Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy. Copyright (C) 2012 S. Karger AG, Base

Systemic Biomarkers of Neutrophilic Inflammation, Tissue Injury and Repair in COPD Patients with Differing Levels of Disease Severity

The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV1, FEV1/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV1/FVC were stronger in patients without metabolic syndrome (r  =  −0.52, p  = 0.005 and r  =  −0.61, p  = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r  =  −0.25, p  = 0.47 and r  =  −0.15, p  = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV1, FEV1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD

Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility “Hot-Spot”

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs—PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616—were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04–1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus

Gamete Therapeutics: Recombinant Protein Adsorption by Sperm for Increasing Fertility via Artificial Insemination

A decrease in fertility can have a negative economic impact, both locally and over a broader geographical scope, and this is especially the case with regard to the cattle industry. Therefore, much interest exists in evaluating proteins that might be able to increase the fertility of sperm. Heparin binding proteins (HBPs), specifically the fertility associated antigen (FAA) and the Type-2 tissue inhibitor of metalloproteinase (TIMP-2), act to favor the capacitation and acrosome reaction and perhaps even modulate the immune system's response toward the sperm. The objective of this research was to determine the effect on fertility of adding recombinant FAA (rFAA) and recombinant TIMP-2 (rTIMP-2) to bovine semen before cryopreservation for use in an artificial insemination (AI) program in a tropical environment. For this experiment, 100 crossbred (Bos taurus x Bos indicus) heifers were selected based on their estrus cycle, body condition score (BCS), of 4 to 6 on a scale of 1 to 9, and adequate anatomical conformation evaluated by pelvic and genital (normal) measurements. Heifers were synchronized using estradiol benzoate (EB), Celosil® (PGF2α) (Shering-Plough) and a controlled internal drug release (CIDR) device was inserted that contained progesterone. Inseminations were performed in two groups at random, 50 animals per group. The control group was inseminated with conventional semen. The treatment group was inseminated with semen containing rFAA (25 µg/mL) and rTIMP-2 (25 µg/mL). In the control group a 16% pregnancy rate was obtained versus a 40% pregnancy rate for the HBP treatment group, resulting in a significant difference (P = 0.0037). Given the results herein, one may conclude that the HBPs can increase fertility and could be an option for cattle in tropical conditions; however, one needs to consider the environment, nutrition, and the genetic interaction affecting the final result in whatever reproductive program that is implemented

The detection of estrus in cattle raised under tropical conditions: What we know and what we need to know

Lack of accuracy in estrus detection in cattle is a major constraint affecting the implementation of techniques such as artificial insemination (Al) and embryo transfer (ET). For this reason clinicians have opted to pharmacologically manipulate the estrus cycle. The advantages and shortcomings of using this approach to improve the implementation of Al and ET are discussed in this review. Moreover, in order to highlight the reasons why estrus detection is difficult in cows kept at grazing in the tropics, this review underlines social and behavioral traits hindering the capacity of the casual observer to accurately identify cows in estrus. (c) 2007 Elsevier Inc. All rights reserved

Progestagen-induced oestrous response in Holstein cows and its influence on the sexual behaviour of non-treated pen mates

Grouped cows with oestrous cycles synchronised by the use of synthetic progestagen (SMB) appear to increase the degree of synchrony among them and this may enhance sexual behaviour in untreated herd mates. One hundred and twenty cycling cows were equally divided among three pens. For the first three days of the experiment, nine cows were induced to display oestrus on each of the three days. On the first day, one cow was programmed in pen 1, in pen 2, and three in pen 3, The following day, the number of cows were three, one, and five, respectively, and on the third day, live, three, and one, in the respective pens. Nine other cows per pen were stimulated to show high levels of progesterone during the expected oestrus of the synchronised ones. The number of animals artificially induced into oestrus was directly related to the number of non-treated herd mates showing sexual behaviour (r = 0.96, P 0.05) in oestrous lengths, onset of oestrus, and sexual activity (mounts given and received) among treatments. Animals with exogenous high levels of P-4 did not participate in sexual activities. It was concluded that a group of animals induced into oestrus by a synchronisation treatment may favour cycling herd mates to display concomitant oestrous behaviour

Cows treated with Synchromate B may cluster their sexual behaviour independent of follicular growth at the time of oestrus

In order to study the relative influence of social versus hormonal influences on sexual behaviour, three groups were formed from a herd of 16 Brahman cows, two of which groups were synchronized, implanting the second group the day the first had the Synchromate B (SMB) withdrawn. The third group was the untreated control. Cows in the sexually active group (SAG) were subjected to an intensive ultrasound (US) schedule to monitor ovarian activity. Alternatively, US examinations and progesterone (P-4) samples were obtained twice weekly starting one week before the SMB implant until one week after the last implant was removed. Twenty mounting series involving 13 cows were observed. All cows in Groups 1 and 2 and 50% of controls displayed mounting behaviour, grouped on two periods. Seven cows showed mounting activity on both periods (8 days apart). Three cows in Group 2 (60%) displayed riding behaviour when the SMB implant was in place. No differences (P=.39) were found between the average size of the major follicle from animals displaying oestrus at the expected time (6.95 +/- 2.6 mm), and those displaying oestrus outside this period in harmony with induced animals (7.79 +/- 1.5 mm), nor (P=. 7 1) between treated (7.72 +/- 2.0 mm) and untreated (7.28 +/- 2.1 mm) cows. It is concluded that treated and untreated animals, and even cows with an implant in place, may display mounting activity concomitantly with oestrous-induced cows and this behaviour is not driven by follicular size at the time of the expected oestrus. Furthermore, the follicular development suggests that SMB treatment does not impede and may even enhance oestrous response in certain cows when applied together with exogenous estrogens. (C) 2002 Elsevier Science Inc. All rights reserved

Consequences of different suckling systems for reproductive activity and productivity of cattle in tropical conditions

The late onset of ovarian activity in mature cattle raised under tropical conditions is the major setback impeding a sound reproductive performance needed for the increasing demand of Livestock products in the area. The effect of suckling has been circled as one of the most important factors impeding ovarian activity. Farmers in this region have used the most diverse set of management tools to overcome the suckling effect without compromising reproduction, the health of the calf, growth until weaning, milk production and a correct function of the mammary gland. Farmer interventions can be divided in: (1) early weaning (about 1 week of age

Sexual behavior of Zebu cattle (Bos indicus) following estrous induction by Syncro-Mate B, with or without estrogen injection

The effect of estrogen administered with norgestomet implants in the expression of behavioral estrous of Zebu cattle was studied in a herd of Is cycling Brahman cows, in two trials. In the first and second trials, six different cows were treated with progestagen on successive days. In addition, in the first trial, estrogen injection was applied with the treatment. With the purpose of enhancing mounting behavior in treated and/or non-treated animals, on the third day of each trial, three other cows with an active CL were injected with 25 mg of PGF(2)alpha. All animals were examined three times a week by rectal ultrasound, and a blood sample was also taken for progesterone analysis. Sexual activity was monitored by a closed-circuit TV from 1500 to 0600 h. Direct observation was carried out from 0900 to 1200 h. A total of 15 cows displayed 36 mounting periods (11 with ovulation). Twenty-five annovulatory estrous periods were observed, 77% supported by large follicles. More cows (66% vs. 16%) showed mounting activity when estradiol valerate was used as part of the progestagen treatment (P=.03). Ovulation rate in response to the effect of norgestomet implant was 16%, independent of treatment. It is concluded that estrogen administered with norgestomet implants increases the expression of behavioral estrous in Bos indicus cattle but does not improve ovulation rate. (C) 2000 Elsevier Science Inc. All rights reserved