maximally compact native states. Characteristic folding times grow as power
laws with the system size. The corresponding exponents are not universal.
Scaling of the thermodynamic stability also indicates size-related
deterioration of the folding properties.Comment: REVTeX, 4 pages, 4 EPS figures, PRL (in press
Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors
The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30Â months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48Â years old (range 18â69). The median follow-up after the completion of radiotherapy was 79Â months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12Â months, 42% at 36Â months, and 48% at 60Â months. Age > 60Â years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity
Energy landscapes, supergraphs, and "folding funnels" in spin systems
Dynamical connectivity graphs, which describe dynamical transition rates
between local energy minima of a system, can be displayed against the
background of a disconnectivity graph which represents the energy landscape of
the system. The resulting supergraph describes both dynamics and statics of the
system in a unified coarse-grained sense. We give examples of the supergraphs
for several two dimensional spin and protein-related systems. We demonstrate
that disordered ferromagnets have supergraphs akin to those of model proteins
whereas spin glasses behave like random sequences of aminoacids which fold
badly.Comment: REVTeX, 9 pages, two-column, 13 EPS figures include
Primary central nervous system lymphomas:EHAâESMO Clinical Practice Guideline for diagnosis, treatment and follow-up<sup>â</sup>
Predicting the outcome of grade II glioma treated with temozolomide using proton magnetic resonance spectroscopy
International audienceBACKGROUND: This study was designed to evaluate proton magnetic resonance spectroscopy ((1)H-MRS) for monitoring the WHO grade II glioma (low-grade glioma (LGG)) treated with temozolomide (TMZ).METHODS: This prospective study included adult patients with progressive LGG that was confirmed by magnetic resonance imaging (MRI). Temozolomide was administered at every 28 days. Response to TMZ was evaluated by monthly MRI examinations that included MRI with volumetric calculations and (1)H-MRS for assessing Cho/Cr and Cho/NAA ratios. Univariate, multivariate and receiver-operating characteristic statistical analyses were performed on the results.RESULTS: A total of 21 LGGs from 31 patients were included in the study, and followed for at least n=14 months during treatment. A total of 18 (86%) patients experienced a decrease in tumour volume with a greater decrease of metabolic ratios. Subsequently, five (28%) of these tumours resumed growth despite the continuation of TMZ administration with an earlier increase of metabolic ratios of 2 months. Three (14%) patients did not show any volume or metabolic change. The evolutions of the metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated over time (Spearman Ï=+0.95) and followed a logarithmic regression (P>0.001). The evolutions over time of metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated with the evolution of the mean relative decrease of tumour volume, mean(ÎV(n)/V(o)), according to a linear regression (P<0.001) in the 'response/no relapse' patient group, and with the evolution of the mean tumour volume (meanV(n)), according to an exponential regression (P<0.001) in the 'response/relapse' patient group. The mean relative decrease of metabolic ratio, mean(Î(Cho/Cr)(n)/(Cho/Cr)(o)), at n=3 months was predictive of tumour response over the 14 months of follow-up. The mean relative change between metabolic ratios, mean((Cho/NAA)(n)-(Cho/Cr)(n))/(Cho/NAA)(n), at n=4 months was predictive of tumour relapse with a significant cutoff of 0.046, a sensitivity of 60% and a specificity of 100% (P=0.004).CONCLUSIONS: The (1)H-MRS profile changes more widely and rapidly than tumour volume during the response and relapse phases, and represents an early predictive factor of outcome over 14 months of follow-up. Thus, (1)H-MRS may be a promising, non-invasive tool for predicting and monitoring the clinical response to TMZ
Primary central nervous system lymphomas:EHAâESMO Clinical Practice Guideline for diagnosis, treatment and follow-up<sup>â</sup>
Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse
Background: Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavors, with low response rates and survival rarely exceeding six months. There are no clearly established chemotherapeutic regimens and the aim of treatment is palliation with improvement in the quality of life. Patients and methods: We report an open-label, uncontrolled, multicenter phase II trial of temozolomide in 138 patients (intent-to-treat [ITI] population) with glioblastoma multiforme at first relapse and a Karnofsky performance status (KPS) â„ 70. One hundred twenty-eight patients were histologically confirmed with GBM or gliosarcoma (GS) by independent central review. Chemotherapy-naĂŻve patients were treated with temozolomide 200 mg/m2/day2/day orally for the first five days of a 28-day cycle. Patients previously treated with nitrosourea- containing adjuvant chemotherapy received 150 mg/m2/day for the first five days of a 28-day cycle. In the absence of grade 3 or 4 toxicity, patients on the 150 mg/m2 dose schedule were eligible for a 200 mg/m2 dose on the next cycle. Results: The primary endpoint was six-month progression-free survival assessed with strict radiological and clinical criteria. Secondary endpoints included radiological response and Health-related Quality of Life (HQL). Progression-free survival at six months was 18% (95% confidence interval (CI): 11%-26%) for the eligible-histology population. Median progression-free survival and median overall survival were 2.1 months and 5.4 months, respectively. The six-month survival rate was 46%. The objective response rate (complete response and partial response) determined by independent central review of gadolinium-enhanced magnetic resonance imaging (MRI) scans was 8% for both the ITT and eligible-histology populations, with an additional 43%;A and 45% of patients, respectively, having stable disease (SD). Objectively assessed response and maintenance of a progression-free status were both associated with HQL benefits (characterized by improvements over baseline in HQL domains). Temozolomide had an acceptable safety profile, with only 9% of therapy cycles requiring a dose reduction due to thrombocytopenia. There was no evidence of cumulative hematologic toxicity. Conclusions: Temozolomide demonstrated modest clinical efficacy, with an acceptable safety profile and measurable improvement in quality of life in patients with recurrent GBM. The use of this drug should be explored further in an adjuvant setting and in combination with other agent
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