The latter two complexes were inactive. Selleck Idelalisib The kinetic study using the LD technique showed that the cleavage of dsDNA by the Cu(bpy)2 complex consists of two first order reactions. The first is proposed to reflect the scission of one strand, whereas the slow reaction is due to the cleavage of the complementary strand near the first cleaved site. The reactive oxygen species is the oxygen radical which is produced by oxidation of the central Cu(II) ion. This study was supported by the National Research Foundation (grant nos. 2012-008875 conferred to S.K. Kim and SRC program 2011-0001335 to J. Kim).

“
“Current Opinion in Chemical Biology 2014, 19:25–33 This review comes from a themed issue on Biocatalysis and biotransformation Edited by Jeffrey C Moore and Uwe T Bornscheuer For a complete overview see the Issue and the Editorial Available online 4th January 2014 1367-5931/$ – see front matter, © 2013 The

Authors. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cbpa.2013.12.010 The formation of carbon-carbon bonds is central to organic chemistry and the aldol condensation [1, 2, 3 and 4], the reaction of two carbonyl compounds to generate a new β-hydroxyl carbonyl compound, is an important tool in building up complexity of organic molecules, Tyrosine Kinase Inhibitor Library since up to two new stereogenic centres are made during the formation of the new C–C bond. Aldol structural units HSP90 are found in many naturally occurring molecules and are the result of reactions catalysed by the aldolase family of enzymes. These enzymes convert their substrates into the aldol products in high yield with high specificity under mild conditions,

but also with great control over the relative and absolute configurations of the new stereogenic centres created. These properties make aldolase-catalysed routes attractive for the production of biologically significant compounds, as these tend to contain multiple functional groups and are often water-soluble making conventional synthetic routes more difficult [5]. However, naturally occurring aldolases do not exist for many industrially important reactions and protein engineering, directed evolution and de novo enzyme design [ 6, 7, 8, 9 and 10] have all been used to alter properties such as stability, substrate specificity and stereoselectivity to produce tailor made aldolases for use as biocatalysts. Since we reviewed this area in 2008 [ 11] it is pleasing to see an increasing use of protein engineering to manipulate aldolases as new biocatalysts, both in their own right and as part of chemical cascade reactions leading to important products (see Table 1 for a summary of recent examples of engineering aldolases).

In many patients, these effects could reflect imminent heart failure.27 In contrast, the faster-walking subcohort had longer-than-average life expectancy and

may have been exposed to the pathologic effects of sustained hypertension, such as death. As gait speed decreases with age in a group of very old people, the association between hypertension and mortality may cease to exist merely in comparison with the overall rising mortality rate. find more The present population-based study involved home visitation of very old people, enabling participation of the frailest individuals and care facility residents. Standardized face-to-face interviews, in combination with data from medical records, provided extensive information on comorbidities that was incorporated in the fully adjusted regression model. The division of BP values into 4 or 5 categories allowed for interpretation of nonlinear associations. Despite these stengths, the present study has some limitations. Although mortality

data were reliable, information on cause of death was not collected. The study was representative of people in the studied geographic Selleck Dabrafenib area aged 85, 90, and 95 years or older, and its results may not apply to a general population of very old individuals. Furthermore, BP was measured while participants were supine, which impedes comparison with other studies. Because of the high prevalence of orthostatic hypotension in very old people,28 and 29 the measurement of BP with participants in a seated position might have produced a wider distribution of BP values and lower mean values. Each participant’s BP was measured only once during a home visit, which may limit the reliability of this measurement. However, data quality

seemed to be acceptable for group-level comparison, as BP was measured using a calibrated manual sphygmomanometer according to a standardized procedure. Finally, the statistical power of some subcohort analyses may have been limited. In conclusion, the association of BP with mortality differed in gait speed subcohorts. High systolic and diastolic BP seem to be independently very associated with increased mortality risk among very old people with gait speeds of 0.5 m/s or faster. In slower-walking and habitually nonwalking individuals, BP does not appear to be independently associated with mortality. Low systolic and diastolic BP may be markers of increased mortality risk in very old people with lower gait speed, possibly secondary to failing health. Future studies should aim to investigate the risks of other complications of hypertension in very old people, with respect to gait speed. The gait speed threshold of 0.5 m/s may be clinically useful for the distinction of very old people with and without increased mortality risk due to elevated systolic and diastolic BP.

The tubes were incubated at 37 °C for 15 min, and the absorption at 505 nm was measured in a cuvette. The following buffers were used in the assays: 0.1 M acetic acid/NaOH MK-2206 research buy (pH 4.5, 5.0 or 5.5),

0.1 M MES/NaOH (pH 6.0, 6.5 or 7.0) and 0.1 M HEPES/NaOH (pH 7.5, 8.0 or 8.5). The blanks were prepared using heat-inactivated samples (2 min in boiling water). Isomaltose was assayed at pH 6.5 using this protocol. For calculations, a standard curve was obtained with different quantities of glucose dissolved in 10 μL of water and reacted with 1 mL of PAP reagent according the method above described. Five insects were dissected in 0.9% (w/v) NaCl. Each intestine was cut into four pieces (anterior midgut, middle midgut, posterior midgut

and hindgut), which were transferred to four different micro centrifuge tubes containing 500 μL of 0.9% (w/v) NaCl and 1% (v/v) Triton X-100. After homogenization, the tubes were centrifuged at 14,000×g for 10 min at 4 °C, and the supernatant was used in the assays. Maltose or trehalose were used as substrates and assayed as described in Section 2.3.2 at pH 6.5 and pH 6.0, respectively. The samples were prepared as described in Section 2.2.3 and assayed using maltose (pH 6.5) or trehalose (pH 6.0) as substrates according the methodology described in Section 2.3.2. To investigate whether the enzymes are bound to intestinal microvilli, the larval microvilli were purified according to the method of Abdul-Rauf and Ellar (1999). Sixty larvae were dissected in 0.9% saline (w/v), the luminal content Baf-A1 in vitro A-1210477 datasheet was discarded, and the midgut walls were washed and transferred to 40 μL of an ice-cold MET solution (300 mM mannitol, 5 mM EGTA, 17 mM TRIS-base/HCl, pH 7.5) in a micro centrifuge tube. The midguts were manually homogenized with an abrasive glass microhomogenizer for 15 min in an ice bath, and the volume was brought to 100 μL with the same solution. One hundred microliters

of ice-cold 24 mM MgCl2 was added to this preparation and the tube content was mixed and separated into two aliquots of 100 μL each. After 20 min on ice, one of the aliquots was centrifuged at 2500×g for 15 min at 4 °C. The supernatant was collected in another tube, and the pellet was rehomogenized in 100 μL of a fresh ice-cold MET/MgCl2 (1:1) solution and centrifuged. After repeating this procedure three times, the supernatants were mixed and centrifuged at 25,000×g for 30 min at 4 °C. The pellet, enriched with microvillosites, was dissolved in 100 μL of MET/MgCl2 (1:1) containing 1% Triton X-100 (v/v). Triton X-100 was also added to the non-centrifuged aliquot to a final concentration of 1% (v/v) and mixed. Both the centrifuged and non-centrifuged aliquots were centrifuged at 14,000×g, and the supernatants were used for the assays.

Bak et al. (1990) recorded threshold minima at depths of 2–3 mm, 4 mm and 4.5 mm in three sighted volunteers undergoing occipital craniotomy for excision of epileptic foci. In the patient with the lowest detection thresholds, they plotted the threshold stimulus current vs. electrode depth, showing the lowest thresholds (20 µA) at a depth of approximately 2.25 mm.

In their subsequent study on a blind volunteer, the same group reported thresholds varying from 1.9 µA to 77 µA using fixed-length electrodes implanted to a depth of 2 mm (Schmidt et al., 1996). As noted by Torab et al. (2011), the undulating nature of the cerebral cortex renders it difficult to ensure consistent penetration depth of all electrodes with an array based on a rigid substrate. Y-27632 concentration Moreover, the ability of electrodes to elicit behavioral responses at current levels not damaging to the electrodes or tissue may be predicated partly on the location of electrode stimulating sites within

laminae containing the most excitable neuronal elements. Spatial differences in threshold current (DeYoe et al., 2005) or depth of lowest threshold (Bak et al., 1990) and natural variations in the thickness of V1 (Fischl and Dale, 2000) may therefore combine to present a significant challenge for ensuring implantation of electrodes to the optimal depth in visual cortex. Possible solutions to these problems include the implantation of arrays with electrode shanks of Caspase phosphorylation varying length as previously

described (Bradley et al., 2005), which may require an increase in the density of electrodes, e.g. (Wark et Cyclooxygenase (COX) al., 2013) to preserve the resolution of the phosphene map. Another possible solution could be the incorporation of multiple stimulating sites onto individual electrode shanks (Changhyun and Wise, 1996) or microdrives that allow independent adjustment of electrode penetration depth (Gray et al., 2007, Yamamoto and Wilson, 2008 and Yang et al., 2010). For the latter, further reductions in the size of the positioning hardware will be required before integration into high electrode count arrays is a realistic possibility. Reductions in the size of electrode arrays may also offer some benefits; for example, the Illinois group and EIC Laboratories recently described a 2×2 mm, 16-electrode array (Kane et al., 2013) that may permit improved consistency of electrode tip depth relative to the curved cortical surface when implanted over a wide area. One potential disadvantage to this approach is the larger number of arrays to be implanted, and its potential implications for the length of the surgical procedure. For example, implanting 650 electrodes in groups of 16 would require approximately 41 arrays (Srivastava et al., 2007), while implanting 500 electrodes in groups of 43 would require only 11 (Lowery, 2013).

, 2010), although a pronociceptive role of endogenous spinal 5-HT was demonstrated by the reduction in nociceptive responses following selective depletion of spinal 5-HT ( Dogrul et al., 2009, Oatway et al., 2004 and Rahman et al., 2006). Nonetheless, descending serotonergic

facilitation may not be exclusive to 5-HT activating the 5-HT3 receptor, as there are several lines of evidence pointing to a pronociceptive role for the 5-HT2 receptor, although controversy exists. The complexity of effects produced by 5-HT acting on 5-HT2 receptors is due to the further existence of subtypes, namely 5-HT2A, 2B and 2C receptors (Alexander et al., 2008). Of these, the evidence to date largely points to a pronociceptive role for the 5-HT2A subtype (Eide and Hole, 1991, Kjorsvik et al., 2001, Nishiyama, 2005,

Silveira et al., 2010 and Thibault et al., 2008) but see (Honda selleckchem et al., 2006, Kommalage and Hoglund, 2005, Sasaki et al., 2001 and Sasaki et al., 2003), and an antinociceptive role for the 5-HT2C receptor subtypes in modulating spinal nociceptive transmission (Aira et al., 2010, Liu et al., 2007, Obata et al., 2004 and Obata et al., 2007). The amino acid sequence of the 5-HT2 receptors share a high degree of homology within the seven transmembrane domains; thus, it is not surprising that conflicting reports exist within the literature since many compounds bind to each subtype with high affinity (Knight etal., 2004). Behavioural studies could be confounded by the multiple functions of 5-HT in the CNS. Here, we evaluate the effect of topical spinal application DZNeP order of the selective 5-HT2A receptor antagonist, ketanserin, on the evoked responses of wide dynamic range dorsal horn neurones in response to electrical and natural stimulation of the peripheral receptive field, in order to evaluate the spinal specific role of this receptor subtype in suprathreshold responses. Ketanserin potently blocks 5-HT2A receptors, less potently blocks 5-HT2C receptors, and has no significant

effect on 5-HT3 or 5-HT4 receptors or any members of the 5-HT1 receptor family (Knight et al., 2004). We also assessed the effects of systemic delivery of the 5-HT2A/2C antagonist, ritanserin, on the same neuronal measures. Inositol oxygenase Ritanserin has equal affinity for the 5-HT2A and 2C subtypes (Knight et al., 2004), and finally, we assessed the effects of spinal application of (±)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI), a mixed 5-HT2A/2C agonist, but with greater relative selectivity for 5-HT2A receptors, on these evoked spinal neuronal responses. Spinally applied ketanserin (1, 10 and 100 μg/50 μl) did not produce any significant effects on any of the electrically evoked neuronal measures, although a trend towards a dose-related inhibition was observed for the Aδ-, C-fibre and input evoked responses (Fig. 1a). In contrast a significant dose-related inhibition was observed on the natural evoked neuronal responses.

With the exception of one papirosi cigarette, all were conventional cigarettes, excluding e.g., bidis and herbal products. Different blend types were included in the sampled set, with a large proportion of American and Virginia blends. The dimension of sampled cigarettes covered the whole available range, with diameters between 5.2 mm (superslim) and 8.0 mm (magnum), and rod lengths between 70 mm and 100 mm. Among the sampled brands, filter designs included single and multiple-plug configurations with up to 4 plugs. In some brands, filters contained activated carbon, present either in the tow or in a cavity between two plugs. Some non-filter brands were also sampled. The numbers of samples selected per country

are presented in Table 1, including information regarding their filter design. Prototype cigarettes were manufactured Selleckchem Gefitinib to study the impact of adsorbents on cadmium, click here arsenic and lead filtration. The control cigarette (without activated carbon) was designed to mimic a commercial king-size American blend with a 27-mm cellulose acetate plug, a ventilation set at 35% and a resistance to draw

of 100 mm H2O. The cigarette had a 7.5-mg tar delivery under ISO machine-smoking regime. The test prototype differed only from the control in the filter design. The test prototype filter was a 27-mm composite filter, consisting of a 7-mm plug of cellulose acetate at the mouth end abutted to a 20-mm Dalmatian plug into which 80 mg of activated carbon was embedded. The prototype cigarette was designed to same resistance to draw as the control. The test had a 7.2-mg tar delivery under ISO machine-smoking regime. The analyses of the different components in both tobacco filler and smoke were conducted

under contract to Philip Morris International by Labstat International ULC (Kitchener, Ont., Canada), an ISO 17025 accredited laboratory, and were performed according to the official Health Canada methods [31]. Alkaloids in tobacco fillers were analyzed by gas chromatography according to method T-301 [32]; three replicates per sample were conducted. Cadmium, lead and arsenic were analyzed in tobacco fillers according to method T-306 [33]. Three replicates per sample were conducted. After conditioning according to ISO [34], cigarettes Succinyl-CoA were smoked under both ISO [35] and HCI [36] machine-smoking regimes. Tar, nicotine and CO in mainstream smoke were analyzed according to method T-115 [36]. Eight replicates per sample were performed. Cadmium, lead and arsenic were analyzed in mainstream smoke according to method T-109 [37], with a rotary smoking machine equipped with an electrostatic precipitator. Three replicates per sample were conducted in the case of the market surveys, and 4 per sample in the case of the assessment of dedicated prototypes. The mainstream smoke yields of samples bought in 2012 were from a set that had only been analyzed using the HCI machine-smoking regime.

This patient with Crohn’s colitis had endoscopic mucosal resection (EMR) of a superficial elevated NP-CRN. The pathology of the lesion showed low-grade dysplasia (LGD). However, the biopsies of www.selleckchem.com/products/VX-809.html the surrounding mucosa also showed LGD. Thus, he was referred for further evaluation. In (A), a slightly more reddish mucosa was seen (open arrows). Chromoendoscopy with indigo carmine was used to delineate the border of the lesion (B). The lesion had a distinct border. It was completely endoscopically resected

and found to be LGD. Note that a distal attachment cap was required to push the fold (double solid arrows) to examine the area proximal to the fold. 5 Figure options Download full-size image Download high-quality image (697 K) Download as PowerPoint slide Fig. 9. Understanding the nomenclature of superficial neoplasms is important. The term superficial is used when the tumor is either noninvasive appearing Dolutegravir research buy or small. Superficial includes noncancer neoplasms, and mucosal and submucosal invasive cancers. A subset of superficial cancers that appear to have a significant invasion into the submucosa is called massive submucosal invasive cancer. Matsuda and colleagues suggested that the presence of redness, firm consistency, expansion, and deep depression are important findings of deeply submucosal invasive cancer.6 In the upper image, the neoplastic lesion appeared benign and limited to

the mucosa. It has none of the findings of deeply submucosal invasion. In the lower image, the lesion was large, and invaded deeply into the wall. The lesion was red, firm appearing, full, and had deep depression. The lesion in the upper image may be removable by endoscopy, whereas surgery would be required for the lesion in the lower image. Figure options Download full-size Rucaparib image Download high-quality image (743 K) Download as PowerPoint slide Fig. 10. The major variants of superficial neoplastic lesions in the colon and rectum. Superficial colorectal neoplasms in patients with IBD can be described.7 and 8 Lesions are classified as protruding (polypoid) and

nonprotruding (nonpolypoid). Polypoid neoplasms may be further divided into pedunculated (0-Ip) or sessile (0-Is). Nonpolypoid lesions can be divided into slightly elevated/table top (IIa), depressed (IIc), or completely flat (IIb). An international group of IBD experts, endoscopists, pathologists, and methodologists who gathered in San Francisco in March 2014 (SCENIC Consensus) suggested that the current classifications for IBD patients should also include: (1) description of an ulcer, if present, within the lesion; and (2) description of the border of the lesion, especially if it cannot be recognized.9 Figure options Download full-size image Download high-quality image (216 K) Download as PowerPoint slide Fig. 11. The presence of an ulcer within a lesion needs to be characterized.

Presumably then, lower volume of the left PFC and integrity of the CC leads to impaired trans-callosal inhibition and additional recruitment of the right PFC found in functional MRI (fMRI) studies. We shall refer to this as the inhibitory hypothesis. However, another possible interpretation

is that of partial compensation ( Duverne et al., 2009 and Rossi et al., 2004), which suggests that whatever auxiliary processing is facilitated by the additional activation found in some older people is not sufficient to fully replicate a normally-functioning network, but would lead to much poorer performance if this alternative cognitive route were not available. We shall selleckchem refer to this as the partial compensation hypothesis. Predictions from these two hypotheses can be formalised and usefully tested by examining the neurostructural correlates of verbal memory performance in older age. We address this question from the following viewpoint: Disruption

to one or more components of the large-scale brain network involved in memory may disrupt the state of normal parallel processing necessary to support unhindered performance (Bressler and Menon, 2010 and Mesulam, 1990). Accumulated brain insults over the life course may well be such a mechanism of disruption. For each component of the large-scale memory network, such insults can be broadly indexed by individual differences in diffusion and structural MRI measures (white matter tract integrity parameters

and regional brain volumes controlled for intracranial volume). We shall therefore use structural brain measures of an ZVADFMK a priori selection of memory network components (hippocampus, CC and lateral frontal lobe) to test competing accounts of frontal lobe involvement in verbal memory performance among Phosphoprotein phosphatase a group of healthy older adults in their early 70s. We first aim to verify that left frontal lobe, hippocampus and CC constitute parts of a memory network and that each contributes unique variance to memory performance (Bressler and Menon, 2010 and Mesulam, 1990). The inhibitory hypothesis would predict positive associations between memory ability and indices of left lateral frontal lobe and anterior CC (genu; Buckner and Logan, 2002, Logan et al., 2002 and Persson et al., 2006; Sullivan & Pfefferbaum, 2007). Furthermore, a significant positive relationship between right frontal volume and memory ability would be incompatible with the inhibitory hypothesis, which suggests no benefit to verbal memory performance from a larger right frontal lobe. Conversely, the partial compensation hypothesis (Duverne et al., 2009 and Rossi et al., 2004) would assert that larger volume of the area providing auxiliary processing (in this case, the right frontal lobe) would positively associate with memory score, but only for poorer performers, who putatively rely on its compensatory function.

, 2010). In conclusion, our present results show that a single administration of ZEA may cause deleterious effects on the male reproductive system, and suggest that GST activity may be a potential target to attenuate ZEA reproductive toxicity. Research supported by FAPERGS (grants #10/0685-8 and #11/1630-1). Luiz Fernando Freire Royes and Lucian Del Fabbro are Protease Inhibitor Library solubility dmso the recipients of CNPq fellowships. Silvana Peterini Boeira is the recipient of a CAPES fellowship. Carlos Borges Filho is the recipient of FAPERGS

fellowships. “
“Among the venomous fish found in Brazil, the scorpionfish Scorpaena plumieri, a member of the Scorpaenidae family, is considered one of the most dangerous ( Figueiredo and Menezes, 1980; Carvalho-Filho, 1999). The venomous secretion of this fish is mainly proteic in nature ( Carrijo et al., 2005) and it is produced by specialized tissues located around the fin spines ( Smith and Wheeler, 2006). Like other venomous fish, scorpionfish use their venom for defensive purposes and human envenomation

occurs accidentally when swimmers or fishermen mishandle or step on the spines of the dorsal fin. The envenomation may incapacitate temporarily the victim, since it is AZD6244 mouse characterized by a highly complex pathophysiological scenario (Haddad Jr., 2000). It includes an extensive local inflammatory response, with persistent edema, intense and irradiant pain, erythema, occasional skin necrosis and systemic effects (nausea, vomiting, agitation, malaise, sweating, diarrhea, tachycardia, arrhythmias). Despite

the pain and edema are the most conspicuous symptoms observed in patients wounded by S. plumieri, there is still little information about the inflammatory response triggered. The treatment protocol of scorpionfish victims is only palliative and symptomatic: some of the local effects are alleviated by immersing the affected member in warm water and administrating anesthetics or analgesics, Nintedanib (BIBF 1120) resulting in slight decrease of the symptoms ( Haddad Jr. et al., 2003; Haddad Jr., 2000). The local inflammatory reaction evoked by other Brazilian venomous fish has been characterized experimentally: freshwater stingrays of Potamotrygon genus induce edematogenic and nociceptive responses, which were associated with increased vascular permeability and increased leukocyte rolling and adherent cells to the endothelium ( Magalhães et al., 2006); the injection of Cathorops spixii crude venom (catfish) in mice is able to evoke peritonitis characterized by release of IL-6, MPC-1 and KC and a lipid inflammatory mediator, LTB4 ( Junqueira et al., 2007); the venom of estuarine toadfish Thalassophryne nattereri induces a prominent edema formation associated with release of pro-inflammatory cytokines ( Lima et al., 2003).

The 1-year survival rate was 47% in the cetuximab group versus 42% in the chemotherapy-alone group. The group receiving cetuximab also had a significantly better response rate (36% vs 29%, p = .012). Number of pre specified subgroup analyses for potential survival benefit were also conducted. While the subgroup of white patients had improved OS with cetuximab (10.5 vs 9.1 months; p = .003). Asian patients in the cetuximab group had worse

survival Carfilzomib ic50 (17.6 vs 20.4 months), suggesting that cetuximab is not effective in this subgroup of patients (who are more likely to harbor EGFR mutations). In patients with squamous-cell tumors, OS was numerically better with cetuximab (10.2 vs 8.9 months; p = .0567); this was also true in patients Duvelisib in vitro with adenocarcinoma (12.0 vs 10.3 months; p = .0673). In a preplanned analysis, the development of early acne-like rash was associated with significant outcome (median OS: 15 months vs 8.8. months, HR 0.63, 95% CI: 0.52–0.77, p < 0.0001) [29]. Data from FLEX indicated that cetuximab does not appear to benefit patients who have K-Ras mutations. Unlike colon cancer, K-Ras testing does not help identify patients who are most likely to benefit from treatment with cetuximab [30]. In IDEAL 1 study, 210 pretreated

patients were randomized to receive gefitinib at 250 or 500 mg/day. The overall RR (ORR) was 18.4% and 19% and overall survival (OS) was 7.6 months and 8.0 months for the lower dose and the higher dose groups, respectively. In IDEAL 2 study, 216 patients who had relapsed after platinum and docetaxel regimens were randomized to receive gefitinib 250 or 500 mg/day. Efficacy results were similar between the dosing groups; the ORR was 12% and the 1-year survival rate was 25%. In both studies, grade 3–4 adverse events (AEs) such as acne form rash and diarrhea were more frequent with the higher dose [31]. Based on the results of IDEAL 2, gefitinib

received accelerated FDA approval as a third-line therapy for NSCLC. However, the 500-mg gefitinib dose was more of toxic as it induced more acne-like rash and diarrhea. Diarrhea was noted in 57% of patients receiving 250 mg and 75% in those receiving 500 mg. Skin toxicity (rash, acne, dry skin, pruritus) was observed in 62% and 75%, respectively. Grade 3/4 toxicities were unusual, but more frequent in the 500-mg dosing. Dose reductions as a result of toxicity were also more frequent in the higher dose [32]. The subsequent phase 3 ISEL (Iressa Survival Evaluation in Lung cancer) trial found that gefitinib did not offer a significant OS benefit compared with placebo (5.6 vs 5.1 months, respectively; p = .087), which led to withdrawal of its FDA approval [33]. The reasons of lack of efficacy are not clear but it can be related to the use of lower dose that are less than the maximum tolerated dose and the inclusion of primary refractory cancers.