EGFR-targeted therapy

Anti-Epidermal Growth Factor Receptor (EGFR) therapies have been recently developed for the treatment of multiple cancer types. At the time when they were introduced in clinical practice, there was little knowledge of the molecular bases of tumor sensitivity and resistance to these novel targeted compounds. By using the framework of anti-EGFR inhibitors as treatment for colorectal cancer patients, we will review the knowledge we have reached until now in improving the development of a personalized cancer therapy and we will try to indicate the future challenges this field will face in the future.     

Subgrouping Patterns in a Group of Wild <Emphasis Type="Italic">Cebus apella nigritus</Emphasis>

Seasonal patterns of group fragmentation, including the size of subgroups and percentage of time spent in subgroups, may provide information on individual decision-making in response to resource distribution. Age-sex class composition of subgroup membership can offer insights into the social dynamics of the group as a whole. At most field sites, capuchins (Cebus spp.) form stable groups with no evidence of group fragmentation. Here I describe seasonal subgrouping patterns, including proportion of time spent in subgroups, subgroup size, age-sex membership, dyadic fidelity, stability of membership, and the effect of subgrouping on individual foraging efficiency, in a group of wild Cebus apella nigritus. From September 1996 to August 1997 the study group at the Estação Biológica de Caratinga, Brazil divided into 148 different subgroups, on 99 of 194 census days. In contrast to expectations for subgrouping patterns as a response to seasonal distribution of resources, the proportion of days spent in subgroups did not vary significantly by season. Subgroup composition was relatively fluid, with multimale multifemale subgroups the most common throughout the year. Unimale multifemale subgroups were restricted to the wet season; in contrast, all-male subgroups and unimale unifemale subgroups occurred in the dry season. For both males and females, low rank predicted membership in smaller subgroups. For males, but not females, subgrouping coincided with increased foraging efficiency, as measured by increased time spent ingesting food and decreased time spent traveling on days with subgrouping compared to days with the group in a cohesive unit.     

Increased plasma α (1 → 3)-l-fucosyltransferase activities in patients with hepatocellular carcinoma

Alpha(1 3)-l-fucosyltransferase (1,3FT) activity was determined in plasma of patients with chronic liver diseases, namely, chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The plasma 1,3FT activity was significantly higher (p<0.01) in chronic liver diseases than that in normal controls. The enzyme activity in plasma of patients with HCC was also significantly higher than that in LC (p<0.05) or that in CH (p<0.01). However, no significant difference was observed in the enzyme activity between LC and CH. Plasma 1,3FT activity in patients with HCC was not significantly changed before and after transcatheter arterial embolization. In addition, the enzyme activity in the homogenate of the cirrhotic liver tissue was higher than that in the preparation of the hepatoma tissue in the same patient. These results suggest that the increased plasma 1,3FT activity in patients with HCC reflects mainly the enzyme activity of cirrhotic liver tissue, not that of hepatoma tissue. The significance of the elevated levels of plasma 1,3FT and its decreased hepatoma tissue activity in patients with HCC, compared with that in LC, remains to be clarified.     

Recognition of Fusobacterium nucleatum subgroups Fn-1, Fn-2 and Fn-3 by ribosomal RNA gene restriction patterns

DNA from representative strains of Fusobacterium nucleatum subgroups Fn-1, Fn-2 and Fn-3 was digested with restriction enzymes EcoRI and TaqI and the electrophoretically separated fragments hybridized with a 32P-16S rRNA gene probe from E. coli. The rRNA gene restriction patterns from DNA digested with either enzyme allowed the clustering of strains into the three subgroups. However, TaqI digested DNA yielded a wider distribution of taxonomically useful bands (ca 0.65 +/- 14.3 kbp) and the pattern produced was characteristic of each subgroup. The present method is a simple and reliable means of identifying the three subgroups of F. nucleatum and provides a useful method for further studies of the heterogeneity of F. nucleatum.     

Bayesian treatment screening and selection using subgroup-specific utilities of response and toxicity

A Bayesian design is proposed for randomized phase II clinical trials that screen multiple experimental treatments compared to an active control based on ordinal categorical toxicity and response. The underlying model and design account for patient heterogeneity characterized by ordered prognostic subgroups. All decision criteria are subgroup specific, including interim rules for dropping unsafe or ineffective treatments, and criteria for selecting optimal treatments at the end of the trial. The design requires an elicited utility function of the two outcomes that varies with the subgroups. Final treatment selections are based on posterior mean utilities. The methodology is illustrated by a trial of targeted agents for metastatic renal cancer, which motivated the design methodology. In the context of this application, the design is evaluated by computer simulation, including comparison to three designs that conduct separate trials within subgroups, or conduct one trial while ignoring subgroups, or base treatment selection on estimated response rates while ignoring toxicity.     

Population structure of Salmonella investigated by amplified fragment length polymorphism

AIMS: This study was undertaken to investigate the usefulness of amplified fragment length polymorphism (AFLP) in determining the population structure of Salmonella. METHODS AND RESULTS: A total of 89 strains were subjected to AFLP analysis using the enzymes BglII and BspDI, a combination that is novel in Salmonella. Both species S. bongori and S. enterica and all subsp. of S. enterica were represented with emphasis on S. enterica subsp. enterica using a local strain collection and strains from the Salmonella Reference Collection B (SARB). The amplified fragments were used in a band-based cluster analysis. The tree resulting from the subgroup analysis clearly separated all subgroups with high bootstrap values with the species S. bongori being the most distantly related of the subgroups. The tree resulting from the analysis of the SARB collection showed that some serotypes are very clonal whereas others are highly divergent. CONCLUSIONS: AFLP clearly clustered strains representing the subgroups of Salmonella together with high bootstrap values and the serotypes of subspecies enterica were divided into polyphyletic or monophyletic types corresponding well with multilocus enzyme electrophoresis (MLEE) and sequence-based studies of the population structure in Salmonella. SIGNIFICANCE AND IMPACT OF THE STUDY: AFLP with the enzyme combination BglII and BspDI allows discrimination of individual strains and provides evidence for the usefulness of AFLP in studies of population structure in Salmonella.     

DNA methylation profiles in primary cutaneous melanomas are associated with clinically significant pathologic features

DNA methylation studies have elucidated a methylation signature distinguishing primary melanomas from benign nevi and provided new insights about genes that may be important in melanoma development. However, it is unclear whether methylation differences among primary melanomas are related to tumor pathologic features with known clinical significance. We utilized the Illumina GoldenGate Cancer Panel array to investigate the methylation profiles of 47 primary cutaneous melanomas. Arraywide methylation patterns revealed a positive association of methylation with Breslow thickness and mutated BRAF, a negative association with mitotic rate, and a weak association with ulceration. Hierarchical clustering on CpG sites exhibiting the most variable methylation (n = 235) divided the melanoma samples into three clusters, including a highly methylated cluster that was positively associated with Breslow thickness and an intermediately methylated cluster associated with Breslow thickness and mitotic rate. Our findings provide support for the existence of methylation‐defined subsets in melanomas with increased methylation associated with Breslow thickness.     

四种杂交组合奥尼罗非鱼及其亲本的生长对比研究

通过RFID电子标记注射、跟踪和生长性状测量,对2个奥利亚罗非鱼品系(ZZ、AA)、2个尼罗罗非鱼品系(XX、EE)自交群体及其杂交奥尼罗非鱼4个群体(XZ、XA、EZ、EA)进行生长对比研究,罗非鱼亲本来自国家罗非鱼产业技术体系研发中心。结果表明:XZ、XA、EZ、EA四个奥尼罗非鱼群体雄性率均达94%以上,全长、体长、头长、体高等性状特征值显著高于亲本品系(P<0.05),奥尼罗非鱼的生长速率相对其亲本品系具有一定的优势,同时4个奥尼群体间生长性状特征值也存在显著差异(P<0.05);生长性状相关分析显示罗非鱼各配组群体的体质量与尾柄长相关性较低(0.690—0.846),与全长、体长、体高、体厚相关性较高;对罗非鱼各配组群体的比例性状进行主成分分析,第1主成分主要代表BS、HS、CDS、BWS性状特征,第2主成分主要代表TS、HS、CLS性状特征,通过第1、第2主成分作图可将AA与其他6个罗非鱼配组群体有效区分。     

Biomarker-based precision dose finding for immunotherapy combined with radiotherapy

Recent success of sequential administration of immunotherapy following radiotherapy (RT), often referred to as immunoRT, has sparked the urgent need for novel clinical trial designs to accommodate the unique features of immunoRT. For this purpose, we propose a Bayesian phase I/II design for immunotherapy administered after standard-dose RT to identify the optimal dose that is personalized for each patient according to his/her measurements of PD-L1 expression at baseline and post-RT. We model the immune response, toxicity, and efficacy as functions of dose and patient's baseline and post-RT PD-L1 expression profile. We quantify the desirability of the dose using a utility function and propose a two-stage dose-finding algorithm to find the personalized optimal dose. Simulation studies show that our proposed design has good operating characteristics, with a high probability of identifying the personalized optimal dose.     

Variability in spider monkeys' vocalizations may provide basis for individual recognition

Analysis of long-range vocalizations given by spider monkeys revealed consistent acoustic differences among the calls of individuals. Of seven acoustic measurements, four exhibited significant variation between individuals. A discriminant analysis demonstrated that two of these variables allowed correct identification of the caller 44% of the time. Including the remainder of the variables increased the percentage correctly identified to 50%. Individual identification by call structure could benefit spider monkeys, where individuals forage separately in subgroups and the interactions between specific pairs of individuals is highly variable. Acoustic recognition of callers would facilitate the choice of which subgroups to join, thus allowing individuals to manipulate the size and composition of their subgroups. In addition, the calls of mothers and offspring appeared to be similar in acoustic properties.