(C) 2012 Crown Copyright Published by Elsevier Inc. All rights reserved.”
“How do we create new artificial proteins? In this review, we present a range of experimental approaches based on combinatorial and directed evolution methods used to explore sequence space and recreate structured

or active proteins. These approaches can help to understand constraints of natural evolution and can lead to new useful proteins. Strategies such as binary patterning or modular assembly can efficiently speed structural and functional innovation. Many natural protein architectures are symmetric or repeated and presumably have emerged by coalescence of simpler fragments. This process can be experimentally reproduced; a range of artificial proteins obtained from idealized fragments has recently been described and some of these have already found direct applications.”
“The major substrate underlying amphetamine (AMPH)-induced locomotor activity Quizartinib cost is associated this website with dopamine forebrain circuits. Brain regions associated with AMPH-induced locomotor activity express high levels of retinoid receptors. However, the role of these transcription factors in dopamine-mediated effects remains poorly understood. Two nuclear receptor families, the retinoic acid receptors (RAR) and the retinoid X receptors (RXR), transduce retinoic acid signal. RARs are specifically involved in retinoid signaling, whereas RXRs also participate in other signaling pathways

as partners for other nuclear receptors such as Nur77, an orphan member of the nuclear receptor family expresses in dopamine system.

To explore the role of retinoid receptors and Nur77 in AMPH-induced locomotor activity, we administered LCL161 in vitro selective retinoid receptor drugs in combination with AMPH in adult wild-type and Nur77-deficient

mice. At a low dose, AMPH similarly increased ambulatory activity in wild-type and Nur77-deficient mice, while it did not alter non-ambulatory activity.

At a high dose, AMPH did not alter ambulatory activity anymore, while non-ambulatory activity strongly increased in wild-type mice. Nur77-deficient mice still displayed a higher ambulatory activity with no change in non-ambulatory activity. HX531, a synthetic RXR antagonist, blocks AMPH-induced ambulatory activity, whereas RAR drugs tested remained without effect. Interestingly, the effect of HX531 was abolished in Nur77-deficient mice, suggesting that this orphan nuclear receptor is essential for the action of the RXR drug.

This study shows that RXR and Nur77 participate in AMPH-induced locomotor activity and prompts for further investigations on the role of Nur77 and RXR in addiction and reward-related behaviors.”
“Semliki Forest virus (SFV) is a member of the Alphavirus genus, which produces its replicase proteins in the form of a nonstructural (ns) polyprotein precursor P1234. The maturation of the replicase occurs in a temporally controlled manner by protease activity of nsP2.

Thus. KARs have been shown to regulate excitatory and inhibitory synaptic transmission. In the case

of the regulation Of L-glutamate release, they can function as facilitatory autoreceptors or inhibitory autoreceptors during repetitive synaptic activation and can respond to ambient levels of L-glutamate to provide a tonic regulation Of L-glutamate this website release. KARs also contribute a component of excitatory synaptic transmission at certain synapses. They can also act as triggers for both long-term potentiation (LTP) and long-term depression (LTD) and rapid alterations in their trafficking can result in altered synaptic transmission during both synaptic plasticity and neuronal development. KARs

also contribute to synchronised rhythmic activity in the brain and are involved in forms of learning and memory. With respect to therapeutic indications, antagonists for GluK1 have shown positive activity in animal models of pain, migraine, epilepsy, stroke and anxiety. This potential has now been confirmed in dental pain and migraine in initial studies in man. (C) 2008 DAPT nmr Elsevier Ltd. All rights reserved.”
“We recently identified and cloned the receptor for subgroup C avian sarcoma and leukosis viruses [ASLV(C)], i.e., Tvc, a protein most closely related to mammalian butyrophilins, which are members of the immunoglobulin protein family. The extracellular domain of Tvc contains two immunoglobulin-like domains, IgV and IgC, which presumably each contain a disulfide bond important for native function of the protein. In this study, we have begun to identify the functional determinants of

Tvc responsible for ASLV(C) receptor activity. We found that the IgV domain of the Tvc receptor is responsible for interacting with the glycoprotein of ASLV(C). Additional experiments demonstrated that a domain was necessary as a spacer between the IgV domain and the membrane-spanning domain for efficient Tvc receptor activity, most likely to orient the IgV domain a proper distance from the cell membrane. The effects on ASLV(C) glycoprotein binding and infection efficiency were also studied by site-directed mutagenesis of IWP-2 solubility dmso the cysteine residues of Tvc as well as conserved amino acid residues of the IgV Tvc domain compared to other IgV domains. In this initial analysis of Tvc determinants important for interacting with ASLV(C) glycoproteins, at least two aromatic amino acid residues in the IgV domain of Tvc, Trp-48 and Tyr-105, were identified as critical for efficient ASLV(C) infection. Interestingly, one or more aromatic amino acid residues have been identified as critical determinants in the other ASLV(A-E) receptors for a proper interaction with ASLV glycoproteins.

Fewer and/or less intensely labeled irNST cells were noted in other regions such as the hippocampus, cortex, amygdala, and cerebellum. Double-labeling hypothalamic sections with NST- and SST-antiserum revealed an extensive overlapping of irNST and irSST cells

in the periventricular nucleus. Pre-absorption of the NST-antiserum with NST (1 mu g/ml) but not with SST (1 mu g/ml) abrogated irNST and vice versa. PF299804 mouse The activity of NST on dissociated and cultured hypothalamic neurons was assessed by the Ca(2+) imaging method. NST (10, 100, 1000 nM) concentration-dependently elevated intracellular Ca(2+) concentrations [Ca(2+)](i) in a population of hypothalamic neurons with two distinct profiles: (1) a fast and transitory increase in [Ca(2+)](i), and (2) an oscillatory response. Whereas, SST (100 nM) reduced the basal [Ca(2+)](i) in 21 of 61 hypothalamic neurons examined; an increase was not observed in any of the cells. Optical imaging with a slow-responding voltage sensitive dye DiBAC(4)(3) showed that NST

MK-0518 price (100 nM) depolarized or hyperpolarized; whereas, SST (100 nM) hyperpolarized a population of hypothalamic neurons. The result shows that NST and SST, though derived from the same precursor protein, exert different calcium mobilizing effects on cultured rat hypothalamic neurons, resulting in diverse cellular activities. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Fibroblast growth factor (FGF)-23 is a recently discovered regulator of calcium-phosphate metabolism. Whereas other known FGFs mainly act in a paracrine manner, FGF-23 has significant systemic effects. Together with its cofactor Klotho, FGF-23 enhances renal phosphate excretion in order to maintain serum phosphate levels within the normal range. In patients with chronic kidney disease (CKD), FGF-23 levels rise in parallel with declining renal function long before learn more a significant increase in serum phosphate concentration can be detected. However, in cross-sectional studies increased FGF-23

levels in patients with CKD were found to be associated not only with therapy-resistant secondary hyperparathyroidism but were also independently related to myocardial hypertrophy and endothelial dysfunction after adjustment for traditional markers of calcium-phosphate metabolism. Finally, in prospective studies high serum FGF-23 concentrations predicted faster disease progression in CKD patients not on dialysis, and increased mortality in patients receiving maintenance hemodialysis. FGF-23 may therefore prove to be an important therapeutic target in the management of CKD.”
“Damage to oligodendrocyte (OL) progenitor cells (OPCs) and hypomyelination are two hallmark features of periventricular leukomalacia (PVL), the most common form of brain damage in premature infants.

Earlier institution of extracorporeal membrane oxygenation may decrease the complication rates and improve the overall survival.”
“Background: Infection MI-503 mw with herpes simplex

virus type 2 (HSV-2) is associated with an increased risk of acquiring infection with the human immunodeficiency virus (HIV). This study tested the hypothesis that HSV-2 suppressive therapy reduces the risk of HIV acquisition.

Methods: Female workers at recreational facilities in northwestern Tanzania who were 16 to 35 years of age were interviewed and underwent serologic testing for HIV and HSV-2. We enrolled female workers who were HIV-seronegative and HSV-2-seropositive in a randomized, double-blind, placebo-controlled trial of suppressive treatment with acyclovir (400 mg twice daily). Participants attended mobile clinics every 3 months for a follow-up period of 12 to 30 months, depending on enrollment date. The primary outcome was the incidence of infection with HIV. We used a modified intention-to-treat analysis; data for participants who became pregnant were censored.

Adherence to treatment was estimated by a tablet count at each visit.

Results: Q-VD-Oph nmr A total of 821 participants were randomly assigned to receive acyclovir (400 participants) or placebo (421 participants); 679 (83%) completed follow-up. Mean follow-up for the acyclovir and placebo groups was 1.52 and 1.62 years, respectively. The incidence of HIV infection was 4.27 per 100 person-years (27 participants in the acyclovir group and 28 in the placebo group), and there was no overall effect of

acyclovir on the incidence of HIV (rate ratio for the acyclovir group, 1.08; 95% confidence interval, 0.64 to 1.83). The estimated median adherence was 90%. Protein Tyrosine Kinase inhibitor Genital HSV was detected in a similar proportion of participants in the two study groups at 6, 12, and 24 months. No serious adverse events were attributable to treatment with acyclovir.

Conclusions: These data show no evidence that acyclovir (400 mg twice daily) as HSV suppressive therapy decreases the incidence of infection with HIV. (Current Controlled Trials number, ISRCTN35385041.).”
“Objective: Mitochondrial permeability transition pore opening is associated with apoptotic signaling and alterations in mitochondrial structure and function. We tested whether inhibition of mitochondrial permeability transition pore opening with cyclosporine A preserved mitochondrial structure and function after cardioplegic arrest and whether this preservation is associated with improved myocardial performance.

Minimizing W(P) is sufficient

to produce statistically significant native like secondary structures and hydrogen bonds in the proteins we simulated. (C) 2009 Elsevier Ltd. All rights reserved.”
“Episodic memory, the recollection of past events in one’s life, has often been considered a memory specific to humans. Recent work in a variety of species has challenged this view, and has raised important questions about the nature of episodic WZB117 nmr memory itself. We present a review of the types of task proposed as episodic-like in animals and consider that these tasks require animals to demonstrate memory for specific occasions in the past. We propose that identifying episodic memory as the memory for what happened where on a specific occasion is a more encompassing definition than one that relies on information about when an event occurred. These episodic-like tasks

in animals support the view that the hippocampal system is necessary for episodic memory, and that the neural substrates of episodic memory can be dissociated from those of other forms of declarative memory. (C) 2009 Elsevier Ltd. All rights reserved.”
“In an inclusive fitness model of social behaviour, a key concept is that of the relatedness between two interactants. This is typically calculated with reference to a “”focal”" actor taken to be representative of all actors, but when there are different interaction configurations, relatedness AZD0156 manufacturer must be constructed as an average over all such configurations. We provide an example of such a calculation in

an island model with local reproduction Blasticidin S manufacturer but global mortality, leading to variable island size and hence variable numbers of individual interactions. We find that the analysis of this example significantly sharpens our understanding of relatedness. As an application, we obtain a version of Hamilton’s rule for a tag-based model of altruism in a randomly mixed population. For large populations, the selective advantage of altruism is enhanced by low (but not too low) tag mutation rates and large numbers of tags. For moderate population sizes and moderate numbers of tags, we find a window of tag mutation rates with critical benefit/cost ratios of between 1 and 3. (C) 2009 Elsevier Ltd. All rights reserved.”
“Here we review our development of an animal model of episodic memory and amnesia that employs a signal detection analyses to characterize recognition memory performance in rats. This approach aims to distinguish episodic recollection of studied items from mere familiarity for recently experienced stimuli, and then to examine the neural basis of these memory processes. Our findings on intact animals indicate that it is possible to distinguish independent components of recognition that are associated with features of recollection and familiarity in humans.

Additionally, a dose-dependent decrease was observed in the mean number of SNpc TH-ir neurons/section in the current study which was not seen in the continuous MPTP protocol. These results suggest that a washout period following each increased MPTP dose allows for observation

of continued cell death that might occur during the week following MPTP C59 wnt supplier administration, and for therapeutic interventions to be applied at any of several stages during progressive neurodegeneration. Published by Elsevier Ltd on behalf of IBRO.”
“Fitness disadvantage of the transitional intermediates compared to the initial R5 viruses has been suggested to constitute one of the blockades to coreceptor switching, explaining the late appearance of X4 viruses. Using a simian model for human immunodeficiency virus type 1 (HIV-1) coreceptor switching, we demonstrate in this study that similar molecular evolutionary pathways to coreceptor switch occur in more than one R5 simian/human immunodeficiency virus (SHIV)(SF162P3N)-infected

macaque. In infected animals where multiple pathways for expansion or switch to CXCR4 coexist, fitness of the transitional intermediates in coreceptor usage efficiency influences their outgrowth and representation in the infecting virus population. Dualtropic and X4 viruses appear at different disease stages, but they have lower entry efficiency than the coexisting R5 strains, which may explain why they do not outcompete the R5 viruses. Similar observations

were made in two infected macaques Selleckchem Bindarit with coreceptor switch, providing in vivo evidence that fitness disadvantage is an obstacle to X4 emergence and expansion.”
“Background and purpose: Positron emission tomography (PET) MK-0518 cell line studies in humans have used C-11-flumazenil (FMZ) to assess neuronal viability after stroke. Here we aimed to study whether C-11-FMZ binding was sensitive to neuronal damage in the acute phase following ischemia/reperfusion in the rat brain. Experimental procedures: Transient (2 h followed by reperfusion) and permanent intraluminal middle cerebral artery occlusion was carried out. C-11-FMZ binding was studied by PET up to 24 h after the onset of ischemia. Tissue infarction was evaluated post-mortem at 24 h. Immunohistochemistry against a neuronal nuclei specific protein (NeuN) was performed to assess neuronal injury. Results: No decrease in C-11-FMZ binding was detected in the ipsilateral cortex up to 24 h post-ischemia in the model of transient occlusion despite the fact that rats developed cortical and striatal infarction, and neuronal injury was clearly apparent at this time. In contrast, C-11-FMZ binding was significantly depressed in the ipsilateral cortex at 24 h following permanent ischemia. Conclusions: This finding evidences that C-11-FMZ binding is not sensitive to neuronal damage on the acute phase of ischemia/reperfusion in the rat brain. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

By means of target prediction, we found that the target mRNAs employed by miR-218 were the most significant among PF-4708671 nmr Ki-67 specific mRNAs. Up-regulation of miR-218 was further demonstrated to reduce Ki-67 expression, promote apoptosis, and induce G0/G1

phase cell cycle arrest in LN229 cells. Conclusions: Ki-67 protein may be regulated by specific miRNA-mRNA interactions which may contribute to the proliferation of glioma cells. (C) 2013 Elsevier Ireland Ltd. All rights reserved.”
“Epstein-Barr virus (EBV) BBLF1 shares 13 to 15% amino acid sequence identities with the herpes simplex virus 1 UL11 and cytomegalovirus UL99 tegument proteins, which are involved in the final envelopment during viral maturation. This study demonstrates that BBLF1 is a myristoylated and palmitoylated protein, as are UL11 and UL99. Myristoylation of BBLF1 both facilitates its membrane anchoring and stabilizes it. BBLF1 is shown to localize to the trans-Golgi network (TGN) along with gp350/220, a site where final envelopment

of EBV particles takes place. The localization of BBLF1 at the find more TGN requires myristoylation and two acidic clusters, which interact with PACS-1, a cytosolic protein, to mediate retrograde transport from the endosomes to the TGN. Knockdown of the expression of BBLF1 during EBV lytic replication reduces the production of virus particles, demonstrating the requirement of BBLF1 to achieve optimal production of virus particles. BBLF1 is hypothesized to facilitate the budding of tegumented capsid into glycoprotein-embedded membrane during viral maturation.”
“Overproduction of membrane proteins can be a cumbersome task, particularly if high yields are desirable. NADH:quinone oxidoreductase (Complex I) contains several very large membrane-spanning protein subunits that hitherto have been impossible to express individually in any appreciable amounts in Escherichia coli. The polypeptides contain no prosthetic groups and are poorly antigenic,

making optimization of protein production a challenging task. In Ulixertinib this work, the C-terminal ends of the Complex I subunits NuoH, NuoL, NuoM, and NuoN from E. coli Complex I and the bona fide antiporters MrpA and MrpD were genetically fused to the cytochrome c domain of Bacillus subtilis cytochrome c(550). Compared with other available fusion-protein tagging systems, the cytochrome c has several advantages. The heme is covalently bound, renders the proteins visible by optical spectroscopy, and can be used to monitor, quantify, and determine the orientation of the polypeptides in a plethora of experiments. For the antiporter-like subunits NuoL, NuoM, and NuoN and the real antiporters MrpA and MrpD, unprecedented amounts of holo-cytochrome fusion proteins could be obtained in E. coli.

“
“A simple technique was developed to separate Cowpea chlorotic mottle virus (CCMV) from Cucumber mosaic virus (CMV) in natural mixed infections. Sap from cowpea leaves infected naturally with a mixture of CCMV and CMV was inoculated mechanically on the first tri-foliolate leaf of cowpea seedlings. Both inoculated and non-inoculated upper leaves were sampled 3 or 8 days post-inoculation and tested by reverse transcription polymerase chain reaction (RT-PCR) using primers specific to CCMV and CMV. RT-PCR analysis

showed the presence of only CCMV in the inoculated leaf and both viruses in the non-inoculated systemically infected upper leaves. Total RNA from the inoculated leaves positive to CCMV only was further confirmed upon re-inoculation to cowpea seedlings. Typical JSH-23 chemical structure CCMV symptoms were produced within 1 week and RT-PCR analysis showed only the presence of CCMV in both inoculated and non-inoculated systemically infected upper leaves. Systemically infected

upper leaves of the same plants were used for CCMV purification. RT-PCR analysis of the purified virion and RNA extracted YM155 research buy from the virion further confirmed the absence of CMV contamination. To our knowledge, this is the first report of a method separating CCMV directly from mixed infections with CMV in cowpea. (C) 2008 Elsevier B.V. All rights reserved.”
“OBJECTIVE: Atypical meningioma (AM) patients often undergo gross total resection (GTR) Alisertib at the time of presentation, but subsequent prognosis and

optimal management remain unclear. We sought to define the long-term recurrence rate of AMs after GTR, along with factors predicting recurrence, including postoperative radiation.

METHODS: We performed a retrospective review of 108 AMs after GTR at our institution from 1993 to 2004. Recurrence risk factors were analyzed using multivariate Cox regression.

RESULTS: There were 600 patient-years of imaging follow-up on 48 men and 60 women. Of 108 tumours, 30 (28%) recurred 3 to 144 months after GTR (mean, 36 months). Actuarial tumor recurrence rates were 7% (1 year), 41% (5 years), and 48% (10 years). Of 108 patients, 8 received postoperative radiation without recurrence (P = 0.1). Multivariate analysis including age, sex, postoperative radiation, tumor location, MIB-1 labeling index, and 6 atypical-defining histological features identified recurrence-predicting factors: older age (hazard ratio, 1.6/decade; P = 0.01), sheeting (hazard ratio, 2.2; P = 0.025), and prominent nucleoli (hazard ratio, 2.1; P = 0.034). Recursive partitioning identified a subset, men with mitoses and prominent nucleoli, with 70% recurrence (n = 14). All patients with recurrences received radiation, and 22 of 30 patients underwent craniotomies (average, 2.7 craniotomies per patient with recurrence; range, 1-7 craniotomies). Only 1 of 22 re-resected meningiomas underwent malignant transformation.

Aims: To explore the conformity of patient recruitment with recommended informed consent procedures among patients who were invited to participate in a clinical study at a general teaching hospital, and to examine the association between consent procedures and the patients’ decision to participate.

Design and Methods: All inpatients discharged during a 1-month period were invited to complete a mailed survey in which they reported whether they were invited to participate in a study and whether 13 recommended elements of informed consent actually occurred.

Results: Among 1303 respondents, 265 (20.3%) reported

that they had been invited to participate in a study, and 191 (72.1%) accepted. While the majority of potential participants were fully informed LCL161 manufacturer about practical issues related to the study (e.g. what their participation would consist in), <50% were informed of possible risks or benefits, and only 20% about the origin of the study funds. Only 60% reported satisfactory answers to items assessing the overall information process (e.g. explanations were easy to understand). Older and sicker patients reported lower levels of conformity

selleck chemical with informed consent procedures, as did patients who refused to participate in a study.

Conclusions: Our results confirm that informed consent procedures fail to meet standards for many patients. In particular, consent information should be adapted to the needs of older and sicker patients. Improving the quality of informed consent may increase patients’ participation in clinical research.”
“Objective: Distal cerebral embolization is a known complication of carotid interventions. We prospectively investigated click here whether subclinical microembolization seen on postoperative magnetic resonance imaging (MRI) leads to cognitive deficits in patients undergoing carotid revascularization procedures.

Methods: Patients undergoing carotid interventions and eligible for MRI scanning were recruited. Among 247 patients who received preoperative and postoperative MRI evaluations, 51 also completed neuropsychologic testing before and at 1 month after their procedure. Cognitive evaluation included the

Rey Auditory Verbal Learning Test (RAVLT) for memory evaluation and the Mini-Mental State Examination (MMSE) for general cognitive impairment screening.

Results: The 51 patients (all men), comprising 16 with carotid artery stenting (CAS) and 35 with carotid endarterectomy (CEA), were a mean age of 71 years (range, 54-89 years). Among them, 27 patients (53%) were symptomatic preoperatively, including 11 who had prior stroke and 16 who had prior preoperative transient ischemic attack symptoms. Most patients had significant medical comorbidities, including hypertension (96%), diabetes (31.3%), coronary artery disease (47%), and chronic obstructive pulmonary disease (15.7%). Two patients (4%) had prior ipsilateral CEA and eight had contralateral carotid occlusion (15.7%).

38.3 months +/- 7.9; P=0.04). The SNPs at +191 A>C of galectin-3 gene did not show positive association with https://www.selleckchem.com/products/nepicastat-hydrochloride.html clinico-pathological characteristics and prognosis of gliomas. The results of this study suggest the SNPs at +292 A>C, not SNPs at +191 A>C, of galectin-3 gene

were associated with the tumor grade and prognosis of gliomas. (C) 2012 Elsevier Ireland Ltd. All rights reserved.”
“Background After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of

breast cancer death to the absolute reduction in 10-year recurrence risk.

Methods We undertook a meta-analysis of individual patient data for 10 801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease.

Findings Overall, https://www.selleckchem.com/products/stattic.html radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35.0% to 19.3% (absolute reduction 15.7%, 95% CI 13.7-17.7, 2p<0.00001) and reduced the 15-year risk of breast cancer death from 25.2% to 21.4% (absolute reduction 3.8%, 1.6-6.0, 2p=0.00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31.0% to 15.6% (absolute

recurrence reduction 15.4%, 13.2-17.6, 2p<0.00001) and from 20.5% to 17.2% (absolute mortality reduction 3.3%, 0.8-5.8, 2p=0.005), respectively. In these women with Selleckchem MEK162 pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (>= 20%), intermediate (10-19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7.8% (95% CI 3.1-12.5), 1.1% (-2.0 to 4.2), and 0.1% (-7.5 to 7.7) respectively (trend in absolute mortality reduction 2p=0.03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63.7% to 42.5% (absolute reduction 21.2%, 95% CI 14.5-27.9, 2p<0.00001) and the 15-year risk of breast cancer death from 51.3% to 42.8% (absolute reduction 8.5%, 1.8-15.2, 2p=0.01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease.

Interpretation After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth.