(C) 2009 Elsevier B.V. All rights reserved.”
“EGF-induced activation of ERK has been extensively studied by both experimental and theoretical approaches. Here, we used a simulation model based mostly LY2835219 on experimentally determined parameters to study the ERK-mediated negative feedback regulation of the Rasguanine nucleotide exchange factor, son of sevenless (SOS). Because SOS1 is phosphorylated at multiple serine residues upon stimulation,

we evaluated the role of the multiplicity by building two simulation models, which we termed the decisive and cooperative phosphorylation models. The two models were constrained by the duration of Ras activation and basal phosphorylation level of SOS1. Possible solutions were found only in the decisive model wherein at least three, and probably more than four, phosphorylation sites decisively suppress the SOS activity. Thus, the combination of experimental approaches and the model analysis has suggested an unexpected role of multiple phosphorylations of SOS1 in the negative regulation.”
“Enzymatic production

PCI 32765 of biodiesel by triglyceride transesterification is a promising alternative to chemically catalyzed biodiesel production despite the challenges involved with using enzymes. Celite (R) supported lipase sol-gels were investigated as an option for solving some of the challenges associated with the use of enzymes for biodiesel production addressing such problems as activity, stability and reusability

of the enzyme. Three types of Celite (R) were considered (R633, R632, and R647) and compared to unsupported lipase sol-gels. Various factors were considered with regard to comparing the support materials. They included surface morphology characterized using surface area analysis and scanning electron microscopy, physical properties including adhesion of the sol-gel to the Celite (R) and the protein loading on the Celite (R), and finally enzymatic properties based on the conversion of methanol to methyl oleate and the enzymatic activity of lipase. All the sol-gels showed good conversion and initial lipase activity, and all the Celite (R) supports had similar sol-gel adhesion and protein loading. Sol-gel immobilized lipase supported on Celite (R) R632 had an average 6-h percent conversion of approximately 60%, and an average initial lipase GDC 0032 solubility dmso activity comparable to that of the unsupported sol-gel formulation. (C) 2009 Elsevier B.V. All rights reserved.”
“Snow and ice play their most important role in the nitrogen cycle as a barrier to land-atmosphere and ocean-atmosphere exchanges that would otherwise occur. The inventory of nitrogen compounds in the polar ice sheets is approximately 260 Tg N, dominated by nitrate in the much larger Antarctic ice sheet. Ice cores help to inform us about the natural variability of the nitrogen cycle at global and regional scale, and about the extent of disturbance in recent decades.

With thorough surgery, RLND lymph node (LN) retrieval numbers have a predictable distribution. Whether patients have inguinal or ilioinguinal dissection varies between institutions. This study was designed to provide LN retrieval parameters for inguinal and ilioinguinal LN dissections, and secondarily, to analyze known predictors for survival outcomes, including LN ratio, i.e., involved/total number LN removed.\n\nA prospective database was used to identify 189 patients who had 200 groin dissections between July 2002 and February 2008 to derive parameters

of LN retrieval. A subgroup of 177 patients who had one RLND was assessed for predictors of survival outcome.\n\nInguinal MDV3100 Endocrinology & Hormones inhibitor dissection had median LN retrieval of 11 (interquartile range, 10-14); 8 LN or more were retrieved in 90% of cases, and 38% of cases had 10 LN or less. Ilioinguinal dissection had median LN retrieval of 21.5 (interquartile range, 17-25); 14 LN or more were retrieved in 90% of cases, and 0 cases had 10 LN or less. The strongest predictors of survival on multivariate analysis were LN ratio, macroscopic LN disease, and ulceration of the primary

melanoma. Overall 39% of ilioinguinal dissections had positive pelvic LNs, but only 9.3% of those completed after positive sentinel node biopsy.\n\nThorough groin RLNDs have a predictable LN yield. LN ratio is the strongest predictor of outcome. Because pelvic LNs are frequently positive ilioinguinal dissection should be considered for all patients, especially those with macroscopic metastases to groin LNs.”
“BACKGROUND selleck chemicals MS-275 research buy Recent studies suggest that cardiac resynchronization therapy (CRT) with a quadripolar left ventricular (LV) lead results in low rates of dislocation and phrenic nerve stimulation (PNS) acutely and at short-term follow-up. Confirmation of these results by long-term observational studies is needed.\n\nOBJECTIVE

To evaluate the long-term procedural and clinical outcomes of CRT patients implanted with a quadripolar LV lead.\n\nMETHODS A total of 154 consecutive heart failure patients (79% men, age 68 +/- 10 years) having CRT implantation attempts with a quadripolar LV lead were included in this observational registry. Demographic and clinical data were preoperatively collected, and patients were followed up for at least 6 months.\n\nRESULTS The overall implant success rate after coronary sinus cannulation was 97.4%. Mean overall duration and fluoroscopy time of successful procedures was 112 +/- 22 and 16 +/- 8 minutes, respectively, while 17 +/- 13 minutes were necessary for the LV lead placement. After implant, the conventional bipolar configuration was used as the final pacing configuration in 33.3% of the patients. Four lead dislodgments (requiring reoperation) and 9 clinical PNS were reported during follow-up; reprogramming of the device was sufficient to prevent PNS in all patients.

This study aimed to determine the quantity and proliferative capacity of circulating CD133(+)VEGFR2(+) and CD34(+)VEGFR2(+) cells in patients with beta-thalassaemia major and those after haematopoietic stem cell transplantation (HSCT), and their relationships with arterial function. Brachial arterial flow-mediated dilation (FMD), carotid arterial stiffness, the quantity of these circulating cells and their number of colony-forming Selonsertib price units (CFUs) were determined in 17 transfusion-dependent thalassaemia

patients, 14 patients after HSCT and 11 controls. Compared with controls, both patient groups had significantly lower FMD and greater arterial stiffness. Despite having increased CD133(+)VEGFR2(+) and CD34(+)VEGFR2(+) cells, transfusion-dependent patients had significantly reduced CFUs compared with Selleck AZD8931 controls (p = 0.002). There was a trend of increasing CFUs across the three groups with decreasing iron load (p = 0.011). The CFUs correlated with brachial FMD (p = 0.029) and arterial stiffness (p = 0.02), but not with serum ferritin level. Multiple linear regression showed that CFU was a significant determinant of FMD (p = 0.043) and arterial stiffness (p = 0.02) after

adjustment of age, sex, body mass index, blood pressure and serum ferritin level. In conclusion, arterial dysfunction found in patients with beta-thalassaemia major before and after HSCT may be related to impaired proliferation of CD133(+)VEGFR2(+) and CD34(+)VEGFR2(+) cells.”
“In this paper, we propose a stochastic model of photoplethysmographic signals that is able to synthesize an arbitrary number of other statistically equivalent signals to the one under analysis. To that end, Combretastatin A4 mouse we first preprocess the pulse signal to normalize and time-align pulses. In a second stage, we design a single-pulse model, which consists of ten parameters. In the third stage, the time evolution of this ten-parameter vector is approximated by means

of two autoregressive moving average models, one for the trend and one for the residue; this model is applied after a decorrelation step which let us to process each vector component in parallel. The experiments carried out show that the model we here propose is able to maintain the main features of the original signal; this is accomplished by means of both a linear spectral analysis and also by comparing two measures obtained from a nonlinear analysis. Finally, we explore the capability of the model to: 1) track physical activity; 2) obtain statistics of clinical parameters by model sampling; and 3) recover corrupted or missing signal epochs by synthesis.”
“The maximal shortening velocity of a muscle (V(max)) provides a link between its macroscopic properties and the underlying biochemical reactions and is altered in some diseases. Two methods that are widely used for determining V(max) are afterloaded and isotonic release contractions.

This review examines the basis for indomethacin and ibuprofen use in the neonatal intensive care population. Despite the call for restrained use of each drug, the most immature infants are likely to need pharmacologic approaches PF-04929113 ic50 to reduce high-grade IVH, avoid the need for PDA ligation, and preserve the opportunity for an optimal outcome.”
“One of the most important and complex diseases of modern society is metabolic syndrome. This syndrome has not been completely

understood, and therefore an effective treatment is not available yet. We propose a possible stem cell mechanism involved in the development of metabolic syndrome. This way of thinking lets us consider also other significant pathologies that could

have similar etiopathogenic pathways, like lipodystrophic syndromes, progeria, and aging. All these clinical situations could be the consequence of a progressive and persistent stem cell exhaustion syndrome (SCES). The main outcome of this SCES would be an irreversible loss of the effective regenerative mesenchymal stem cells (MSCs) pools. In this way, the normal repairing capacities of the organism could become inefficient. Our point of view could open the possibility MEK inhibitor for a new strategy of treatment in metabolic syndrome, lipodystrophic syndromes, progeria, and even aging: stem cell therapies.”
“The brain morphometry of 21 children, who were followed from birth and underwent structural brain magnetic resonance imaging at 8-10 years, was studied. This cohort included 11 children with prenatal cocaine Rigosertib exposure (CE) and 10 noncocaine-exposed children (NCE).

We compared the CE versus NCE groups using FreeSurfer to automatically segment and quantify the volume of individual brain structures. In addition, we created a pediatric atlas specifically for this population and demonstrate the enhanced accuracy of this approach. We found an overall trend towards smaller brain volumes among CE children. The volume differences were significant for cortical gray matter, the thalamus and the putamen. Here, reductions in thalamic and putaminal volumes showed a robust inverse correlation with exposure levels, thus highlighting effects on dopamine-rich brain regions that form key components of brain circuitry known to play important roles in behavior and attention. Interestingly, head circumferences (HCs) at birth as well as at the time of imaging showed a tendency for smaller size among CE children. HCs at the time of imaging correlated well with the cortical volumes for all subjects. In contrast, HCs at birth were predictive of the cortical volume only for the CE group. A subgroup of these subjects (6 CE, 4 NCE) was also scanned at 13-15 years of age. In subjects who were scanned twice, we found that the trend for smaller structures continued into teenage years.

“
“Monoamine oxidase (MAO) inhibitors were the first antidepressant drugs to be prescribed and are still used today with great success, especially in patients resistant to other antidepressants. In this study, we evaluated the MAO inhibitory properties and the potential

antidepressant action of 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice. We found that 2-DMPI inhibited both MAO isoforms (K-i values were 1.53 (1.3-1.8) mu M and 46.67 (31.8-68.4) mu M for MAO-A and MAO-B, respectively) with 30-fold higher selectivity toward MAO-A. In relation to the nature of MAO-A inhibition, 2-DMPI showed BIBF 1120 chemical structure to be a mixed and reversible inhibitor. The treatment with 2-DMPI (100-1000 mu mol/kg, s.c.) caused a significant decrease in immobility

time in the tail suspension test (TST) without affecting locomotor activity, motor coordination or anxiety-related activities. Conversely, moclobemide (1000 mu mol/kg, s.c.) caused a significant increase in immobility time in the TST, which appeared to be mediated by a nonspecific effect on motor coordination function. 2-DMPI (300 mu mol/kg, s.c.) decreased serotonin turnover in the cerebral cortex, hippocampus and striatum, whereas MI-503 mw dopamine turnover was diminished only in the striatum, and norepinephrine turnover was not changed. The antidepressant-like effect of 2-DMPI was inhibited by the pretreatment of mice with methysergide (2 mg/kg, s.c., a non-selective serotonin receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT1A receptor antagonist) or haloperidol (0.05 mg/kg, i.p., a non-selective dopamine receptor antagonist). These results suggest that 2-DMPI is a prototype reversible and preferential MAO-A inhibitor with potential antidepressant activity, due to its modulatory effect on serotonergic and dopaminergic systems. (c) 2012 Elsevier Inc. All rights reserved.”
“The operational and analytical performance of two automated triplex VX-770 molecular weight hepatitis

B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) nucleic acid test (NAT) systems were compared in four screening laboratories of the French Blood Service.\n\nTwo laboratories evaluated the Procleix Tigris system (Chiron/Gen-Probe) in individual donation (ID) format and two sites used the cobas s 201 system (Roche Molecular Systems) on minipools (MPs) of six donations. The analytical sensitivity, the specificity, and operational performance were compared.\n\nThe ID to MP-NAT relative sensitivity factors in standard dilution panels of different genotypes varied between 8.7 and 21.9 for HCV RNA, 6.7 and 14.8 for HIV RNA, and 0.71 and 11.6 for HBV DNA. Tigris was 800-fold more sensitive than cobas s 201 (1:6) for a HIV group O sample, but did not detect the HIV-2 sample picked up by cobas s 201 with equal sensitivity as the HIV-1 group M samples. The specificity of both NAT systems after initial screening of 10,520 donations with Tigris and 1444 test pools on s 201 was 99.

All Brucella isolates were identified as Brucella melitensis biovar 3. M-RT-PCR assay targeted bcsp31 gene and the specific integration of 15711 elements within the genome of the respective Brucella species. For the identification of Brucella spp. the primers and probes which targeted the bcsp31 gene were used. The Brucella abortus primers and probe set targeted the specific insertion of an 15711 element downstream of the alkB gene, whereas the B.melitensis primers and probe set targeted the insertion of an 15711 element downstream selleck chemicals of BMEI1162.

M-RT-PCR results were found to be 100% compatible with the reference conventional typing methods. Due to its high sensitivity, the M-RT-PCR assay could be a valuable tool for the rapid detection and differentiation of Brucella species in clinical samples which usually have very low bacterial load. These findings indicated that

B.melitensis selleck screening library biovar 3 was by far the most frequent species for human brucellosis in these specific regions of Turkey and multiplex-RT-PCR seemed to be promising in the detection and differentiation of Brucella species.”
“The investigation of functional neuronal synchronization has recently become a growing field of research. With high temporal resolution, electroencephalography and magnetoencephalography are AS1842856 datasheet well-suited measurement techniques to identify networks of interacting sources underlying the recorded data. The analysis of the data in terms of effective connectivity, nevertheless, contains intrinsic issues such as the problem of volume conduction

and the non-uniqueness of the inverse solution. Here, we briefly introduce a series of existing methods assessing these problems. To determine the locations of interacting brain sources robust to volume conduction, all computations are solely based on the imaginary part of the cross-spectrum as a trustworthy source of information. Furthermore, we demonstrate the feasibility of estimating causal relationships of systems of neuronal sources with the phase slope index in realistically simulated data. Finally, advantages and drawbacks of the applied methodology are highlighted and discussed.”
“PURPOSE\n\nThe goal of the present study was to compare the patellar tendon cross-sectional area with the patellar tendon thickness and to determine the intra-observer compliance level in the cross-sectional area and thickness measurements. This comparison was used to describe the effects of playing volleyball on the patellar tendon.

A performance gain was achieved in both binary classification

and multiclass classification of AD. The advantages and limitations of the proposed framework are discussed.”
“Background: Several wheat flour allergens relevant to baker’s asthma have been identified in the last 25 years. The aim of this study was to determine the frequency of sensitization to these allergens in German bakers.\n\nMethods: Using recombinant DNA technology, the following BI-2536 wheat flour allergens were cloned, expressed in Escherichia coli and purified: five subunits of the wheat alpha-amylase inhibitors (WTAI-CM1, WTAI-CM2, WTAI-CM3, WDAI-0.19 and WMAI-0.28), thioredoxin, thiol reductase or 1-cys-peroxiredoxin homologues, triosephosphate-isomerase, alpha beta-gliadin, serpin, glyceraldehyde-3-phosphate-dehydrogenase, a nonspecific lipid transfer protein (nsLTP), dehydrin, profilin and peroxidase. In addition, ImmunoCAPs with the recombinant allergen omega-5-gliadin and two cross-reactive carbohydrate determinants (CCDs), horse radish

peroxidase (HRP) and the N-glycan of bromelain (MUXF), were used. Specific IgE was measured in wheat flour-positive sera from 40 German bakers with work-related asthma/rhinitis and 10 controls with pollinosis.\n\nResults: Thirty bakers (75%) had IgE to at least one of the 19 single allergens. Most frequent was IgE to WDAI-0.19, HRP and MUXF (25% each), followed by WTAI-CM1 (20%), thiol reductase (16%), WTAI-CM3 VX-689 order (15%), WTAI-CM2 and thioredoxin

(12.5%), WMAI-28, triosephosphate-isomerase, alpha beta-gliadin (10%), 1-cys-peroxiredoxin (7.5%), dehydrin, serpin, glyceraldehyde-3-phosphate-dehydrogenase (5%), omega-5-gliadin, nsLTP and profilin (2.5%). Fifteen Compound C clinical trial bakers (38%) had IgE to any alpha-amylase inhibitor and 12 (30%) to at least one CCD. The controls reacted exclusively to CCDs (80%), profilin (60%), thioredoxin (30%), triosephosphate isomerase and nsLTP (10%).\n\nConclusions: The single allergen sensitization profiles obtained with 17 recombinant wheat flour allergens and two CCDs revealed no major allergen for German bakers. The highest frequencies were found for alpha-amylase inhibitors and CCDs.”
“Cytogenetic analyses were performed in Cyphocharax modestus, collected at Paranapanema River and Tiete River (Sao Paulo State, Brazil). A karyotype with 2n = 54 chromosomes was observed in the animals from both Brazilian freshwater river systems. One to four B chromosomes were also detected in individuals from the Paranapanema River, which represents the probable first report of more than a single supernumerary element in a species of the Curimatidae group. C-banding revealed centromeric and telomeric heterochromatin blocks in several chromosomes of the normal karyotype complement of C. modestus. Moreover, while some B chromosomes were characterized by the complete absence of C-bands, others were totally heterochromatic. Although there was a prevalence of B chromosomes in males of C.

These results imply that differentially expressed proteins under the LG condition may provide further information on the aging and differentiation of stem cells.”
“Constrained to develop within the seed, the plant embryo must adapt its shape and size to fit the space available. Here, we demonstrate how this adjustment shapes metabolism of photosynthetic embryo. Noninvasive NMR-based imaging of the developing oilseed rape (Brassica napus) seed illustrates that, following embryo bending, gradients in lipid concentration became established. These were correlated with the local photosynthetic electron transport rate and the accumulation of storage products. Experimentally

induced changes in embryo morphology and/or light supply altered these gradients and were accompanied

Bafilomycin A1 price by alterations in both proteome and metabolome. Tissue-specific metabolic models predicted that the outer cotyledon and hypocotyl/radicle generate the bulk of plastidic reductant/ATP via photosynthesis, while the inner cotyledon, being enclosed by the outer cotyledon, is forced selleck compound to grow essentially heterotrophically. Under field-relevant highlight conditions, major contribution of the ribulose-1,5-bisphosphate carboxylase/oxygenase-bypass to seed storage metabolism is predicted for the outer cotyledon and the hypocotyl/radicle only. Differences between in vitro-versus in planta-grown embryos suggest that metabolic heterogeneity of embryo is not observable by in vitro approaches. We conclude that in vivo metabolic fluxes are locally regulated and connected to seed architecture, driving the embryo toward an efficient use of available light and space.”
“Human SP110 plays an important role in resisting intracellular pathogens, and hence has become an important drug target for preventing intracellular pathogen diseases, such as tuberculosis, hepatic veno-occlusive disease, and intracellular cancers. Unfortunately, so far little is known about

the interactions of SP110 with the other proteins in a cell, which is considered to be the key for revealing its action mechanism and mediated pathway. Using both the genetic ACY-241 and structural analyses as well as the segment-docking approach, we have identified two proteins: the human remodeling and spacing factor 1 (RSF1) and the activating transcription factor 7 interacting protein (ATF7IP). They are very likely interacting with human SP110 during the process of viral infections. Owing to the close relationship of RSF1 with the chromatin remodeling and ATF7IP with the chromatin formation, it is logical to infer that human SP110 may be involved in the chromatin remodeling and formation as well. These findings may provide useful insights into the development of new drugs for treating and preventing intracellular pathogen diseases.”
“A rare blood group: p phenotype. A rare blood group is usually defined as the absence of a high prevalence antigen or the absence of several antigens within a single blood group system.

The stop-signal reaction time provided a behavioral measure of response inhibition.

The neural correlates of response inhibition were assessed in a region-of-interest analysis that included the presupplementary motor area, inferior frontal gyrus, subthalamic nucleus, and inferior parietal cortex.\n\nResults: p38 MAPK inhibitor Patients with OCD had greater stop-signal reaction times relative to healthy comparison subjects. The numerical stop-signal reaction time difference between siblings and comparison subjects failed to reach significance. Both patients with OCD and their siblings showed greater activity in the left presupplementary motor area during successful inhibition relative to comparison subjects. Relative to both the comparison subjects and the siblings, DMH1 nmr patients with OCD showed decreased activity in the right inferior parietal cortex and inferior frontal gyrus. In patients and siblings, presupplementary motor area activity correlated negatively with stop-signal reaction time.\n\nConclusions: These findings suggest that presupplementary motor area hyperactivity is a neurocognitive endophenotype of OCD that is possibly related to inefficient neural processing within the presupplementary

motor area itself. Patients with OCD further showed a state-dependent deficit in recruiting right inferior parietal cortex and inferior frontal gyrus, which may contribute to their inhibition deficit. (Am J Psychiatry 2012; 169:1100-1108)”
“Head and neck cancer represents 3.3% of all new malignancies and 2.0% of cancer deaths in the USA, the selleck majority of which are squamous in origin. The overall 5 year survival is 60% and worsens with increasing stage at diagnosis. Thus, novel biomarkers for early detection of squamous cell carcinoma of the head and neck (SCCHN) are needed. MicroRNA-137 (miR-137) plays a role in cell cycle control and seems to undergo

promoter methylation in oral squamous cell carcinoma tissue. The main objectives of this study were to ascertain whether miR-137 promoter methylation is detectable in oral rinse samples, assess its association with SCCHN and identify potential risk factors for its occurrence. Oral rinse samples were collected from 99 SCCHN patients with no prior history of cancer and 99 cancer-free controls, frequency matched on gender; tumor tissue for 64 patients was also tested. Methylation of the miR-137 promoter, assessed using methylation-specific polymerase chain reaction, was detected in 21.2% oral rinses from SCCHN patients and 3.0% from controls [odds ratio (OR) = 4.80, 95% confidence interval (CI): 1.23-18.82]. Among cases, promoter methylation of miR-137 was associated with female gender (OR = 5.30, 95% CI: 1.20-23.44) and inversely associated with body mass index (BMI) (OR = 0.88, 95% CI: 0.77-0.99). Promoter methylation of miR-137 appears to be a relatively frequently detected event in oral rinse of SCCHN patients and may have future utility as a biomarker in DNA methylation panels.

\n\nResults: Effect size estimates indicate that men (n = 1,630) and women (n = 2,754) who binge eat experience comparable levels of clinical impairment. They also report substantially greater impairment when compared

with men and women who do not binge eat.\n\nDiscussion: The underrepresentation of men in treatment-seeking samples does not appear to reflect lower levels of impairment in men versus women. Efforts are needed to raise awareness of the clinical significance of binge eating in men so that this group can receive appropriate screening and treatment services. (C) 2011 by Wiley Periodicals, Inc.”
“In the elderly, malnutrition is highly prevalent and a major contributor to increased morbidity CHIR98014 and mortality. We aimed to evaluate the fat-soluble vitamin status and potential determinants in patients bigger than 65 years of age. Serum vitamins A, D and E were determined by liquid chromatography in 166 patients. Gender, age, season, hospitalization, nutritional markers (albumin and cholesterol), acute-phase reactants (ferritin and

C-reactive protein) and renal function (creatinine and glomerular filtrate) were’ assessed as potential determinants. Prevalence of vitamin deficiency was highly variable, ranging from 0 (vitamin E/cholesterol ratio) to 94% (for

vitamin D in hospitalized patients). Vitamin status did not differ according to gender, but age, season, hospitalization, www.selleckchem.com/products/AZD1480.html a poor nutritional status and impaired renal function, and the presence of acute-phase response significantly affected serum levels of vitamin A, E and D. In conclusion, in subjects bigger than 65 years both demographic and clinical factors determined the fat-soluble vitamin status.”
“Sustained imatinib treatment in chronic myeloid leukemia patients can result in complete molecular response allowing discontinuation without relapse. We set out to evaluate the frequency of complete molecular response selleck chemical in imatinib de novo chronic phase chronic myeloid leukemia patients, to identify base-line and under-treatment predictive factors of complete molecular response in patients achieving complete cytogenetic response, and to assess if complete molecular response is associated with a better outcome. A random selection of patients on front-line imatinib therapy (n=266) were considered for inclusion. Complete molecular response was confirmed and defined as MR4.5 with undetectable BCR-ABL transcript levels. Median follow up was 4.43 years (range 0.79-10.8 years). Sixty-five patients (24%) achieved complete molecular response within a median time of 32.7 months.