[Single dose of misoprostol for abortion until 9 weeks of gestation]. / Efficacité d'une dose unique de misoprostol pour les interruptions volontaires de grossesse jusqu'à 9 semaines d'aménorrhée.

OBJECTIVES: The primary objective was to compare the efficacy of a single-dose misoprostol for abortion before 7 weeks of gestation and between 7 and 9 weeks of gestation. The secondary objectives were to compare the amount of misoprostol required for complete expulsion, the need for endo-uterine aspiration, and to assess pain and patient experience in these two groups. METHODS: This was a single-centre prospective observational study conducted at the University Hospitals of Strasbourg from 1st October 2019 to 31st December 2020. RESULTS: A total of 306 patients were included, 150 in the group before 7 weeks of gestation and 156 in the group between 7 and 9 weeks of gestation. There was no significant difference in the success rate of the single dose of misoprostol between the two groups with 34.7 and 37.8% respectively (P=0.63). After taking painkillers, there is no difference in terms of pain relief (EN ≤ 4 for 92 et 95% of patients P=0.37). CONCLUSION: The single dose of misoprostol for in-hospital abortion is as effective between 7 and 9 weeks of gestation as it is before 7. By extension, therefore, we would suggest that there should be no difference in efficacy between home abortions before 7 weeks of gestation and between 7 and 9 weeks of gestation and therefore suggest that home abortions can be performed up to 9 weeks of gestation without fear of a decrease in the rate of complete expulsion and the efficacy of analgesia, with potentially less use of misoprostol compared with the hospital setting.

[Focus on axillary anatomy: The Carl Langer muscle, a great forgotten muscle in the training of medical residents in gynecology and obstetrics]. / Mise au point sur l'anatomie de la région axillaire : l'arc musculaire du grand dorsal ou muscle de Carl Langer, un grand oublié dans la formation des internes.

OBJECTIVE: The Carl Langer muscle is the main anatomical variation of the walls of the axillary area, its incidence being about 7%. The presence of this muscle crossing the anterior edge of the axillary vessels can induce difficulties of exposure, location and dissection during axillary surgery. In addition, it may be responsible for primary lymphedema of the upper limb, venous thrombosis of the axillary vein or thoracic outlet syndrome due to vascular or nervous compression. The objective of this work was to evaluate the state of knowledge on Carl Langer muscle of the gynecology-obstetrics medical residents of the French Eastern Region. MATERIAL AND METHODS: All the medical residents enrolled in the specialized diploma in gynecology-obstetrics in the 5 regions (Alsace, Bourgogne, Lorraine, Champagne-Ardenne and Franche-Comté) were questioned by means of a questionnaire sent by e-mail. RESULTS: From February to March 2021, 94 of the 160 medical residents interviewed answered to the questionnaire. Ninety-one of them (97%) did not know Carl Langer's muscle. Three medical residents thought they knew this muscle (3%) but their knowledge was imperfect. CONCLUSION: Our work has highlighted the general lack of knowledge of this anatomical variation, which is relatively frequent, among French gynecology-obstetrics medical residents who are required to examine or perform surgery on this area. This updated review of the literature should optimize the knowledge of the anatomy of the axillary area and consequently its surgery.

Reproductive biology of Syagrus coronata (Arecaceae): sex-biased insect visitation and the unusual case of scent emission by peduncular bracts.

Several monoecious species of palms have developed complex strategies to promote cross-pollination, including the production of large quantities of floral resources and the emission of scents that are attractive to pollinators. Syagrus coronata constitutes an interesting model with which to understand the evolution of plant reproductive strategies in a monoecious species adapted to seasonally dry forests. We monitored blooming phenology over 1 year, during which we also collected and identified floral visitors and putative pollinators. We identified potential floral visitor attractants by characterizing the scent composition of inflorescences as well as of peduncular bracts, during both male and female phases, and the potential for floral thermogenesis. Syagrus coronata produces floral resources throughout the year. Its inflorescences are predominantly visited by a diverse assortment of small-sized beetles, whose richness and abundance vary throughout the different phases of anthesis. We did not find evidence of floral thermogenesis. A total of 23 volatile compounds were identified in the scent emitted by the inflorescences, which did not differ between male and female phases; whereas the scent of the peduncular bracts was composed of only 4-methyl guaiacol, which was absent in inflorescences. The composition of floral scent chemistry indicates that this palm has evolved strategies to be predominantly pollinated by small-sized weevils. Our study provides rare evidence of a non-floral scent emitting structure involved in pollinator attraction, only the second such case specifically in palms. The peculiarities of the reproductive strategy of S. coronata might play an important role in the maintenance of pollination services and pollen dispersion.

Influence of Polishing Systems on Surface Roughness of Composite Resins: Polishability of Composite Resins.

OBJECTIVES: The objective of this in vitro study was to compare, with a threshold value of 200 nm, the surface roughness obtained when using 12 different polishing systems on four different composite resins (microfill, nanofill, and two nanohybrids). METHODS AND MATERIALS: A total of 384 convex specimens were made using Durafill VS, Filtek Supreme Ultra, Grandio SO, and Venus Pearl. After sandblasting and finishing with a medium-grit finishing disc, initial surface roughness was measured using a surface roughness tester. Specimens were polished using 12 different polishing systems: Astropol, HiLuster Plus, D♦Fine, Diacomp, ET Illustra, Sof-Lex Wheels, Sof-Lex XT discs, Super-Snap, Enhance/Pogo, Optrapol, OneGloss and ComposiPro Brush (n=8). The final surface roughness was measured, and data were analyzed using two-way analysis of variance. Pairwise comparisons were made using protected Fisher least significant difference. RESULTS: There were statistical differences in the final surface roughness between polishing systems and between composite resins (p<0.05). The highest surface roughness was observed for all composite resins polished with OneGloss and ComposiPro Brush. Enhance/Pogo and Sof-Lex Wheels produced a mean surface roughness greater than the 200-nm threshold on Filtek Supreme Ultra, Grandio SO, and Venus Pearl. Data showed that there was an interaction between the composite resins and the polishing systems. CONCLUSIONS: A single polishing system does not perform equally with all composite resins. Except for Optrapol, multi-step polishing systems performed generally better than one-step systems. Excluding Enhance/Pogo, diamond-impregnated polishers led to lower surface roughness. Durafill VS, a microfill composite resin, may be polished more predictably with different polishers.

Pollination ecology of the Neotropical gesneriad Gloxinia perennis: chemical composition and temporal fluctuation of floral perfume.

Although common among orchids, pollination by perfume-gathering male euglossine bees is quite rare in other Neotropical families. In Gesneriaceae, for example, it is reported in two genera only, Drymonia and Gloxinia. Flowers of G. perennis are known to emit perfume, thereby attracting male euglossine bees as pollinators. However, detailed reports on the pollination ecology, as well as on chemistry of floral perfume of individuals in natural populations, are still missing. In this study, we report on the pollination ecology of G. perennis, focusing on the ecological significance of its floral perfume. In natural populations in Peru, we documented the floral biology and breeding system of G. perennis, as well as its interaction with flower visitors. We also characterised the chemical composition of floral perfume, as well as its timing of emission. Gloxinia perennis is self-compatible and natural pollination success is high. Spontaneous self-pollination occurs as a 'just in case strategy' when pollinators are scarce. Perfume-collecting males of Eulaema cingulata and El. meriana were identified as pollinators. The perfume bouquet of G. perennis consists of 16 compounds. (E)-Carvone epoxide (41%) and limonene (23%) are the major constituents. Perfume emission is higher at 09:00 h, matching the activity peak of Eulaema pollinators. Flowers of G. perennis have evolved a mixed strategy to ensure pollination (i.e. self- and cross-pollination), but cross-pollination is favoured. The size and behaviour of Eulaema males enables only these bees to successfully cross-pollinate G. perennis. Furthermore, G. perennis floral perfume traits (i.e. chemistry and timing of emission) have evolved to optimise the attraction of these bees.

A Wireless Optoelectronic Neuroscience Platform for Chronic Fluorescence Sensing in Freely Behaving Rodents.

We present a new head mountable wireless fiber biophotometry microsystem conceived to detect fluorescent signal fluctuations correlated with neuronal activity. The proposed system incorporates all aspects of a conventional tethered fiber-based biophotometry system encompassed into a wireless microsystem. The interface includes an LED as excitation light source, a custom designed CMOS biosensor, a multimode fiber, a microcontroller (MCU), and a wireless data transceiver enclosed within a 3D-printed, small and light weight, plastic housing. Precisely, the system incorporates a new optoelectronic biosensor merging two individual building blocks, namely a low-noise sensing front-end and $\mathrm {a}2 ^{nd}$ order continuous-time $\Sigma \Delta $ modulator (CTSDM), into a single module for enabling high-sensitivity and high energy-efficiency photo-sensing. The proposed CMOS biosensor is implemented in $\mathrm {a}0 .18- \mu m$ CMOS technology, consuming $41 \mu W$ from $\mathrm {a}1 .8- V$ supply voltage, while achieving a peak dynamic range of $86 dB$ over a $50- Hz$ input bandwidth at a 20-kS/s sampling rate. This new interface opens new avenues for conducting in-vivo experiments with live animals.

Seismic imaging and petrology explain highly explosive eruptions of Merapi Volcano, Indonesia.

Our seismic tomographic images characterize, for the first time, spatial and volumetric details of the subvertical magma plumbing system of Merapi Volcano. We present P- and S-wave arrival time data, which were collected in a dense seismic network, known as DOMERAPI, installed around the volcano for 18 months. The P- and S-wave arrival time data with similar path coverage reveal a high Vp/Vs structure extending from a depth of ≥20 km below mean sea level (MSL) up to the summit of the volcano. Combined with results of petrological studies, our seismic tomography data allow us to propose: (1) the existence of a shallow zone of intense fluid percolation, directly below the summit of the volcano; (2) a main, pre-eruptive magma reservoir at ≥ 10 to 20 km below MSL that is orders of magnitude larger than erupted magma volumes; (3) a deep magma reservoir at MOHO depth which supplies the main reservoir; and (4) an extensive, subvertical fluid-magma-transfer zone from the mantle to the surface. Such high-resolution spatial constraints on the volcano plumbing system as shown are an important advance in our ability to forecast and to mitigate the hazard potential of Merapi's future eruptions.

Effects of TNF receptor blockade on in vitro cell survival and response to negative energy balance in dairy cattle.

BACKGROUND: Associative data and some controlled studies suggest that the inflammatory cytokine tumor necrosis factor (TNF) α can induce fatty liver in dairy cattle. However, research demonstrating that TNFα is a necessary component in the etiology of bovine fatty liver is lacking. The aim of this work was to evaluate whether blocking TNFα signaling with a synthetic cyclic peptide (TNF receptor loop peptide; TRLP) would improve liver metabolic function and reduce triglyceride accumulation during feed restriction. RESULTS: Capability of TRLP to inhibit TNFα signaling was confirmed on primary bovine hepatocytes treated with recombinant bovine TNFα and 4 doses of TRLP (0, 1, 10, 50 µmol/L) over 24 h. Next, 4 lactating Holstein cows (parity 1.4 ± 0.5, 433 ± 131 d in milk) in an incomplete Latin rectangle design (3 × 2) were subcutaneously administered with different TRLP doses (0, 1.5, 3.0 mg/kg BW) every 4 h for 24 h, followed by an intravenous injection of TNFα (5 µg/kg BW). Before and for 2 h after TNFα injection, TRLP decreased plasma non-esterified fatty acid (NEFA) concentration (P ≤ 0.05), suggesting an altered metabolic response to inflammation. Finally, 10 non-pregnant, non-lactating Holstein cows (3.9 ± 1.1 yr of age) were randomly assigned to treatments: control (carrier: 57% DMSO in PBS) or TRLP (1.75 mg TRLP /kg BW per day). Treatments were administrated every 4 h for 7 d by subcutaneous injection to feed-restricted cows fed 30% of maintenance energy requirements. Daily blood samples were analyzed for glucose, insulin, ß-hydroxybutyrate, NEFA, and haptoglobin concentrations, with no treatment effects detected. On d 7, cows completed a glucose tolerance test (GTT) by i.v. administration of a dextrose bolus (300 mg glucose/kg BW). Glucose, insulin, and NEFA responses failed to demonstrate any significant effect of treatment during the GTT. However, plasma and liver analyses were not indicative of dramatic lipolysis or hepatic lipidosis, suggesting that the feed restriction protocol failed to induce the metabolic state of interest. Injection site inflammation, assessed by a scorer blinded to treatment, was enhanced by TRLP compared to control. CONCLUSIONS: Although the TRLP inhibited bovine TNFα signaling and altered responses to i.v. administration of TNFα, repeated use over 7 d caused apparent local allergic responses and it failed to alter metabolism during a feed restriction-induced negative energy balance. Although responses to feed restriction seemed atypical in this study, side effects of TRLP argue against its future use as a tool for investigating the role of inflammation in metabolic impacts of negative energy balance.

Autocatalytic association of proteins by covalent bond formation: a Bio Molecular Welding toolbox derived from a bacterial adhesin.

Unusual intramolecular cross-links present in adhesins from Gram-positive bacteria have been used to develop a generic process amenable to biotechnology applications. Based on the crystal structure of RrgA, the Streptococcus pneumoniae pilus adhesin, we provide evidence that two engineered protein fragments retain their ability to associate covalently with high specificity, in vivo and in vitro, once isolated from the parent protein. We determined the optimal conditions for the assembly of the complex and we solved its crystal structure at 2 Å. Furthermore, we demonstrate biotechnological applications related to antibody production, nanoassembly and cell-surface labeling based on this process we named Bio Molecular Welding.

Influence of treatment of vulvovaginal atrophy with intravaginal prasterone on the male partner.

OBJECTIVE: The aim was to analyze the opinion of the male partner of women treated for vulvovaginal atrophy (VVA) with intravaginal 0.50% DHEA (prasterone), thus providing information on both members of the couple. METHODS: On a voluntary basis, in a prospective, randomized, double-blind and placebo-controlled phase-III clinical trial, the male partner filled a questionnaire at baseline and at 12 weeks stating his observations related to his penis and intercourse before and after VVA treatment. RESULTS: Sixty-six men having a partner treated with intravaginal DHEA and 34 others having a partner treated with placebo answered the questionnaires. Concerning the feeling of vaginal dryness of their female partner, the severity score following DHEA treatment improved by 81% (0.76 units) over placebo (p = 0.0347). Thirty-six percent of men having a partner treated with DHEA did not feel the vaginal dryness of the partner at the end of treatment compared to 7.8% in the placebo group. When analyzing the situation at 12 weeks compared to baseline, an improved score of 1.09 units was the difference found for the DHEA group compared to 0.76 for the placebo group (p = 0.05 vs. placebo). In the DHEA group, 38% of men scored very improved compared to 18% in the placebo group. No adverse event has been reported. CONCLUSION: The male partner had a very positive evaluation of the treatment received by his female partner.

Decreased efficacy of twice-weekly intravaginal dehydroepiandrosterone on vulvovaginal atrophy.

OBJECTIVE: While daily intravaginal administration of 0.50% (6.5 mg) dehydroepiandrosterone (DHEA, prasterone) for 12 weeks has shown clinically and statistically significant effects on moderate to severe (MS) dyspareunia as the most bothersome symptom (MBS), the present study analyzes the effect of a reduced dosing regimen on MBS vaginal dryness. METHOD: Daily intravaginal 0.50% prasterone for 2 weeks followed by twice weekly for 10 weeks versus placebo. RESULTS: Maximal beneficial changes in vaginal parabasal and superficial cells and pH were observed at 2 weeks as observed for intravaginal 10 µg estradiol (E2). This was followed by a decrease or lack of efficacy improvement after switching to twice-weekly dosing. The decrease in percentage of parabasal cells, increase in percentage of superficial cells and decrease in vaginal pH were all highly significant (p < 0.0001 to 0.0002 over placebo) at 12 weeks. In parallel, the statistical significance over placebo (p value) on MBS vaginal dryness at 6 weeks was 0.09 followed by an increase to 0.198 at 12 weeks. For MBS dyspareunia, the p value of 0.008 at 6 weeks was followed by a p value of 0.077 at 12 weeks, thus illustrating a decrease of efficacy at the lower dosing regimen. The improvements of vaginal secretions, color, epithelial integrity and epithelial surface thickness were observed at a p value < 0.01 or 0.05 over placebo at 2 weeks, with a similar or loss of statistical difference compared to placebo at later time intervals. No significant adverse event was observed. Vaginal discharge related to the melting of Witepsol was reported in 1.8% of subjects. CONCLUSION: The present data show that daily dosing with 0.50% DHEA for 2 weeks followed by twice-weekly dosing is a suboptimal treatment of the symptoms/signs of vulvovaginal atrophy resulting from a substantial loss of the efficacy achieved at daily dosing.

[Mechanisms of resistance to anti-BRAF treatments]. / Mécanismes de résistance aux inhibiteurs de BRAF.

CONTEXT: In patients with melanoma positive for the BRAF V600 mutation, clinical response to specific BRAF inhibitors is usually rapid and striking, with significant benefits in terms of progression-free survival and overall survival. However, resistance to treatment almost invariably arises, typically within a median timeframe of 6 months. Indeed, very few patients exhibit long-lasting response to these targeted therapies. AIMS: It is essential to better understand the mechanisms of resistance to targeted anti-BRAF therapies in order to increase both response rates and the duration of clinical response to treatment. This literature review describes the signaling pathways involving BRAF and presents recent data from clinical trials with these molecules. Furthermore, we aim to describe the main resistance mechanisms linked with targeted anti-BRAF therapies. METHODS: The keywords (resistance, BRAF, melanoma, targeted therapy, vemurafenib, and dabrafenib) were used to extract relevant articles in the Medline/Pubmed database published before 31 January 2014. DISCUSSION: Improved knowledge and understanding of the mechanisms of resistance to targeted anti-BRAF therapies should enable the development of new therapeutic strategies in order to overcome such resistance and allow more significant and sustained response rates to be achieved among melanoma patients.

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma.

Intrinsic and acquired chemoresistance are frequent causes of cancer eradication failure. Thus, long-term cis-diaminedichloroplatine(II) (CDDP) or cisplatin treatment is known to promote tumor cell resistance to apoptosis induction via multiple mechanisms involving gene expression modulation of oncogenes, tumor suppressors and blockade of pro-apoptotic mitochondrial membrane permeabilization. Here, we demonstrate that CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (>80 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6, without any alteration in ER-cytosol Ca(2+) fluxes. Using pharmacological and genetic inhibition, we show that inactivation of both proteins directly stimulates CDDP-induced cell death by different cellular signaling pathways. PDIA4 inactivation restores a classical mitochondrial apoptosis pathway, while knockdown of PDIA6 favors a non-canonical cell death pathway sharing some necroptosis features. Overexpression of both proteins has also been found in lung adenocarcinoma patients, suggesting a clinical importance of these proteins in chemoresistance.

[Pathophysiology of primary Sjögren's syndrome]. / Physiopathologie du syndrome de Gougerot-Sjögren primitif.

Primary Sgögren's syndrome (SSP) is one of the most common connective tissue disorder with an estimated prevalence between 0.6 and 1.7% of the general population. Lymphocytic infiltration of salivary gland is easily accessible favoring the diagnosis, and clinical and fundamental research. However, while many advances have been obtained in the recent decades, the pathophysiology of SSP remains unclear combining environmental factors with genetic predisposition. A central role tends to be attributed to salivary gland epithelial cells, originally designated as "innocent bystanders" and to B cells through the intervention of survey factors like BAFF. New T cells subsets are also carefully studied, particularly natural T regulatory and Th17 cells. They could indeed represent new therapeutic targets.

Anti-inflammatory activity of Mitraphylline isolated from Uncaria tomentosa bark.

ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria tomentosa (Willd. ex Roem. & Schult.) DC. (Rubiaceae) is widely used by populations living in South America to treat many ailments associated with inflammatory disorders. Mitraphylline was shown to be the major pentacyclic oxindolic alkaloid present in the bark chloroformic extract of this plant. Its activity against cytokines involved in inflammation process was tested in a murine model in vivo. MATERIALS AND METHODS: Mice received mitraphylline once a day for 3 days at 30 mg/kg/day by oral route. Then, they were subjected to bacterial lipopolysaccharide (LPS) endotoxin (15 mg/kg) and the LPS-induced production of 16 different cytokines was determined by Elisa multiplex. Control group received dexamethasone orally at 2mg/kg/day. Toxicity on K565 cells and murine peritoneal macrophages, in vitro, at doses up to 100 µM was monitored by XTT-colorimetric assay. RESULTS AND CONCLUSIONS: For the first time mitraphylline was tested in vivo against a large range of cytokines that play a crucial role in inflammation. Mitraphylline inhibited around 50% of the release of interleukins 1α, 1ß, 17, and TNF-α. This activity was similar to dexamethasone. It also reduced almost 40% of the production of interleukin 4 (IL-4) while the corticoid did not. Lastly it did not show any toxicity on K565 cells nor murine macrophages at doses up to 100 µM.

IGL-1 solution reduces endoplasmic reticulum stress and apoptosis in rat liver transplantation.

Injury due to cold ischemia reperfusion (I/R) is a major cause of primary graft non-function following liver transplantation. We postulated that I/R-induced cellular damage during liver transplantation might affect the secretory pathway, particularly at the endoplasmic reticulum (ER). We examined the involvement of ER stress in organ preservation, and compared cold storage in University of Wisconsin (UW) solution and in Institute Georges Lopez-1 (IGL-1) solution. In one group of rats, livers were preserved in UW solution for 8 h at 4 °C, and then orthotopic liver transplantation was performed according to Kamada's cuff technique. In another group, livers were preserved in IGL-1 solution. The effect of each preservation solution on the induction of ER stress, hepatic injury, mitochondrial damage and cell death was evaluated. As expected, we found increased ER stress after liver transplantation. IGL-1 solution significantly attenuated ER damage by reducing the activation of three pathways of unfolded protein response and their effector molecules caspase-12, C/EBP homologous protein-10, X-box-binding protein 1, tumor necrosis factor-associated factor 2 and eukaryotic translation initiation factor 2. This attenuation of ER stress was associated with a reduction in hepatic injury and cell death. Our results show that IGL-1 solution may be a useful means to circumvent excessive ER stress reactions associated with liver transplantation, and may optimize graft quality.

Triclosan antagonizes fluconazole activity against Candida albicans.

Triclosan is a broad-spectrum antimicrobial compound commonly used in oral hygiene products. Investigation of its activity against Candida albicans showed that triclosan was fungicidal at concentrations of 16 mg/L. However, at subinhibitory concentrations (0.5-2 mg/L), triclosan antagonized the activity of fluconazole. Although triclosan induced CDR1 expression in C. albicans, antagonism was still observed in cdr1Δ and cdr2Δ strains. Triclosan did not affect fluconazole uptake or alter total membrane sterol content, but did induce the expression of FAS1 and FAS2, indicating that its mode of action may involve inhibition of fatty acid synthesis, as it does in prokaryotes. However, FAS2 mutants did not exhibit increased susceptibility to triclosan, and overexpression of both FAS1 and FAS2 alleles did not alter triclosan susceptibility. Unexpectedly, the antagonistic effect was specific for C. albicans under hypha-inducing conditions and was absent in the non-filamentous efg1Δ strain. This antagonism may be due to the membranotropic activity of triclosan and the unique composition of hyphal membranes.

A phase I study of bortezomib and temozolomide in patients with advanced solid tumors.

PURPOSE: The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs). METHODS: Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1-5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not. RESULTS: Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (>8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CL(sys)) on day 9 was 51% of the CL(sys) on day 2 (P < 0.01) Similarly, the normalized area under the concentration-time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 (P < 0.01). The median bortezomib CL(sys) on days 2 and 9 was significantly higher (P < 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower (P < 0.04). CONCLUSIONS: The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m(2), respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients.