How Do Students Critically Evaluate Outdated Language That Relates to Gender in Biology?

Cisheteronormative ideologies are infused into every aspect of society, including undergraduate science. We set out to identify the extent to which students can identify cisheteronormative language in biology textbooks by posing several hypothetical textbook questions and asking students to modify them to make the language more accurate (defined as "correct; precise; using language that applies to all people"). First, we confirmed that textbooks commonly use language that conflates or confuses sex and gender. We used this information to design two sample questions that used similar language. We examined what parts of the questions students modified, and the changes they recommended. When asked to modify sample textbook questions, we found the most common terms or words that students identified as inaccurate were related to infant gender identity. The most common modifications that students made were changing gender terms to sex terms. Students' decisions in this exercise differed little across three large biology courses or by exam performance. As the science community strives to promote inclusive classrooms and embrace the complexity of human gender identities, we provide foundational information about students' ability to notice and correct inaccurate language related to sex and gender in biology.

Peer-led team learning in an undergraduate biology course: Impacts on recruitment, retention, and imposter phenomenon.

OBJECTIVES: The data presented in this note were collected during a multi-year project conducted in the context of large-enrollment introductory biology course at a large private R-1 research institution in the Northeastern United States. The project aimed to examine the impact of Peer-Led Team Learning (PLTL) on the recruitment and retention of marginalized groups in Science, Technology, Engineering, and Mathematics (STEM) majors. While several results from the project have been published, additional data of interest have yet to be reported. This data note reports on additional associations between PLTL participation and improved outcomes for students from groups that have historically been excluded in STEM. Additional data reported herein were collected to determine if students in the course experienced imposter phenomenon, and whether PLTL may be associated with reduced levels of imposter feelings. DATA DESCRIPTION: The data in this note includes academic information such as final course grades and academic level; socio-demographic information such as gender identity, minority status, and first-generation status; and information on student recruitment, retention, imposter feelings, and participation in Peer-Led Team Learning (PLTL). These data might be useful and of value to education researchers and undergraduate STEM instructors who are interested in improving equity in STEM education.

A comparison study of human examples vs. non-human examples in an evolution lesson leads to differential impacts on student learning experiences in an introductory biology course.

BACKGROUND: Instructors can teach evolution using any number of species contexts. However, not all species contexts are equal, and taxa choice can alter both cognitive and affective elements of learning. This is particularly true when teaching evolution using human examples, a promising method for evolution instruction that nevertheless comes with unique challenges. In this study, we tested how an evolution lesson focused on a human example may impact students' engagement, perceived content relevance, learning gains, and level of discomfort, when compared to the same lesson using a non-human mammal example. We use this isomorphic lesson and a pre-post study design administered in a split-section introductory biology classroom to isolate the importance of the species context. RESULTS: For two of the four measurements of interest, the effect of using human examples could not be understood without accounting for student background. For learning gains, students with greater pre-class content knowledge benefited more from the human examples, while those with low levels of knowledge benefited from the non-human example. For perceived relevance, students who were more accepting of human evolution indicated greater content relevance from the human example. Regardless of condition, students with lower evolution acceptance reported greater levels of discomfort with the lesson. CONCLUSIONS: Our results illustrate the complexities of using human examples to teach evolution. While these examples were beneficial for many students, they resulted in worse outcomes for students that were less accepting of evolution and those who entered the course with less content knowledge. These findings demonstrate the need to consider diverse student backgrounds when establishing best practices for using human examples to teach evolution. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12052-021-00148-w.

Pilot randomized trial of an electronic symptom monitoring intervention for hospitalized patients with cancer.

BACKGROUND: Hospitalized patients with cancer experience a high symptom burden, which is associated with poor health outcomes and increased health care utilization. However, studies investigating symptom monitoring interventions in this population are lacking. We conducted a pilot randomized trial to assess the feasibility and preliminary efficacy of a symptom monitoring intervention to improve symptom management in hospitalized patients with advanced cancer. PATIENTS AND METHODS: We randomly assigned patients with advanced cancer who were admitted to the inpatient oncology service to a symptom monitoring intervention or usual care. Patients in both arms self-reported their symptoms daily (Edmonton Symptom Assessment System and Patient Health Questionnaire-4). Patients assigned to the intervention had their symptom reports presented graphically with alerts for moderate/severe symptoms during daily team rounds. The primary end point of the study was feasibility. We defined the intervention as feasible if >75% of participants hospitalized >2 days completed >2 symptom reports. We observed daily rounds to determine whether clinicians discussed and developed a plan to address patients' symptoms. We used regression models to assess intervention effects on patients' symptoms throughout their hospitalization, readmission risk, and hospital length of stay (LOS). RESULTS: Among 150 enrolled patients (81.1% enrollment), 94.2% completed >2 symptom reports. Clinicians discussed 60.4% of the symptom reports and developed a plan to address the symptoms highlighted by the symptom reports 20.8% of the time. Compared with usual care, intervention patients had a greater proportion of days with lower psychological distress (B = 0.12, P = 0.008), but no significant difference in the proportion of days with improved Edmonton Symptom Assessment System-physical symptoms (B = 0.07, P = 0.138). Intervention patients had lower readmission risk (hazard ratio = 0.68, P = 0.224), although this difference was not significant. We found no significant intervention effects on hospital LOS (B = 0.16, P = 0.862). CONCLUSIONS: This symptom monitoring intervention is feasible and demonstrates encouraging preliminary efficacy for improving patients' symptoms and readmission risk.ClinicalTrials.gov identifier NCT02891993.

Parkour LIMS: high-quality sample preparation in next generation sequencing.

MOTIVATION: This paper presents Parkour, a software package for sample processing and quality management of next generation sequencing data and samples. RESULTS: Starting with user requests, Parkour allows tracking and assessing samples based on predefined quality criteria through different stages of the sample preparation workflow. Ideally suited for academic core laboratories, the software aims to maximize efficiency and reduce turnaround time by intelligent sample grouping and a clear assignment of staff to work units. Tools for automated invoicing, interactive statistics on facility usage and simple report generation minimize administrative tasks. Provided as a web application, Parkour is a convenient tool for both deep sequencing service users and laboratory personal. A set of web APIs allow coordinated information sharing with local and remote bioinformaticians. The flexible structure allows workflow customization and simple addition of new features as well as the expansion to other domains. AVAILABILITY AND IMPLEMENTATION: The code and documentation are available at https://github.com/maxplanck-ie/parkour. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice.

Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (methyl donor-rich diet (MD) F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. Hippocampal overexpression of Kcnmb2 in MD F1 mice ameliorated altered spatial learning and memory, supporting a role of this BK channel subunit in the MD F1 behavioral phenotype. Behavioral and gene expression changes did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.

Counterclockwise maxillomandibular advancement surgery and disc repositioning: can condylar remodeling in the long-term follow-up be predicted?

This study investigated predictive risk factors of condylar remodeling changes after counterclockwise maxillomandibular advancement (CCW-MMA) and disc repositioning surgery. Forty-one female patients (75 condyles) treated with CCW-MMA and disc repositioning had cone beam computed tomography (CBCT) scans taken pre-surgery, immediately after surgery, and at an average 16 months post-surgery. Pre- and post-surgical three-dimensional models were superimposed using automated voxel-based registration on the cranial base to evaluate condylar displacements after surgery. Regional registration was performed to assess condylar remodeling in the follow-up period. Three-dimensional cephalometrics, shape correspondence (SPHARM-PDM), and volume measurements were applied to quantify changes. Pearson product-moment correlations and multiple regression analysis were performed. Highly statistically significant correlation showed that older patients were more susceptible to overall condylar volume reduction following CCW-MMA and disc repositioning (P≤0.001). Weak but statistically significant correlations were observed between condylar remodeling changes in the follow-up period and pre-surgical facial characteristics, magnitude of the surgical procedure, and condylar displacement changes. After CCW-MMA and disc repositioning, the condyles moved mostly downwards and medially, and were rotated medially and counterclockwise; displacements in the opposite direction were correlated with a greater risk of condylar resorption. Moreover, positional changes with surgery were only weakly associated with remodeling in the follow-up period, suggesting that other risk factors may play a role in condylar resorption.

Peer-Led Team Learning Helps Minority Students Succeed.

Active learning methods have been shown to be superior to traditional lecture in terms of student achievement, and our findings on the use of Peer-Led Team Learning (PLTL) concur. Students in our introductory biology course performed significantly better if they engaged in PLTL. There was also a drastic reduction in the failure rate for underrepresented minority (URM) students with PLTL, which further resulted in closing the achievement gap between URM and non-URM students. With such compelling findings, we strongly encourage the adoption of Peer-Led Team Learning in undergraduate Science, Technology, Engineering, and Mathematics (STEM) courses.

Genetic relationships between detailed reproductive traits and performance traits in Holstein-Friesian dairy cattle.

The objective of the study was to estimate the genetic relationships between detailed reproductive traits derived from ultrasound examination of the reproductive tract and a range of performance traits in Holstein-Friesian dairy cows. The performance traits investigated included calving performance, milk production, somatic cell score (i.e., logarithm transformation of somatic cell count), carcass traits, and body-related linear type traits. Detailed reproductive traits included (1) resumed cyclicity at the time of examination, (2) multiple ovulations, (3) early ovulation, (4) heat detection, (5) ovarian cystic structures, (6) embryo loss, and (7) uterine score, measured on a 1 (little or no fluid with normal tone) to 4 (large quantity of fluid with a flaccid tone) scale, based on the tone of the uterine wall and the quantity of fluid present in the uterus. (Co)variance components were estimated using a repeatability animal linear mixed model. Genetic merit for greater milk, fat, and protein yield was associated with a reduced ability to resume cyclicity postpartum (genetic correlations ranged from -0.25 to -0.15). Higher genetic merit for milk yield was also associated with a greater genetic susceptibility to multiple ovulations. Genetic predisposition to elevated somatic cell score was associated with a decreased likelihood of cyclicity postpartum (genetic correlation of -0.32) and a greater risk of both multiple ovulations (genetic correlation of 0.25) and embryo loss (genetic correlation of 0.32). Greater body condition score was genetically associated with an increased likelihood of resumption of cyclicity postpartum (genetic correlation of 0.52). Genetically heavier, fatter carcasses with better conformation were also associated with an increased likelihood of resumed cyclicity by the time of examination (genetic correlations ranged from 0.24 to 0.41). Genetically heavier carcasses were associated with an inferior uterine score as well as a greater predisposition to embryo loss. Despite the overall antagonistic relationship between reproductive performance and both milk and carcass traits, not all detailed aspects of reproduction performance exhibited an antagonistic relationship.

Factors associated with the differential in actual gestational age and gestational age predicted from transrectal ultrasonography in pregnant dairy cows.

The objective of the study was to determine (1) how gestational age predicted using transrectal ultrasonography related to actual gestational age derived as the number of days from the most recent artificial insemination date, (2) what factors, if any, were associated with the differential between the two measures, and (3) the association between this differential in gestational age and the likelihood of subsequent pregnancy loss, stillbirth, or calving dystocia. The data set contained 7340 ultrasound records from 6805 Holstein Friesian dairy cows in 175 herds. Ultrasonography assessment underestimated gestational age relative to days since last service by 0.51 days (standard error [SE]: 0.040), although the differential was less during embryonic development phase (i.e., ≤42 days of gestation; mean overestimation of 0.31 days) versus fetal development phase (i.e., >42 days of gestation; mean underestimation of 0.81 days). Predicted calving date calculated from ultrasonography was 1.41 days (SE: 0.040) later than the actual subsequent calving date and was, on average, 0.52 days later than predicted calving date, assuming a gestation length of 282 days. Parity of the dam (P < 0.05), stage of pregnancy (P < 0.001), and sex of the calf born (P < 0.001) were all associated with the differential in gestational age based on ultrasonography versus days since last service. No obvious trend among parities was evident in the difference between the methods in predicting gestational age. Ultrasonography underestimated gestational age by 0.83 (SE: 0.15) days in parity 5+ cows and underestimated gestational age by 0.41 (SE: 0.14) days in the first-parity cows. Relative to gestational age predicted from the most recent service, ultrasonography underestimated gestational age by 0.75 (SE: 0.13) days for heifer fetuses and underestimated gestational age by 0.36 (SE: 0.13) days for bull fetuses. The heritability of the differential in gestational age between the methods of prediction was low 0.05 (SE: 0.022), corroborating heritability estimates for most cow reproductive traits. Overestimation of gestational age using ultrasonography was associated with an increased likelihood of pregnancy loss (P < 0.001). Gender of calf born (P < 0.001), sire breed of calf (P < 0.001), and parity (P < 0.001) were all associated with gestation length. Gestation length was 1.27 days longer (SE: 0.01) for bull calves compared to heifer calves. Calves from beef sires had a longer gestation length than calves from dairy sires, and older parity cows had a longer gestation length than younger cows. The results highlight factors associated with differences in gestational age obtained from ultrasonography and insemination data and illustrate the value of ultrasonography for the prediction of calving date and pregnancy loss.

Genetic parameters of ovarian and uterine reproductive traits in dairy cows.

The objective of the study was to estimate genetic parameters of detailed reproductive traits derived from ultrasound examination of the reproductive tract as well as their genetic correlations with traditional reproductive traits. A total of 226,141 calving and insemination records as well as 74,134 ultrasound records from Irish dairy cows were used. Traditional reproductive traits included postpartum interval to first service, conception, and next calving, as well as the interval from first to last service; number of inseminations, pregnancy rate to first service, pregnant within 42 d of the herd breeding season, and submission in the first 21 d of the herd breeding season were also available. Detailed reproductive traits included resumed cyclicity at the time of ultrasound examination, incidence of multiple ovulations, incidence of early postpartum ovulation, heat detection, ovarian cystic structures, embryo loss, and uterine score; the latter was a subjectively assessed on a scale of 1 (little fluid with normal uterine tone) to 4 (large quantity of fluid with a flaccid uterine tone). Variance (and covariance) components were estimated using repeatability animal linear mixed models. Heritability for all reproductive traits were generally low (0.001-0.05), with the exception of traits related to cyclicity postpartum, regardless if defined traditionally (0.07; calving to first service) or from ultrasound examination [resumed cyclicity at the time of examination (0.07) or early postpartum ovulation (0.10)]. The genetic correlations among the detailed reproductive traits were generally favorable. The exception was the genetic correlation (0.29) between resumed cyclicity and uterine score; superior genetic merit for cyclicity postpartum was associated with inferior uterine score. Superior genetic merit for most traditional reproductive traits was associated with superior genetic merit for resumed cyclicity (genetic correlations ranged from -0.59 to -0.36 and from 0.56 to 0.70) and uterine score (genetic correlations ranged from -0.47 to 0.32 and from 0.25 to 0.52). Genetic predisposition to an increased incidence of embryo loss was associated with both an inferior uterine score (0.24) and inferior genetic merit for traditional reproductive traits (genetic correlations ranged from -0.52 to -0.42 and from 0.33 to 0.80). The results from the present study indicate that selection based on traditional reproductive traits, such as calving interval or days open, resulted in improved genetic merit of all the detailed reproductive traits evaluated in this study. Additionally, greater accuracy of selection for calving interval is expected for a relatively small progeny group size when detailed reproductive traits are included in a multitrait genetic evaluation.

A phase II, open-label, multicenter study to evaluate the antitumor efficacy of CO-1.01 as second-line therapy for gemcitabine-refractory patients with stage IV pancreatic adenocarcinoma and negative tumor hENT1 expression.

BACKGROUND: Nucleotide transporters such as human equilibrative nucleoside transporter-1 (hENT1) play a major role in transporting gemcitabine into cells. CO-1.01 (gemcitabine-5'-elaidate) is a novel cytotoxic agent consisting of a fatty acid derivative of gemcitabine, which is transported intracellularly independent of hENT1. CO-1.01 was postulated to have efficacy as a second-line treatment in gemcitabine-refractory pancreatic adenocarcinoma in patients with negative tumor hENT1 expression. METHODS: Eligibility criteria included patients with either a newly procured or archival biopsy tumor confirming the absence of hENT1 and either gemcitabine-refractory metastatic pancreas adenocarcinoma or with progression of disease following resection during or within 3 months of adjuvant gemcitabine therapy. Patients were treated with intravenous infusion of CO-1.01 dosed at 1250 mg/m(2) on Days 1, 8, and 15 of a 4-week cycle. The primary end point was disease control rate (DCR). RESULTS: Nineteen patients were enrolled of which 18 patients were evaluable for efficacy assessment. Thirteen patients (68%) had liver metastases, 6 (32%) had lymph node metastases, and 10 (53%) had lung metastases. Two of 18 patients (11%) achieved disease control. The median survival time was 4.3 (95% CI 2.1-8.1) months. All patients experienced at least one treatment-related adverse event with the majority of events being mild or moderate. CONCLUSION: This study did not meet its primary endpoint and no efficacy signal was identified for CO-1.01 in treating progressive metastatic pancreas adenocarcinoma.

Ovarian structures and uterine environment are associated with phenotypic and genetic merit for performance in lactating dairy cows.

The objective of this study was to estimate the association between detailed reproductive phenotypes for cows categorized as divergent for phenotypic and genetic performance. The hypothesis was that higher yielding animals, either phenotypically or genetically, would have compromised ovarian and uterine reproductive performance. Detailed reproductive traits including multiple ovulations, cystic ovarian structures, corpus luteum (CL) presence, and uterine environment were available on 9675 ultrasound records from 8174 dairy lactating cows, calved between 10 and 70 days. Cows were categorized, within parity, into low, average, or high for each of the performance traits. There was a greater likelihood of multiple ovulations in cows with greater phenotypic yields (odds ratio: 1.53-1.81) and greater genetic merit for yield (odds ratio: 1.31-1.59) relative to lower performing contemporaries. After adjustment for genetic merit, a similar trend of increased odds (odds ratio: 1.29-1.87) of multiple ovulations in higher yielding cows was observed compared with the lowest yielding category. There was no association between either phenotypic milk composition or genetic merit for milk composition with the likelihood of multiple ovulations. The likelihood of cystic ovarian structures was highest in cows with greatest phenotypic milk yields (odds ratio: 2.75-3.24), greater genetic merit for milk yield (odds ratio: 1.30-1.51), and even after adjustment for genetic merit there was a greater likelihood of cystic ovarian structures in cows with the highest milk yields (odds ratio: 2.71-2.95), compared with cows in the lowest category for each of the milk traits. Cows with average phenotypic milk yields were more likely to have a CL, compared with the lowest yielding category (odds ratio: 1.20-1.23), and these associations remained after adjustment for genetic merit of the trait. The likelihood of CL presence was highest in cows with the lowest genetic merit for milk. Lower fat:protein ratio was associated with an increased likelihood of CL presence compared with cows with greater fat:protein ratio and cows with the highest phenotypic milk composition were more likely to have a CL compared with cows in the lowest composition category. Genetic predisposition to higher somatic cell score was associated with a reduced risk of multiple ovulations (odds ratio: 0.69; 95% CI: 0.55-0.87) but an increased likelihood of CL presence (odds ratio: 2.66; 95% CI: 2.09-3.37) and poorer uterine health score (odds ratio: 1.36; 95% CI: 1.20-1.55). There was a lower likelihood of multiple ovulations, cystic ovarian structures, and poorer uterine health and an increased likelihood of CL presence in cows with superior genetic merit for reproductive performance and survival.

Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer.

BACKGROUND: Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer. METHODS: Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0-2 were treated with panitumumab 6 mg kg(-1), GEM 1000 mg m(-2) (10 mg m(-2) min(-1)) and OX 85 mg m(-2) on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival. RESULTS: Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5-24 months) and median overall survival 20.3 months (95% CI 9-25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%. CONCLUSIONS: The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.

Risk factors associated with multiple ovulation and twin birth rate in Irish dairy and beef cattle.

The objective of this study was to quantify the phenotypic and genetic risk factors associated with multiple ovulations and twin births in cattle. Prevalence and cow- and herd-level risk factors associated with ovulation rate were determined using 40,617 ultrasonographic records of the reproductive tract from 27,907 dairy and beef cows from 738 commercial herds. Prevalence of twin births was estimated from the Irish national database containing 23,658,351 calving events from 8,546,695 cows from 125,251 dairy and beef herds; factors associated with twin births were determined using a random subsample of 505,200 calving events from 280,638 cows in 81,329 herds. The mean prevalence of multiple ovulations was 6.83% while the prevalence of twin births was 1.74%. Occurrence of both multiple ovulations and twin births was associated with the month of scan (P < 0.0001) and month of calving (P < 0.0001), respectively, and peaked in November for multiple ovulations and October for twin births. The likelihood of multiple ovulations increased with interval postpartum and peaked between 45 to 185 d postcalving, after which the likelihood declined. The likelihood of both multiple ovulations (P < 0.0001) and twin births (P < 0.0001) increased with increasing cow parity. A greater proportion of Holstein, Friesian, Simmental, Hereford, and Charolais breed fractions were associated with a greater likelihood of multiple ovulations. There was no difference between breed proportion of the cow and incidence of twin births, where all breed proportions examined, litter difference existed among breeds in their association with risk of twin births. Although multiple ovulations were lowly heritable (0.028 ± 0.003), their occurrence was repeatable (0.326 ± 0.342) while twin birth rate in cattle was lowly heritable (0.017 ± 0.004) and repeatable (0.018 ± 0.011). The genetic SD of the presence of multiple ovulations and twin births was 0.04 and 0.02, respectively, indicating considerable genetic variation, especially for multiple ovulations. A moderate genetic correlation (0.66 ± 0.16) existed between multiple ovulations and twin births.

Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer.

BACKGROUND: To determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab and safety and efficacy of this combination in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Patients with Magnetic resonance imaging (MRI) or ultrasound defined T3 or T4 adenocarcinoma of the rectum and without evidence of metastatic disease were enrolled. Patients received infusional 5-FU 225 mg/M2/day continuously, along with bevacizumab 5 mg/kg days 14, 1, 15 and 29. Standard radiotherapy was administered to 50.4 Gy in 28 fractions. Erlotinib started at a dose of 50 mg orally daily and advanced by 50 mg increments in the subsequent cohort. Open total mesorectal excision was carried out 6-9 weeks following the completion of chemoradiation. RESULTS: Thirty-two patients received one of three dose levels of erlotinib. Erlotinib dose level of 100 mg was determined to be the maximally tolerated dose. Thirty-one patients underwent resection of the primary tumor, one refused resection. Twenty-seven patients completed study therapy, all of whom underwent resection. At least one grade 3-4 toxicity occurred in 46.9% of patients. Grade 3-4 diarrhea occurred in 18.8%. The pathologic complete response (pCR) for all patients completing study therapy was 33%. With a median follow-up of 2.9 years, there are no documented local recurrences. Disease-free survival at 3 years is 75.5% (confidence interval: 55.1-87.6%). CONCLUSIONS: Erlotinib added to infusional 5-FU, bevacizumab and radiation in patients with locally advanced rectal cancer is relatively well tolerated and associated with an encouraging pCR.

Mechanisms of RNA-induced toxicity in CAG repeat disorders.

Several inherited neurodegenerative disorders are caused by CAG trinucleotide repeat expansions, which can be located either in the coding region or in the untranslated region (UTR) of the respective genes. Polyglutamine diseases (polyQ diseases) are caused by an expansion of a stretch of CAG repeats within the coding region, translating into a polyQ tract. The polyQ tract expansions result in conformational changes, eventually leading to aggregate formation. It is widely believed that the aggregation of polyQ proteins is linked with disease development. In addition, in the last couple of years, it has been shown that RNA-mediated mechanisms also have a profound role in neurotoxicity in both polyQ diseases and diseases caused by elongated CAG repeat motifs in their UTRs. Here, we review the different molecular mechanisms assigned to mRNAs with expanded CAG repeats. One aspect is the mRNA folding of CAG repeats. Furthermore, pathogenic mechanisms assigned to CAG repeat mRNAs are discussed. First, we discuss mechanisms that involve the sequestration of the diverse proteins to the expanded CAG repeat mRNA molecules. As a result of this, several cellular mechanisms are aberrantly regulated. These include the sequestration of MBNL1, leading to misregulated splicing; sequestration of nucleolin, leading to reduced cellular rRNA; and sequestration of proteins of the siRNA machinery, resulting in the production of short silencing RNAs that affect gene expression. Second, we discuss the effect of expanded CAG repeats on the subcellular localization, transcription and translation of the CAG repeat mRNA itself. Here we focus on the MID1 protein complex that triggers an increased translation of expanded CAG repeat mRNAs and a mechanism called repeat-associated non-ATG translation, which leads to proteins aberrantly translated from CAG repeat mRNAs. In addition, therapeutic approaches for CAG repeat disorders are discussed. Together, all the findings summarized here show that mutant mRNA has a fundamental role in the pathogenesis of CAG repeat diseases.

A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors.

The IGF pathway has been implicated in the regulation of neuroendocrine tumor (NET) growth, and preliminary studies suggested that ganitumab (AMG 479), a human MAB against IGF1R, may have antitumor activity in this setting. We performed a two-cohort phase II study of ganitumab in patients with metastatic progressive carcinoid or pancreatic NETs (pNETs). This open-label study enrolled patients (≥18 years) with metastatic low- and intermediate-grade carcinoid or pNETs. Inclusion criteria included evidence of progressive disease (by Response Evaluation Criteria in Solid Tumors (RECIST)) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar <160  mg/dl. Prior treatments were allowed and concurrent somatostatin analog therapy was permitted. The primary endpoint was objective response. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Sixty patients (30 carcinoid and 30 pNETs) were treated with ganitumab 18  mg/kg every 3 weeks, among whom 54 patients were evaluable for survival and 53 patients for response. There were no objective responders by RECIST. The median PFS duration was 6.3 months (95% CI, 4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients, and 4.2 months for pNET patients. The OS rate at 12 months was 66% (95% CI, 52-77%) for the entire cohort. The median OS has not been reached. Grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%), and infusion reaction (1%). Although well tolerated, treatment with single-agent ganitumab failed to result in significant tumor responses among patients with metastatic well-differentiated carcinoid or pNET.

Sunitinib in combination with gemcitabine for advanced solid tumours: a phase I dose-finding study.

BACKGROUND: This phase I, dose-finding study determined the maximum tolerated dose (MTD), safety, and pharmacokinetics of sunitinib plus gemcitabine in patients with advanced solid tumours. METHODS: Two schedules with sunitinib (25-50 mg per day) and IV gemcitabine (750-1250 mg m(-2)) in escalating doses were studied. First, patients received sunitinib on a 4-weeks-on-2-weeks-off schedule (Schedule 4/2) plus gemcitabine on days 1, 8, 22, and 29. Second, patients received sunitinib on a 2-weeks-on-1-week-off schedule (Schedule 2/1) plus gemcitabine on days 1 and 8. The primary endpoint was determination of MTD and tolerability. RESULTS: Forty-four patients received the combination (Schedule 4/2, n=8; Schedule 2/1, n=36). With no dose-limiting toxicities (DLTs) at maximum dose levels on Schedule 2/1, MTD was not reached. Grade 4 treatment-related AEs and laboratory abnormalities included cerebrovascular accident, hypertension, and pulmonary embolism (n=1 each), and neutropenia (n=3), thrombocytopenia and increased uric acid (both n=2), and lymphopenia (n=1). There were no clinically significant drug-drug interactions. Antitumor activity occurred across dose levels and tumour types. In poor-risk and/or high-grade renal cell carcinoma patients (n=12), 5 had partial responses and 7 stable disease ≥ 6 weeks. CONCLUSION: Sunitinib plus gemcitabine on Schedule 2/1 with growth factor support was well tolerated and safely administered at maximum doses of each drug, without significant drug-drug interactions.