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In humans, three genes--ADRB1, ADRB2 and ADRB3--encode beta-adrenoreceptors (ADRB); these molecules mediate the action of catecholamines in multiple tissues and play pivotal roles in cardiovascular, respiratory, metabolic, and immunological functions. Genetic variants in ADRB genes have been associated with widespread diseases and conditions, but inconsistent results have often been obtained. Here, we addressed the recent evolutionary history of ADRB genes in human populations. Although ADRB1 is neutrally evolving, most tests rejected neutral evolution for ADRB2 in European, African, and Asian population samples. Analysis of inferred haplotypes for ADRB2 revealed three major clades with a coalescence time of 1-1.5 million years, suggesting that the gene is either subjected to balancing selection or undergoing a selective sweep. Haplotype analysis also revealed ethnicity-specific differences. Additionally, we observed significant deviations from Hardy-Weinberg equilibrium (HWE) for ADRB2 genotypes in distinct European cohorts; HWE deviation depends on sex (only females are in disequilibrium), and genotypes displaying maximum and minimum relative fitness differ across population samples, suggesting a complex situation possibly involving epistasis or maternal selection. Overall, our data indicate that future association studies involving ADRB2 will benefit from taking into account ethnicity-specific haplotype distributions and sex-based effects. With respect to ADRB3, our data indicate that the gene has been subjected to a selective sweep in African populations, the Trp64 variant possibly representing the selection target. Given the previous association of the ancestral ADRB3 Arg64 allele with obesity and type 2 diabetes, dietary adaptations might represent the underlying selective force.

Background: The most common complaint of adults with hearing loss is understanding speech in noise. One class of masker that may be particularly useful in the assessment of speech-in-noise abilities is interrupted noise. Interrupted noise usually is a continuous noise that has been multiplied by a square wave that produces alternating intervals of noise and silence. Wilson and Carhart found that spondaic word thresholds for listeners with normal hearing were 28 dB lower in an interrupted noise than in a continuous noise, whereas listeners with hearing loss experienced only an 11 dB difference. Purpose: The purpose of this series of experiments was to determine if a speech-in-interrupted-noise paradigm differentiates better (1) between listeners with normal hearing and listeners with hearing loss and (2) among listeners with hearing loss than do traditional speech-in-continuous-noise tasks. Research Design: Four descriptive/quasi-experimental studies were conducted. Study Sample: Sixty young adults with normal hearing and 144 older adults with pure-tone hearing losses participated. Data Collection and Analysis: A 4.3 sec sample of speech-spectrum noise was constructed digitally to form the 0 interruptions per second (ips; continuous) noise and the 5, 10, and 20 ips noises with 50% duty cycles. The noise samples were mixed digitally with the Northwestern University Auditory Test No. 6 words at selected signal-to-noise ratios and recorded on CD. The materials were presented through an earphone, and the responses were recorded and analyzed at the word level. Similar techniques were used for the stimuli in the remaining experiments. Results: In Experiment 1, using 0 ips as the reference condition, the listeners with normal hearing achieved 34.0, 30.2, and 28.4 dB escape from masking for 5, 10, and 20 ips, respectively. In contrast, the listeners with hearing loss only achieved 2.1 to 2.4 dB escape from masking. Experiment 2 studied the 0 and 5 ips conditions on 72 older listeners with hearing loss, who were on average 13 yr younger and more varied in their hearing loss than the listeners in Experiment 1. The mean escape from masking in Experiment 2 was 7 dB, which is 20–25 dB less than the escape achieved by listeners with normal hearing. Experiment 3 examined the effects that duty cycle (0–100% in 10% steps) had on recognition performance in the 5 and 10 ips conditions. On the 12 young listeners with normal hearing, (1) the 50% correct point increased almost linearly between the 0 and 60% duty cycles (slope = 4.2 dB per 10% increase in duty cycle), (2) the slope of the function was steeper between 60 and 80% duty cycles, and (3) about the same masking was achieved for the 80–100% duty cycles. The data from the listeners with hearing loss were inconclusive. Experiment 4 varied the interburst ratios (0, –6, –12, –24, –48, and –∞ dB) of 5 ips noise and evaluated recognition performance by 24 young adults. The 50% points were described by a linear regression (R 2 = 0.98) with a slope of 0.55 dB/dB. Conclusion: The current data indicate that interrupted noise does provide a better differentiation both between listeners with normal hearing and listeners with hearing loss and among listeners with hearing loss than is provided by continuous noise.

Background: There is a significant body of in vitro evidence and pre-clinical data which demonstrates that aspirin inhibits the growth of tumours and prevents the development of metastases[1]. A recent meta-analysis using individual patient data from randomized trials evaluating the cardiovascular effects of aspirin reports a reduction in cancer deaths after 5 years (hazard ratio 0.46, 95% confidence interval 0.27-0.77)[2]. Effects on risk of metastases and death following a cancer diagnosis have also been observed[3]. An analysis of the Nurses’ Health Study found that aspirin use following a diagnosis of stage I-III breast cancer was associated with a lower risk of breast cancer death (for those taking aspirin 2-5 times per week, relative risk 0.27, 95% confidence interval 0.15-0.47)[4]. Concerns over toxicity have limited the use of aspirin as a primary prevention agent against cancer. In the adjuvant setting the benefit:risk ratio will be different with higher morbidity and mortality from recurrent cancer potentially outweighing the risks associated with regular aspirin use. The Add-Aspirin trials will investigate whether regular aspirin use after curative treatment for localised malignancy can prevent tumour recurrence and prolong survival. As an inexpensive drug with a potential therapeutic role in several common cancers, aspirin could have a huge impact on the global cancer burden. Trial design: Multicentre, international, phase III, double-blind, placebo-controlled randomized trial in patients with early breast cancer. Participants will be randomised to enteric-coated aspirin 100mg, aspirin 300mg or matching placebo daily for at least 5 years. Parallel trials based on a common infrastructure will be conducted in colorectal, gastro-oesophageal and prostate cancer. Eligibility criteria: Patients who have undergone primary therapy, including curative surgery and appropriate neoadjuvant/adjuvant therapies for histologically confirmed invasive breast cancer which is node positive or node negative with high-risk features. Patients who have already participated in other primary treatment trials may be eligible subject to agreement from the trial management groups. Specific aims: The primary outcome will be disease-free survival. Secondary endpoints include overall survival, toxicity, cardiac morbidity and assessment of overall healthcare benefits. Translational work will investigate mechanisms of action and biomarkers for toxicity and treatment efficacy (including PIK3CA mutation status and COX-2 expression). Statistical methods: Approximately 3100 patients will be needed to test for a 4% improvement in DFS associated with aspirin use. [1] Langley RE et al. Br J Cancer. 2011;105(8):1107-13. [2] Rothwell PM et al. Lancet. 2011;377(9759):31-41. [3] Rothwell PM et al. Lancet. 2012;379(9826):1591-601. [4] Holmes MD et al. J Clin Oncol 2010;28(9):1467-72. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-4-01.

Background: We determined how CXC-chemokine signalling and necrosis factor-κB (NF-κB) activity affected heat-shock protein 90 (Hsp90) inhibitor (geldanamycin (GA) and 17-allylamino-demethoxygeldanamycin (17-AAG)) cytotoxicity in castrate-resistant prostate cancer (CRPC). Methods: Geldanamycin and 17-AAG toxicity, together with the CXCR2 antagonist AZ10397767 or NF-κB inhibitor BAY11-7082, was assessed by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay in two CRPC lines, DU145 and PC3. Flow cytometry quantified apoptotic or necrosis profiles. Necrosis factor-κB activity was determined by luciferase readouts or indirectly by quantitative PCR and ELISA-based determination of CXCL8 expression. Results: Geldanamycin and 17-AAG reduced PC3 and DU145 cell viability, although PC3 cells were less sensitive. Addition of AZ10397767 increased GA (e.g., PC3 IC20: from 1.67±0.4 to 0.18±0.2 nM) and 17-AAG (PC3 IC20: 43.7±7.8 to 0.64±1.8 nM) potency in PC3 but not DU145 cells. Similarly, BAY11-7082 increased the potency of 17-AAG in PC3 but not in DU145 cells, correlating with the elevated constitutive NF-κB activity in PC3 cells. AZ10397767 increased 17-AAG-induced apoptosis and necrosis and decreased NF-κB activity/CXCL8 expression in 17-AAG-treated PC3 cells. Conclusion: Ansamycin cytotoxicity is enhanced by inhibiting NF-κB activity and/or CXC-chemokine signalling in CRPC cells. Detecting and/or inhibiting NF-κB activity may aid the selection and treatment response of CRPC patients to Hsp90 inhibitors.

Purpose: P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. Experimental Design: Patients first received tariquidar alone to assess effects on the accumulation of 99mTc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. Results: Twenty-six patients were enrolled. Vinorelbine 20 mg/m2 on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver 99mTc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased 99mTc-sestamibi retention in a majority of tumor masses visible by 99mTc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. Conclusions: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.

We sought to characterise whether dexamethasone (DEX) may enhance tumour response to docetaxel in in vitro and in vivo models of metastatic prostate cancer (CaP). In vitro experiments conducted on PC3 and human bone marrow endothelial cells (hBMECs) determined that administration of DEX (10 nM) reduced constitutive nuclear factor-kappaB (NF-kappaB) activity, decreasing interleukin (IL)-8, CXCL1 and VEGF gene expression in PC3 cells. Dexamethasone also attenuated docetaxel-induced NF-kappaB and activator protein-1 transcription and reduced docetaxel-promoted expression/secretion of IL-8 and CXCL1 in PC3 and hBMECs. Although DEX failed to enhance docetaxel cytotoxicity on PC3 cells, DEX potentiated the antiangiogenic activity of docetaxel in vitro, further reducing vessel area and vessel length in developing endothelial tubes (P0.05). Docetaxel had a potent antiangiogenic activity in the dorsal skin flap-implanted PC3 tumours in vivo. Small blood vessel formation was further suppressed in tumours co-treated with docetaxel and DEX, substantiated by an increased average vessel diameter and segment length and a decreased number of branch points in the residual tumour vasculature (P0.001). Our data show that DEX potentiates the antiangiogenic activity of docetaxel, suggesting a putative mechanism for the palliative and survival benefits of these agents in metastatic CaP.

Constitutive activation of nuclear factor (NF)-kappaB is linked with the intrinsic resistance of androgen-independent prostate cancer (AIPC) to cytotoxic chemotherapy. Interleukin-8 (CXCL8) is a transcriptional target of NF-kappaB whose expression is elevated in AIPC. This study sought to determine the significance of CXCL8 signaling in regulating the response of AIPC cells to oxaliplatin, a drug whose activity is reportedly sensitive to NF-kappaB activity. Administration of oxaliplatin to PC3 and DU145 cells increased NF-kappaB activity, promoting antiapoptotic gene transcription. In addition, oxaliplatin increased the transcription and secretion of CXCL8 and the related CXC-chemokine CXCL1 and increased the transcription and expression of CXC-chemokine receptors, especially CXC-chemokine receptor (CXCR) 2, which transduces the biological effects of CXCL8 and CXCL1. Stimulation of AIPC cells with CXCL8 potentiated NF-kappaB activation in AIPC cells, increasing the transcription and expression of NF-kappaB-regulated antiapoptotic genes of the Bcl-2 and IAP families. Coadministration of a CXCR2-selective antagonist, AZ10397767 (Bioorg Med Chem Lett 18:798-803, 2008), attenuated oxaliplatin-induced NF-kappaB activation, increased oxaliplatin cytotoxicity, and potentiated oxaliplatin-induced apoptosis in AIPC cells. Pharmacological inhibition of NF-kappaBorRNA interference-mediated suppression of Bcl-2 and survivin was also shown to sensitize AIPC cells to oxaliplatin. Our results further support NF-kappaB activity as an important determinant of cancer cell sensitivity to oxaliplatin and identify the induction of autocrine CXCR2 signaling as a novel mode of resistance to this drug.

Purpose: To analyze the 50% correct recognition data that were from the Wilson et al (this issue) study and that were obtained from 24 listeners with normal hearing; also to examine whether acoustic, phonetic, or lexical variables can predict recognition performance for monosyllabic words presented in speech-spectrum noise. Research Design: The specific variables are as follows: (a) acoustic variables (i.e., effective root-mean-square sound pressure level, duration), (b) phonetic variables (i.e., consonant features such as manner, place, and voicing for initial and final phonemes; vowel phonemes), and (c) lexical variables (i.e., word frequency, word familiarity, neighborhood density, neighborhood frequency). Data Collection and Analysis: The descriptive, correlational study will examine the influence of acoustic, phonetic, and lexical variables on speech recognition in noise performance. Results: Regression analysis demonstrated that 45% of the variance in the 50% point was accounted for by acoustic and phonetic variables whereas only 3% of the variance was accounted for by lexical variables. These findings suggest that monosyllabic word-recognition-in-noise is more dependent on bottom-up processing than on top-down processing. Conclusions: The results suggest that when speech-in-noise testing is used in a pre- and post-hearing-aid-fitting format, the use of monosyllabic words may be sensitive to changes in audibility resulting from amplification.

PURPOSE To determine the frequency of the ACTN3 R577X polymorphism (functional R allele and nonfunctional X allele) in a variety of African populations and to examine its influence on the success of elite East African endurance runners and West African sprinters. METHODS The R577X polymorphism was genotyped in 198 Ethiopian controls and 76 elite Ethiopian endurance athletes, 158 Kenyan controls and 284 elite Kenyan endurance runners, and 60 Nigerian controls and 62 elite Nigerian power athletes. Statistical analyses were performed by exact tests of population differentiation, using Arlequin, version 3. Analyses were carried out using 1 x 10(6) Markov chain steps, and 1 x 10(5) dememorization steps. RESULTS The frequency of the X allele was extremely low among Kenyans and Nigerians (approximately 1% homozygosity) and higher in Ethiopians (approximately 11% homozygosity). The low baseline frequencies of the three populations tested mean that any associations with sprint performance would likely be obscured. In Ethiopians, where baseline levels of 577XX were about 11%, there was no increased frequency in the endurance athletes. CONCLUSION Our data suggest that alpha-actinin-3 deficiency is not a major influence on performance in African athletes.

OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma.A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity.Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients.The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).

Background: A previous experiment with 70 interrupted monosyllabic words demonstrated that recognition performance was influenced by the location of an interruption pattern (Wilson, 2014). The interruption paradigm (10 interruptions/sec, 50% duty cycle periodic interruption) was referenced to word onset. The words were interrupted such that alternate 50-msec segments were parsed to separate files. In the 0-msec condition the first on-segment coincided with the word onset, whereas in the 50-msec condition the first on-segment occurred 50 msec after word onset. The 0- and 50-msec conditions were complementary halves. Recognition performance by young listeners was 19% better on the 0-msec condition (86%) than on the 50-msec condition (68%); there were a minority number of words on which the results were just the opposite. A second study using the same interruption paradigm but 300 different words reported similar relations, with 63% correct recognition on the 0-msec condition and 48% on the 50-msec condition (Wilson and Irish, 2015). Both studies suggest the importance that the first 50 msec of the target word has on intelligibility. Purpose: To define in detail the effects that interruption patterns have on word recognition as the interruption pattern was incremented with reference to word onset from 0 to 90 msec in 10-msec steps. Research Design: A repeated-measures design with ten interruption patterns (onset conditions). Study Sample: Twenty-four young listeners (19–29 yr) with normal hearing for pure tones participated in this study. Data Collection and Analyses: Seventy consonant-nucleus-consonant words formed the corpus of materials with 25 additional words used for practice. For each participant, the 700 stimuli (70 words by ten onset conditions) were interrupted (10 interruptions/sec; 50% duty cycle), randomized, and recorded on compact disc in 28, 25-word tracks. Results: The overall mean recognition performance was 80.4% with mean performances for the ten conditions ranging from 73.0% (50-msec condition) to 87.7% (90-msec condition). The mean recognition performances changed systematically, decreasing from the 0-msec condition to the 50-msec condition and then increasing to the 90-msec condition, which formed a U-shaped function of the means. Of the 45 mean paired comparisons (post hoc t-tests with Bonferroni corrections), there were 17 significant differences at the p ≤ 0.001 level, increasing to 31 significant differences when the significance level was increased to the p ≤ 0.01 level. Visual inspection of the 70-word performance functions revealed that 32 words had flat functions, 34 words had U-shaped functions, two functions were rising, one was an inverted V-shape, and one was irregular. Conclusions: First, some words (utterances of those words) were immune to any differential effects of the ten interruption patterns. These words with flat performance functions constituted 46% of the word corpus. Second, 49% of the words exhibited U-shaped performance functions that were always systematic, going from maximum to minimum and back to maximum. These words were thought to be more dependent on the initial consonant to attain maximum performance. The conclusion is that some words are not affected by the location of the interruption pattern (those with flat functions) whereas other words are substantially affected (those with U-shaped functions).

Aim\ud \ud MicroRNAs (miRNAs) are stable in the circulation and are likely to function in inter-organ communication during a variety of metabolic responses that involve changes in gene expression, including exercise training. However, it is unknown whether differences in circulating-miRNA (c-miRNA) levels are characteristic of training modality.\ud \ud Methods\ud \ud We investigated whether levels of candidate c-miRNAs differ between elite male athletes of two different training modalities (n = 10 per group) - endurance (END) and strength (STR) - and between these groups and untrained controls (CON; n = 10). Fasted, non-exercised, morning plasma samples were analysed for 14 c-miRNAs (miR-1, miR-16-2, miR-20a-1, miR-21, miR-93, miR-103a, miR-133a, miR-146a, miR-192, miR-206, miR-221, miR-222, miR-451, miR-499). Moreover, we investigated whether c-miRNA levels were associated with quantitative performance-related phenotypes within and between groups.\ud \ud Results\ud \ud miR-222 was present at different levels in the three participant groups (p = 0.028) with the highest levels being observed in END and the lowest in STR. A number of other c-miRNAs were present at higher levels in END than in STR (relative to STR, ± 1 SEM; miR-222: 1.94 fold (1.73-2.18), p = 0.011; miR-21: 1.56 fold (1.39-1.74), p = 0.013; miR-146a: 1.50 fold (1.38-1.64), p = 0.019; miR-221: 1.51 fold (1.34-1.70), p = 0.026). Regression analyses revealed several associations between candidate c-miRNA levels and strength-related performance measures before and after adjustment for muscle or fat mass, but not following adjustment for group.\ud \ud Conclusion\ud \ud Certain c-miRNAs (miR-222, miR-21, miR-146a and miR-221) differ between endurance- and resistance-trained athletes and thus have potential as useful biomarkers of exercise training and / or play a role in exercise mode-specific training adaptations. However, levels of these c-miRNAs are probably unrelated to muscle bulk or fat reserves.

Cancer clinical trials have been the catalyst for many practice changing clinical advances in oncology [1, 2]. Increasingly, however, there is a realization that (a) the traditional drug discovery/drug development model is unsustainable [3]; (b) adult participation in cancer clinical trials is underwhelming, with recruitment rates sometimes as low as 5% [4]; and (c) in the era of targeted therapies, the classic drug A versus drug B strategy may no longer be fit for purpose [5], in many cases producing little or no incremental benefit when transformative improvement is what our patients need. Recognizing the limits of this traditional two arm approach (which frequently fails to demonstrate superiority after many years of effort [3]), Parmar et al. [6] have recently argued for a cultural shift in clinical trial methodology toward a multiarm design that can answer several clinical questions in the same time frame. We submit that this thesis also has important implications for biomarker-stratified clinical trials, in which evaluation of multiple novel therapies is often required, underpinned by precise biomarker-guided patient selection. In metastatic colorectal cancer (mCRC), a more granular understanding of disease biology has fueled the development of a number of gene or pathway-targeted therapeutic approaches, increasing the armamentarium of drugs at our disposal to treat this aggressive malignancy. However, the design of clinical trials that incorporate these novel drugs in their appropriate genetic context is crucial. Recognizing and responding to this challenge, we propose a change in the clinical trial paradigm, eschewing the increasingly limited two-arm approach in favor of a more progressive multistage protocol that integrates one or more treatment comparisons against controls in each of several biomarker-selected subgroups within a single trial program. FOCUS4 is a population-enriched biomarker-stratified clinical trial program for first-line treatment of mCRC [7], designed to allow the efficacy and safety of multiple novel therapies to be assessed rapidly and efficiently in a single protocol, while also evaluating the effectiveness of a biomarker-guided stratified approach. FOCUS4 is a single trial design, in which each biomarker cohort is evaluated through a phase II/III enrichment approach. Putative biomarkers have already been identified for each treatment arm. In our initial staged analysis, the principle is that we first identify a positive effect, which then informs evaluation of both biomarker-positive and biomarker-negative patient groups. This enrichment approach allows refinement of the biomarker strategy as the program evolves—codevelopment of the companion diagnostic(s) and the different treatment arms is an important capability that is specifically built into our overarching trial design. FOCUS4 is also part of a recently funded Medical Research Council (MRC)–Cancer Research UK Stratified Medicine Program (Stratification in Colorectal Cancer [S-CORT]) [8]; one of the work streams specifically focuses on developing new molecular stratifiers for the FOCUS4 trial. The design of FOCUS4 overcomes the inefficiencies and compromises inherent in most biomarker-stratified trials. The vast majority of mCRC patients are eligible for this trial, thus maximizing timely and efficient recruitment and ensuring the largest possible number of patients can benefit. An inclusive clinical trial design is also attractive to patients and patient advocacy groups, funding bodies, and pharmaceutical, biotechnology, and diagnostic companies. The trial design is flexible; currently, four molecularly defined cohorts are included with novel inhibitors selected for each biological subgroup: group A, BRAF mutant; group B, PI3 kinase mutant; group C, RAS mutant; and group D, all wild-type cohort (Fig. 1). Figure 1. Structure of FOCUS4 trail for advanced colorectal cancer. Statistical considerations are a key component of our innovative trial design [7, 9] and are indicated in detail in Table 1. A specific priority order has been established for allocating patients who could potentially fit into more than one biomarker cohort. This priority depends on, first, how closely the targeted agent appears to be linked to the biomarker (e.g., BRAF mutation and combined BRAF pathway inhibition for FOCUS4-A) and, second, on the size of the cohort. These prioritization decisions, like other aspects of the trial, also can be improved or refined during the course of the study based on developing biomarker evidence. When new developments (inevitable in this fast-moving field) are supported by an appropriate evidence base, other validated biomarkers, new cohorts, or other novel agents can be added (or substituted for ineffective treatment arms), all by amendment rather than by developing an entirely separate new trial. Table 1. Estimates of sample sizes for FOCUS4 trial The BRAF mutant subgroup is an example of a cohort in which adding a multiarm comparison into the design is helpful, both to clarify underlying biology and to maximize therapeutic efficacy. BRAF inhibitor monotherapy is normally ineffective in mCRC, as escape signaling through the epidermal growth factor receptor (EGFR) occurs [10]. Downstream inhibition of mitogen-activated protein kinase kinase enzymes (MEKs) can reduce aberrant signal transduction. Thus, a multiarm trial design comparing BRAF tyrosine kinase (TK) inhibitor (BRAFi) + MEK inhibitor + EGFR monoclonal antibody (mAb) versus BRAFi + EGFR mAb versus placebo allows two relevant questions to be answered in parallel: (a) does combined targeting of the mutant BRAF TK plus its feedback signaling through EGFR improve progression-free survival in BRAF mutant mCRC, and (b) is the additional inhibition of downstream MEK essential or additive to this benefit? The design of our trial promotes efficiency, significantly shortening the recruitment time and thus the overall trial duration. This allows novel therapies to be evaluated quickly, with a commensurate reduction in costs compared with multiple individual two-arm trials that test each novel therapy in isolation. More importantly, this approach increases the likelihood of therapeutic success, which is further enhanced by the biomarker-stratified design. Crucially, the multistage statistical design allows agents with insufficient activity to be reliably identified at an early stage (and potentially replaced), and the biomarker enrichment strategy used can be tested and validated in the later stages of the trial, together maximizing the ability to identify true clinical benefit. Repetitive tumor resampling is built into the trial to counter the effects of potential tumor heterogeneity Our increasing knowledge of the molecular taxonomy of cancer, informed by The Cancer Genome Atlas project and the International Cancer Genome Consortium, is fueling a number of biomarker-driven clinical trial initiatives, both specifically in colorectal cancer (e.g., SPECTAcolor [Screening Patients for Efficient Clinical Trial Access in Advanced Colorectal Cancer], which uses the European Organisation for Research and Treatment of Cancer SPECTA Biomarker screening platform [11], and MODUL [a biomarker-driven randomized clinical trial in mCRC] [12]) and more generally in multiple cancers (e.g., the National Cancer Institute’s Molecular Analysis for Therapy Choice [NCI-MATCH], which has approximately 20 arms, each addressing a particular molecular profile [13]). The increasing fragmentation of clinically recognized diseases into multiple separate biologically defined subtypes threatens the current cornerstone of evidence-based medicine—the randomized controlled trial. Multiarm, multistage trials, such as STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial) [14], and the incorporation of biomarker stratification, such as in FOCUS4, emphasize the changing paradigm of clinical trial design, charting a course for the effective evaluation of novel therapies and the identification of the responsive patient subgroup(s) that maintains the rigor of a randomized controlled trial but allows its successful adaptation to the era of stratified medicine.

The functional allele (577R) of ACTN3, which encodes human alpha-actinin-3, has been reported to be associated with elite athletic status and with response to resistance training, while the nonfunctional allele (577X) has been proposed as a candidate metabolically thrifty allele. In a study of 992 adolescent Greeks, we show that there is a significant association (P=0.003) between the ACTN3 R577X polymorphism and 40 m sprint time in males that accounts for 2.3% of phenotypic variance, with the 577R allele contributing to faster times in an additive manner. The R577X polymorphism is not associated with other power phenotypes related to 40 m sprint, nor with an endurance phenotype. Furthermore, the polymorphism is not associated with obesity-related phenotypes in our population, suggesting that the 577X allele is not a thrifty allele, and thus the persistence of this null allele must be explained in other terms.

Developments that may improve existing cytotoxic therapy for colorectal cancer (CRC) include alternatives to 5-fluorouracil (5-FU) such as the liposomal Thymidylate Synthase inhibitor OSI-7904L and the multitargeted antifolate pemetrexed. Studies have explored means of reformulating irinotecan, modulating its pharmacokinetics, and enhancing its activity by maximizing DNA damage through poly(ADP-ribose) polymerase inhibition. Cell cycle inhibitors may offer an alternative to combination with 5-FU. However, as standard regimens become more complex, so do the clinical trials needed to develop new agents, and the path to registration becomes ever more tortuous. It is therefore likely that several drugs with promise in CRC will not be developed for this indication.

Dichotic word recognition was evaluated in free-recall, directed-attention right, and directed-attention left response conditions. All participants were right-handed and included a group of young adults with normal hearing and two groups of older adults with sensorineural hearing loss. Dichotic word recognition performance was best for young adults and decreased for each older group. A right-ear advantage (REA) was observed for all groups. REAs observed in the older groups were larger than those for the young adults, resulting from a greater deficit in dichotic word recognition performance for words presented to the left ear. A subset of older adults exhibited few to no responses (≤3/100) for the left ear for all response conditions, which may relate to a compromise in auditory processing. The results support an age-related disadvantage in recognition performance for dichotic stimuli presented to the left ear not entirely accounted for by differences in hearing sensitivity between subject groups.

The purpose of this study was to determine the list equivalency of the 18 QuickSIN™ (Quick Speech in Noise test) lists. Individuals with normal hearing (n = 24) and with sensorineural hearing loss (n = 72) were studied. Mean recognition performances on the 18 lists by the listeners with normal hearing were 2.8 to 4.3 dB SNR (signal-to-noise ratio), whereas the range was 10.0 to 14.3 dB SNR for the listeners with hearing loss. The psychometric functions for each list showed high performance variability across lists for listeners with hearing loss but not for listeners with normal hearing. For listeners with hearing loss, Lists 4, 5, 13, and 16 fell outside of the critical difference. The data from this study suggest nine lists that provide homogenous results for listeners with and without hearing loss. Finally, there was an 8.7 dB difference in performances between the two groups indicating a more favorable signal-to-noise ratio required by the listeners with hearing loss to obtain equal performance.

Purpose: Inhibition of steroid sulfatase (STS), the enzyme responsible for the hydrolysis of steroid sulfates, represents a potential novel treatment for postmenopausal women with hormone-dependent breast cancer. Estrone and DHEA are formed by this sulfatase pathway and can be converted to steroids (estradiol and androstenediol, respectively), which have potent estrogenic properties. Experimental Design: STX64 (667 Coumate), a tricylic coumarin-based sulfamate that irreversibly inhibits STS activity, was selected for entry into the first phase I trial of a STS inhibitor in postmenopausal women with breast cancer. STX64 was administered orally (nine patients at 5 mg and five patients at 20 mg) as an initial dose followed 1 week later by 3 × 2 weekly cycles, with each cycle comprising daily dosing for 5 days followed by 9 days off treatment. Blood and tumor tissue samples were collected for the assessment of STS activity and serum was obtained for steroid hormone measurements before and after treatment. Results: The median inhibition of STS activity by STX64 was 98% in peripheral blood lymphocytes (PBL) and 99% in breast tumor tissue at the end of the 5-day dosing period. As expected, serum concentrations of estrone, estradiol, androstenediol, and DHEA all decreased significantly from pretreatment levels. Unexpectedly, androstenedione and testosterone concentrations also decreased. Four patients, all of whom had previously progressed on aromatase inhibitors, showed evidence of stable disease for 2.75 to 7 months. The drug was well tolerated with only minor drug-related adverse events recorded. Conclusion: STX64 is a potent, well-tolerated STS inhibitor. It inhibits STS activity in PBLs and tumor tissues and causes significant decreases in serum concentrations of steroids with estrogenic properties.

Background: Several European countries have demonstrated successful use of telephone screening tests for auditory function. The screening test consists of spoken three-digit sequences presented in a noise background. The speech-to-noise ratios of the stimuli are determined by an adaptive tracking method that converges on the level required to achieve 50% correct recognition. Purpose: A version of the three-digit telephone screening protocol for the United States was developed: the US National Hearing Test (NHT). The objective of the current study was to determine the sensitivity and specificity as well as the feasibility of the NHT for use within the Department of Veterans Affairs (VA). Research Design and Study Sample: Using a multisite study design with convenience sampling, we used the NHT to collect data from 693 participants (1379 ears) from three geographical areas of the United States (Florida, Tennessee, and California). Data Collection and Analysis: The NHT procedures were as follows: the participants (1) called a toll-free telephone number, (2) entered their assigned ear-specific identification code, (3) listened to 40-sets of digit triplets presented in speech-spectrum background noise, and (4) entered in the numbers that they heard on the telephone key pad. The NHT was performed on each ear, either at home or in a VA clinic. In addition to collecting data from the experimental task, we gathered demographic data and the data from other standard-of-care tests (i.e., audiometric thresholds and speech recognition tests in quiet and in noise). Results: A total of 505 participants completed the NHT at a VA clinic, whereas 188 completed the test at home. Although the ear-specific NHT and mean pure-tone threshold all correlated significantly (p < 0.001), there were more modest correlations in the low- and high-frequency ranges with the highest correlation seen with the 2000 Hz mean pure-tone threshold. When the NHT 50% point or threshold was compared with the three-frequency PTA at 500, 1000, and 2000 Hz, the sensitivity was 0.87 and specificity was 0.54. When comparing the NHT with the four-frequency PTA at 500, 1000, 2000, and 4000 Hz, the sensitivity was 0.81 and specificity increased to 0.65. The NHT also correlated strongly with other speech-in-noise measures. Conclusions: The NHT was found to correlate with other audiometric measures, including pure-tone thresholds and speech recognition tests in noise, at sufficiently high correlation values to support its use as a screening test of auditory function.

Oxaliplatin, an effective cytotoxic treatment in combination with 5-fluorouracil for colorectal cancer, is associated with sensory, motor and autonomic neurotoxicity. Motor symptoms include hyperexcitability while autonomic effects include urinary retention, but the cause of these side-effects is unknown. We examined the effects on motor nerve function in the mouse hemidiaphragm and on the autonomic system in the vas deferens. In the mouse diaphragm, oxaliplatin (0.5 mM) induced multiple endplate potentials (EPPs) following a single stimulus, and was associated with an increase in spontaneous miniature EPP frequency. In the vas deferens, spontaneous excitatory junction potential frequency was increased after 30 min exposure to oxaliplatin; no changes in resting Ca(2+) concentration in nerve terminal varicosities were observed, and recovery after stimuli trains was unaffected. In both tissues, an oxaliplatin-induced increase in spontaneous activity was prevented by the voltage-gated Na(+) channel blocker tetrodotoxin (TTX). Carbamazepine (0.3 mM) also prevented multiple EPPs and the increase in spontaneous activity in both tissues. In diaphragm, beta-pompilidotoxin (100 microM), which slows Na(+) channel inactivation, induced multiple EPPs similar to oxaliplatin's effect. By contrast, blockers of K(+) channels (4-aminopyridine and apamin) did not replicate oxaliplatin-induced hyperexcitability in the diaphragm. The prevention of hyperexcitability by TTX blockade implies that oxaliplatin acts on nerve conduction rather than by effecting repolarisation. The similarity between beta-pompilidotoxin and oxaliplatin suggests that alteration of voltage-gated Na(+) channel kinetics is likely to underlie the acute neurotoxic actions of oxaliplatin.

The purpose of this study was to determine if performances on a 500 Hz MLD task and a word-recognition task in multitalker babble covaried or varied independently for listeners with normal hearing and for listeners with hearing loss. Young listeners with normal hearing (n = 25) and older listeners (25 per decade from 40–80 years, n = 125) with sensorineural hearing loss were studied. Thresholds at 500 and 1000 Hz were ≤30 dB HL and ≤40 dB HL, respectively, with thresholds above 1000 Hz

Purpose To determine the clinical toxicities of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks. Patients and Methods Nineteen patients received 17-AAG over six dose levels (10 to 56 mg/m2) using an accelerated titration scheme. Drug levels of 17-AAG were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored by changes in the content of target proteins by immunoblot analysis of lysates prepared from peripheral-blood mononuclear cells. Results Toxicity was acceptable at doses up to 28 mg/m2. The cohort was expanded to three patients at 40 mg/m2 because a second occurrence of grade 2 hepatic transaminitis occurred. Two of six assessable patients who received 56 mg/m2 had reversible, grade 3 hepatic transaminitis. Five additional patients were enrolled at 40 mg/m2; none had dose-limiting toxicity. The maximum plasma concentrations (Cmax) of 17-AAG at 40 and 56 mg/m2 were 1,724 and 2,046 ng/mL, respectively; the average plasma exposures (AUC) were 2,809 and 6,708 hours·ng/mL, respectively. Less than 3% of the daily dose was excreted into the urine. Clearance did not correlate with body-surface area. Possible biologic activity was suggested by apparent increased protein content of either glucose-related 78 kd protein or heat shock protein 70 with ≥ 14 mg/m2 and decreased protein content of either Lck or Raf1 with ≥ 28 mg/m2 of 17-AAG. Conclusion 17-AAG 40 mg/m2 (median dose, 70 mg) was well tolerated when given daily for 5 days every 3 weeks.

The World Health Organization's Disability Assessment Scale II (WHO-DAS II) is a generic health-status instrument that provides six domain scores and a total, aggregate score. Two of the domain scores, communication and participation, and the total score, have good validity, internal-consistency reliability, and test-retest stability in individuals with adult-onset hearing loss. As such, these two domain scores and the total WHO-DAS II score may be useful as generic outcome measures to assess the effectiveness of hearing aid intervention for this population. Before the use of the WHO-DAS II in hearing aid clinical trials, however, the responsiveness of the instrument and the short- and long-term outcomes to hearing aid intervention had to be determined. Responsiveness and outcomes were assessed in 380 veterans (approximately half received hearing aids and half served as controls) by examining group differences, effect-size estimates, and individual differences as a function of hearing aid intervention. For comparison, data also were obtained on two disease-specific measures, the APHAB and the HHIE. The WHO-DAS II communication domain and total scores were sufficiently responsive to hearing aid intervention for use in future studies in which group differences are to be detected. The WHO-DAS II participation domain was not sufficiently responsive to hearing aid intervention. The APHAB and HHIE, both disease-specific measures, were more sensitive to hearing aid intervention than the generic measure. The short- and long-term outcomes of hearing aid intervention were also examined in the present study. Group outcomes for hearing aid intervention can be expected to be stable for at least 6 months when measured by WHO-DAS II total score and for at least 12 months when measured by the WHO-DAS II communication domain scores. Effect-size estimates and examination of the number of individuals exhibiting change scores exceeding 90% critical differences for true changes in scores indicate that for clinical applications, disease-specific instruments are more useful than the WHO-DAS II. The findings of this study support the use of the WHO-DAS II as a generic measure in hearing aid trials research so as to allow for comparisons of health-status outcomes across different diseases or disorders.

The World Health Organization's (WHO) Disability Assessment Scale II (WHO-DAS II) is a generic health-status instrument firmly grounded in the WHO's International Classification of Functioning, Disability and Health (WHO-ICF). As such, it assesses functioning for six domains: communication, mobility, self-care, interpersonal, life activities, and participation. Domain scores aggregate to a total score. Because the WHO-DAS II contains questions relevant to hearing and communication, it has good face validity for use as an outcome measure for audiologic intervention. The purpose of the present study was to determine the psychometric properties of the WHO-DAS II on a sample of individuals with adult-onset hearing loss, including convergent validity, internal consistency, and test-retest stability. Convergent validity was established by examining correlations between the WHO-DAS II (domain and total scores) and the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Hearing Aid Handicap for the Elderly (HHIE), two disease-specific measures, as well as with the Short Form-36 for veterans (SF-36V), a second generic measure. Data on all four measures were collected from 380 older individuals with adult-onset hearing loss who were not hearing aid users. The results of the convergent validity analysis revealed that the WHO-DAS II communication domain score was moderately and significantly correlated with scores on the APHAB and the HHIE. WHO-DAS II interpersonal and participation domain scores and the total scores were also moderately and significantly correlated with HHIE scores. These findings support the validity of using the WHO-DAS II for assessing activity limitations and participation restrictions of adult-onset hearing loss. Several WHO-DAS II domain scores and the total score were also significantly and moderately-markedly correlated with scores from the SF-36V. These findings support the validity of the WHO-DAS II as a generic health-status instrument. Internal consistency reliability for all the domain scores was adequate for all but the interpersonal domain. Test-retest stability for all the domain scores was adequate. Critical difference values were calculated for use in clinical application of the WHO-DAS II. From these findings, we concluded that the WHO-DAS II communication, participation, and total scores can be used to examine the effects of adult-onset hearing loss on functional health status. Further work examining the utility of the WHO-DAS II as an outcome measure for hearing aid intervention is warranted.

East African athletes now dominate international distance running events from the 800 m to the marathon. Explanations for their phenomenal success have included optimal environmental conditions for developing distance running performance, psychological advantage and advantageous physiological characteristics. It is well established that genetics plays a role in determining inter-individual differences in exercise performance and adaptation to training stimuli. It is not known, however, to what extent inter-population differences (i.e. between ‘races’ and/or ethnic groups) in exercise performance can be attributed to genetics. There have been considerations that ‘black’ athletes are genetically adapted towards performance, given the concurrent success of athletes of West African ancestry in sprint events. However, the current notion of ‘race’ is not universally accepted, and genetic differences within and between populations are not clearly delineated by geographical or ethnic categorizations. Recent findings from mitochondrial DNA show that the populations from which Ethiopian athletes are drawn have not been isolated populations and are not genetically distinct from other Ethiopians. Y-chromosome analysis of the same population shows concurrent results, although some differences are present between athletes and the general Ethiopian population, suggesting an influence of the Y chromosome on athlete status in Ethiopia. It is concluded that there may be a role for genetics in the success of East African athletes; however, any genetic component to their success is unlikely to be limited to East Africans and is more likely to be found in other populations. At present it is unjustified to implicate a role for genetics in the success of East African runners when no genes have been identified as being important to their performance.

Favourable genetic endowment has been proposed as part of the explanation for the success of East African endurance athletes, but no evidence has yet been presented. The Y chromosome haplogroup distribution of elite Ethiopian athletes (n=62) was compared with that of the general Ethiopian population (n=95) and a control group from Arsi (a region producing a disproportionate number of athletes; n=85). Athletes belonged to three groups: marathon runners (M; n=23), 5-km to 10-km runners (5-10K; n=21) and other track and field athletes (TF; n=18). DNA was extracted from buccal swabs and haplogroups were assigned after the typing of binary markers in multiplexed minisequencing reactions. Frequency differences between groups were assessed by using contingency exact tests and showed that Y chromosome haplogroups are not distributed amongst elite Ethiopian endurance runners in the same proportions as in the general population, with statistically significant (P

A simple word-recognition task in multitalker babble for clinic use was developed in the course of four experiments involving listeners with normal hearing and listeners with hearing loss. In Experiments 1 and 2, psychometric functions for the individual NU No. 6 words from Lists 2, 3, and 4 were obtained with each word in a unique segment of multitalker babble. The test paradigm that emerged involved ten words at each of seven signal-to-babble ratios (S/B) from 0 to 24 dB. Experiment 3 examined the effect that babble presentation level (70, 80, and 90 dB SPL) had on recognition performance in babble, whereas Experiment 4 studied the effect that monaural and binaural listening had on recognition performance. For listeners with normal hearing, the 90th percentile was 6 dB S/B. In comparison to the listeners with normal hearing, the 50% correct points on the functions for listeners with hearing loss were at 5 to 15 dB higher signal-to-babble ratios.

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The purpose of this series of experiments was to develop a simple, 500-Hz masking-level difference (MLD) protocol that could be implemented easily in the clinic to assess auditory perceptual abilities using an audio compact disc. Five, 300-ms tones with 250-ms intertone intervals were embedded in 3-s bursts of 200-800 Hz noise presented at 42.2-dB pressure-spectrum level with 4-5 s inter-stimulus intervals. The homophasic and antiphasic conditions were interleaved with the signal-to-noise ratios decreasing in 2-dB steps. A single-interval, "yes/no" response task was used. Three experiments were performed on 24-28 listeners with normal hearing. The mean SoNo thresholds (58.1- to 59.5-dB SPL) and the mean SπNo thresholds (45.1- to 46.0-dB SPL) produced ˜13-dB MLDs. Experiment 3 included a SoNπ condition that had a mean threshold of 48.8-dB SPL and a 10.0-dB MLD. The mean test, retest ot the SoNo and SπNo thresholds on 15 listeners was

OBJECTIVES This study compared speech recognition performance on the Northwestern University Auditory Test No. 6 (NU-6) and the Connected Speech Test (CST) for three hearing aid circuits (peak clipping [PC], compression limiting [CL], and wide dynamic range compression [WDRC]) in adults with symmetrical sensorineural hearing loss. The study also questioned whether or not hearing aid benefit for the three circuits was dependent upon the speech level and the signal-to-babble ratio (S/B) and upon the degree and slope of hearing loss. DESIGN Unaided speech recognition performance for NU-6 and CST materials presented from a loudspeaker at 0 degrees was measured during Visit 1, and both unaided and aided performance was measured at 3-mo intervals during Visits 2 to 4. The NU-6 was presented in quiet at a conversational speech level of 62 dB SPL. The CST was presented in 10 listening conditions-three S/B (-3, 0, and 3 dB) at each of three speech levels (soft speech at 52 dB SPL, conversational speech at 62 dB SPL, and loud speech at 74 dB SPL) and in quiet at 74 dB SPL. Uncorrelated multi-talker babble was presented from two loudspeakers at 45 degrees on each side of the main speaker. Hearing aid benefit was examined for 360 subjects divided into four groups of hearing loss, pure tone average 10 dB/octave and hearing loss >40 dB HL for the two slope categories. RESULTS Hearing aid benefit (aided minus unaided performance) measured on the NU-6 in quiet exceeded 31 rau for all three circuits. Although small statistical advantages were found for the WDRC, the differences were approximately 2% and are not considered clinically relevant. Unaided CST performance showed a complex relationship between presentation level and signal-to-babble ratio that was further confounded by the degree of hearing loss. For the two mild hearing loss groups and for each of the three nominal signal-to-babble ratios, CST performance decreased by 20 rau for the -3 dB S/B to 6 rau for the 3 dB S/B as speech level increased from 52 to 74 dB SPL. In contrast, unaided performance increased by 32 to 13 rau with signal level for all signal-to-babble ratios for the two >40 dB hearing loss groups. Overall, aided CST performance exceeded unaided performance for all 10 conditions. As expected, hearing aid benefit was greatest (27 rau) for soft speech and smallest for loud speech (6 rau). Differences among the hearing aid circuits were small with only one significant difference; the WDRC at 62/0 was poorer by 3 rau than the other two circuits. When the CST data were analyzed as a function of hearing loss, five pair-wise comparisons were significant. In contrast to the unaided performance, aided performance for all hearing loss groups decreased as presentation level increased, even though the signal-to-babble ratio was constant. CONCLUSIONS All three hearing aids circuits provided benefit over the unaided condition in both quiet and noise. The greatest benefit was measured for soft speech in the more severe hearing loss groups. Although only small differences were measured among the three hearing aid circuits, significant differences favored the PC and CL circuits over the WDRC in the mild hearing loss groups and favored the WDRC over the PC in the more severe, sloping hearing loss group. An interesting interaction between speech level, signal-to-babble ratio, degree of hearing loss, and amplification was found. For a constant signal-to-babble ratio, recognition performance decreased as speech level increased from 52 to 74 dB SPL. The effect was most marked in the milder hearing loss groups and in the aided conditions, and occurred at even the lowest speech levels.

2571 Background: In ovarian cells isolated from ascites, p-S6K levels were found to correlate with resistance to chemotherapy. We hypothesised that inhibiting p-S6K signalling with dual m-TORC1/2 inhibitor vistusertib (V) in addition to paclitaxel (P) would improve outcomes of patients with high-grade serous ovarian cancer (HGSOC). Methods: In the dose escalation part, weekly P 80mg/m2IV (6/7 weeks) was evaluated in combination with two schedules of V; Schedule A: V (25, 50 or 75mg) BID PO on day(D) 1-3/week and Schedule B: V (75 or 100mg) BID PO D1-2/week. This was followed by an expansion cohort in 25 HGSOC patients. Results: Dose limiting toxicities in Schedule A were fatigue and mucositis and in Schedule B were diarrhoea, rash and fatigue. The AUC, Cmax and half-life of V in the 50mg-cohort were 2821ng.hr/ml, 926ng/ml and 3hrs, comparable to single agent studies. PD analysis (from six 50mg-cohort patients) in platelet-rich plasma showed increased phosphorylation of Ser473 AKT following P induction (1.4 fold, p = 0.1378). Following addition of V to P, phosphorylation levels 4hrs post-treatment with V fell significantly to 53% of pre-dose levels (p = 0.0495). This was 61% lower than the corresponding time point following P alone. Based on toxicity, pharmacokinetic and PD evaluation, recommended phase 2 dose was established as P 80mg/m2 D1 and V 50mg BID D1-3 for 6/7 weeks. In the HGSOC expansion, 96% of patients had relapsed within 12 months of last platinum therapy and 100% had received previous paclitaxel, with a median of 3 previous lines of treatments. RECIST and GCIG CA125 response rates were 13/25 (52%) and 15/25 (60%) respectively, with median progression free survival of 5.5 months. MC was performed on archival tumor tissue of 24/25 HGSOC expansion cohort patients, with the most common mutations occurring in p53 (100%), BRCA (17%), and MUC16 (17%). ATM mutations occurred in 17% (n = 4), 3 of whom had a response. Conclusions: We report a highly active combination of paclitaxel with an intermittent schedule of vistusertib in patients with HGSOC. This combination is now being evaluated in a randomised controlled trial for this indication. Clinical trial information: NCT02193633.

Background: The abrupt transition of a signal from off to on and vice versa typically produces spectral splatter that can mask other signals that are spectrally removed from the nominal signal frequency. Both the Miller and Licklider (1950) and Cherry (1953) studies of interrupted speech and alternated speech, respectively, acknowledged the generation of extraneous noise by the rapid on and off characteristics of their unshaped signals but noted for slower interruption rates (e.g., 10 interruptions per second); the masking effects were minimal. Recent studies of interrupted speech have avoided this issue by shaping the rise-fall times with a digital algorithm (e.g., Jin and Nelson, 2010; Wang and Humes, 2010). A second variable in the interrupted speech paradigm is the temporal location or placement of the interruptions (i.e., where in the waveform the interruptions occur). Here the issue is this: what parts of an utterance are necessary to enable intelligibility (e.g., Fogerty and Kewley-Port, 2009)? Interruptions may or may not disturb these necessary cues. Purpose: Here is the prompting question: do shaped and unshaped rise-fall characteristics of the on-segments of interrupted speech produce the same or different recognition performances? A second question arises: are recognition performances on complementary halves of an interrupted signal the same or different? Research Design: This study used a mixed-model design with two within-subject variables (unshaped and shaped rise-fall characteristic, complementary halves) and one between-subjects variable (listener group). Study Sample: A total of 12 young listeners (age range: 19–29 yr) with normal hearing and 12 older listeners (age range: 53–80 yr) with hearing loss for pure tones participated. Data Collection and Analysis: A total of 95 consonant-vowel nucleus-consonant words were interrupted (10 interruptions per second; 50% duty cycle) by parsing alternate 50 msec segments to separate files, which provided complementary temporal halves of the target word referenced to word onset; the first on-segment of the 0 msec condition started at word onset, whereas the first on-segment of the 50 msec condition started 50 msec after word onset. The interruption routine either applied no shaping of the 4 msec rise-fall times or a cos2 shape. Each listener received 25 practice words then a unique randomization of 280 interrupted words (70 words, 2 rise-fall shapes, and 2 interrupt onset conditions). Results: The listeners with normal hearing performed 8–16% better on the various comparable conditions than did the older listeners with hearing loss. The mean performance differences between shaped and unshaped rise-fall characteristics ranged from Conclusions: The rise-fall shape of the onset and offset of the on-segment of the interruption cycle does not affect recognition performance of words. The location of the interruptions in a word can have a significant effect on recognition performance.

Diarrhoea induced by chemotherapy in cancer patients is common, causes notable morbidity and mortality, and is managed inconsistently. Previous management guidelines were based on poor evidence and neglect physiological causes of chemotherapy-induced diarrhoea. In the absence of level 1 evidence from randomised controlled trials, we developed practical guidance for clinicians based on a literature review by a multidisciplinary team of clinical oncologists, dietitians, gastroenterologists, medical oncologists, nurses, pharmacist, and a surgeon. Education of patients and their carers about the risks associated with, and management of, chemotherapy-induced diarrhoea is the foundation for optimum treatment of toxic effects. Adequate--and, if necessary, repeated--assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step. Use of octreotide and seeking specialist advice early for patients who do not respond to treatment will reduce morbidity and mortality. In view of the burden of chemotherapy-induced diarrhoea, appropriate multidisciplinary research to assess meaningful endpoints is urgently required.

Background: For the past 50+ years, audiologists have been taught to measure the pure-tone thresholds at the interoctave frequencies when the thresholds at adjacent octave frequencies differ by 20 dB or more. Although this so-called 20 dB rule is logical when enhanced audiometric resolution is required, the origin of the rule is elusive, and a thorough literature search failed to find supporting scientific data. Purpose: This study purposed to examine whether a 20 dB difference between thresholds at adjacent octave frequencies is the critical value for whether the threshold of the interoctave frequency should be measured. Along this same line of questioning is whether interoctave thresholds can be predicted from the thresholds of the adjacent or bounding octave frequencies instead of measured, thereby saving valuable time. Research Design: Retrospective, descriptive, correlational, and cross-sectional. Study Sample: Audiograms from over a million veterans provided the data, which were archived at the Department of Veterans Affairs, Denver Acquisition and Logistics Center. Data Collection and Analysis: Data from the left and right ears were independently evaluated. For each ear three interoctave frequencies (1500, 3000, and 6000 Hz) were studied. For inclusion, thresholds at the interoctave frequency and the two bounding octave frequencies had to be measurable, which produced unequal numbers of participants in each of the six conditions (2 ears by 3 interoctave frequencies). Age tags were maintained with each of the six conditions. Results: Three areas of analyses were considered. First, relations among the octave-frequency thresholds were examined. About 62% of the 1000–2000 Hz threshold differences were ≥20 dB, whereas about 74% of the 4000–8000 Hz threshold differences were 20 dB. There was an inverse relation between frequency and the percent of negative slopes between octave-frequency thresholds, ranging from 89% at 1500 Hz to 54% at 6000 Hz. The majority of octave-frequency pairs demonstrated poorer thresholds for the higher frequency of the pair. Second, interoctave frequency thresholds were evaluated using the median metric. As the interoctave frequency increased from 1500 to 6000 Hz, the percent of thresholds at the interoctave frequencies that were not equal to the median threshold increased from ˜9.5% (1500 Hz) to 15.6% (3000 Hz) to 28.2% (6000 Hz). Bivariate plots of the interoctave thresholds and the mean octave-frequency thresholds produced 0.85–0.91 R2 values and 0.79–0.92 dB/dB slopes. Third, the predictability of the interoctave thresholds from the mean thresholds of the bounding octave frequencies was evaluated. As expected, as the disparity between octave-frequency thresholds increased, the predictability of the interoctave threshold decreased; for example, using a ±5 dB criterion at 1500 Hz, 53% of the thresholds were ±5 dB when the octave thresholds differed by ≥20 dB, whereas 77% were ±5 dB when the octave thresholds differed by Conclusions: The current findings support the 20 dB rule for testing interoctave frequency thresholds and suggest the rule could be increased to 25 dB or more with little adverse effect.

Background:\ud \ud Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.\ud \ud \ud Patients and Methods:\ud \ud Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients’ tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.\ud \ud \ud Results:\ud \ud A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.\ud \ud \ud Conclusions:\ud \ud Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Background: Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2′-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer. Methods: Patients progressing 6–12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma. Results: After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%). Conclusions: With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.

INTRODUCTION PET-computed tomography (PET-CT) is a useful staging imaging modality in colorectal liver metastases (CRLM). This study aimed to determine whether PET-CT parameters, standardized uptake value (SUV) and reconstructed tumour volume (RTV), are predictors of prognosis and survival. METHODS A study of all resectable CRLM patients in the regional HPB unit from 2007-2009 was performed. Preoperative PET-CT scans were retrospectively reviewed; SUV, diameter and RTV for each lesion was recorded. Correlation analysis was performed with other pathological and biochemical parameters, by Pearson's correlation analysis. Survival analysis was performed using Cox regression hazard model. A P value of less than 0.05 was considered statistically significant. RESULTS A total of 79 patients were included. SUV moderately correlated with tumour diameter, both PET-CT (r=0.4927; P

The sentence stimuli developed in this project combined aspects from several traditional approaches to speech audiometry. Sentences varied with respect to frequency of word use and phonetic confusability. Familiar consonant-vowel-consonant words, nouns and modifiers, were used to form 500 sentences of seven to nine syllables. Based on concepts from the Neighborhood Activation Model for spoken word recognition, each sentence contained three key words that were all characterized as high- or low-use frequency and high or low lexical confusability. Use frequency was determined by published indices of word use, and lexical confusability was defined by a metric based on the number of other words that were similar to a given word using a single phoneme substitution algorithm. Thirty-two subjects with normal hearing were randomly assigned to one of seven presentation levels in quiet, and an additional 32 listeners were randomly assigned to a fixed-level noise background at one of six signal-to-noise ratios. The results indicated that in both quiet and noise listening conditions, high-use words were more intelligible than low-use words, and there was an advantage for phonetically unique words; the position of the key word in the sentence was also a significant factor. These data formed the basis for a sequence of experiments that isolated significant nonacoustic sources of variation in spoken word recognition. Abbreviations: CVC = consonant-vowel-consonant, HD = high frequency of use word from a dense neighborhood, HS = high frequency of use word from a sparse neighborhood, LD = low frequency of use word from a dense neighborhood, LS = low frequency of use word from a sparse neighborhood, NAM = Neighborhood Activation Model, SIN = Speech in Noise, SNR = signal-to-noise ratio

An option for estimating the word-recognition performance of patients who do not speak English as a first language involves using auditory materials, presented in the patient’s native language, in conjunction with a closed-set response mode incorporating pictures or written words. The advantage of this auditory/visual paradigm is that the audiologist is not required to know the foreign language and is therefore not required to judge the accuracy of an oral response to speech stimuli in a foreign language. Spanish auditory/visual materials, known as the Spanish Picture-Identification Task, were developed to be used in a computer- driven multimedia administration and scoring format. Performance data, both in open- (word-recognition) and closed-set (word-identification) response modes, were established for the Spanish Picture-Identification Task using subjects whose first language was Spanish. The results from the open-set paradigm indicate that the Spanish Picture-Identification Task word lists are essentially equivalent to conventional Spanish and English materials used for word recognition. Findings from the closed-set conditions indicate that the Spanish Picture- Identification Task materials are appropriate for estimating the word-identification abilities of Spanish-speaking adult listeners.

A sensitive HPLC assay has been developed to determine the concentration of 17-(allylamino)-17-demethoxygeldanamycin (AAG) in human plasma over the concentration range of 12.5 to 2,500 nM (7.33 to 1,465 ng/mL). After the addition of 1,000 nM geldanamycin as the internal standard, 1 mL samples of human plasma were subjected to solid-phase extraction, via Bond-Elut C18 cartridges, followed by analysis using an isocratic reversed-phase HPLC assay with UV detection. A Phenomenex Kingsorb, 3 micron, C18, 150x4.60 mm column and a Phenomenex Security Guard pre-column, C18 (ODS, Octadecyl), were used to achieve separation. AAG and GM were monitored at 334 and 308 nm, respectively, on a Hewlett-Packard 1050 Diode-Array Detector. The mobile phase, run at a flow-rate of 1 mL/min, was composed of 50% (v/v) 25 mM sodium phosphate (pH 3.00) with 10 mM triethylamine and 50% acetonitrile. HPLC effectively resolved AAG with retention times of 14.60 +/- 0.54 min and the internal standard geldanamycin at 10.72+/-0.38 min (n = 15). This assay was able to measure plasma concentrations of AAG, the lower limit of quantitation being 12.5 nM, at a starting dose of 10 mg/m2 infused intravenously over 1 h in a Phase I clinical trial in adult patients with solid tumors.

Four patients who preferred monaural as compared with binaural amplification were evaluated. For these patients, audiometric data, recognition performance on a dichotic digit task, and monaural and binaural hearing aid performance using four amplification strategies (National Acoustic Laboratories-Revised, a speech in noise algorithm, multiple-microphone arrays, and frequency modulated [FM]) are described. The results of dichotic testing using a one-, two-, and three-pair dichotic digit task in free- and directed-recall conditions indicated a left-ear deficit for all subjects that could not be explained by peripheral auditory findings or by a cognitive-based deficit. The results of soundfield testing using a speech in multitalker babble paradigm indicated that when listening in noise, there was little difference between aided and unaided word-recognition performance, suggesting that the binaural hearing aids originally fit for each patient were not providing substantial benefit when listening in a competing babble background. Word-recognition performance when aided monaurally in the right ear was superior to performance when aided monaurally in the left ear and when aided bin- aurally. The only successful binaural amplification strategy was the FM system. The results indicate that listeners with an auditory-based deficit in dichotic listening may function better with a monaural hearing aid fitting or with an assistive listening device such as an FM system. The findings also suggest that a test of dichotic listening is an important component in the evaluation of patients being considered for amplification. Abbreviations: ALD = assistive listening device, BTE = behind the ear, DM = directional microphone, FM = frequency modulated, ITE = in the ear, NAL-R = National Acoustic Laboratories-Revised, NU-6 = Northwestern University Auditory Test No. 6, S/B = signal-to-babble ratio, S/N - signal-to-noise ratio

Dichotic listening was evaluated using monosyllabic word pairs that differed in lexical difficulty as defined by the Neighborhood Activation Model of spoken word recognition. Four combinations of lexically EASY and lexically HARD words were evaluated (same pair: EASY-EASY, HARD-HARD; or mixed pair: EASY-HARD, HARD-EASY) in young adult listeners with normal hearing and older adult listeners with mild-to-moderate hearing loss. The same-pair data indicated that for all subjects, EASY words were identified correctly more often than HARD words, and recognition performance on words presented to the right ear was better than performance on words presented to the left ear. Overall performance was lower and the right-ear advantage was larger for the older group. The mixed-pair data for the young group revealed that EASY words were recognized more accurately than HARD words, regardless of the ear to which they were presented. For the older adults, the words presented to the right ear were recognized more accurately than were the words presented to the left ear, regardless of the type of word. The efficiency of the processing of stimuli from the left ear is discussed as an explanation of the results for the mixed-pair conditions. Abbreviations: ANCOVA = analysis of covariance, ANOVA = analysis of variance, CV = consonant-vowel, NAM = Neighborhood Activation Model

This tutorial paper examines the relation between the slope of a mean word recognition function and the homogeneity or variability (with respect to recognition) of the individual stimulus items that compose the test materials. This was studied in terms of both the location (Cartesian) and slope of the psychometric functions of the individual words that compose the materials. Word recognition performances were measured for 100 CID W-22 (Hirsh) words and 100 PB-50 (Rush Hughes) words in quiet (0 to 56 dB HL in 8-dB steps) on 12 subjects with normal hearing. The functions for the individual W-22 words were more homogeneous (less variable) than were the functions for the individual PB-50 words. The mean function for the W-22 words was steeper (3.1%/dB) than the function for the PB-50 words (1.9%/dB). This evaluation of the individual words demonstrates the direct relation between variability of the test items and the slope of the mean psychometric function. The more homogeneous performance is on the individual test items with respect to both location and slope, the steeper the slope of the mean psychometric function. Abbreviations: ANOVA = analysis of variance, CD = compact disc