Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: IGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. METHODS: Patients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). RESULTS: 61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1-18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8-89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0-3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8-2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. CONCLUSIONS: IGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Use of mesenchymal stem cells for cutaneous repair and skin substitute elaboration.

Human mesenchymal stem cells (MSCs) are a heterogeneous population of fibroblast-like cells, which are present in different locations, including bone marrow, adipose tissue, extra-foetal tissues, gingiva and dermis. MSCs, which present multipotency capacities, important expansive potential and immunotolerance properties, remain an attractive tool for tissue repair and regenerative medicine. Currently, several studies and clinical trials highlight the use of MSCs in cutaneous repair underlining that their effects are essentially due to the numerous factors that they release. MSCs are also used in skin substitute development. In this study, we will first discuss the different sources of MSCs actually available. We will then present results showing that bone marrow-derived MSCs prepared according to Good Manufacturing Practices and included in a dermal equivalent are able to promote appropriate epidermis growth and differentiation. These data demonstrate that bone marrow-derived MSCs represent a satisfactory alternative to dermal fibroblasts in order to develop skin substitute. In addition, MSCs could provide a useful alternative to sustain epidermis development and to promote wound healing.

Analysis of the medical causes of death in cerebral palsy.

AIM: To investigate causes of death and age at death in cerebral palsy subjects compared with the general population. METHOD: Analysis of data supplied by the centre of epidemiology on the medical causes of death within the National Institute of Health and Medical Research in France was conducted. Three thousand and thirty-one death certificates indicating a diagnosis of cerebral palsy (ICD-10 code G80) were reported between 2000 and 2008. RESULTS: Median age at death was between 45-54 years and principal cause of death (24%) comprised the category "symptoms, signs, and abnormal results of clinical and laboratory tests, not classified elsewhere". Of these, 66% were related to the circulatory and respiratory systems. "Diseases of the respiratory system" were the second most common cause of death (19% compared with 6% in the French general population). The third most common cause of death was "diseases of the circulatory system" (15% compared with 29% in the French general population). While deaths caused by tumour pathologies in the general population are the most common cause of deaths, these represented only 7% of deaths in subjects with cerebral palsy. INTERPRETATION: These results concur with other published data, i.e. subjects with cerebral palsy die younger than the French general population, and the principal causes of death are respiratory and circulatory problems. This study emphasises the importance of access to epidemiological data about the French cerebral palsy population.

Abnormal apical-to-basal transport of dietary ovalbumin by secretory IgA stimulates a mucosal Th1 response.

In celiac disease, enhanced permeability to gliadin peptides can result from their apico-basal transport by secretory immunoglobulin A1 (SIgA1) binding to the CD71 receptor ectopically expressed at the gut epithelial surface. Herein, we have established a mouse model in which there is apico-basal transport of the model antigen ovalbumin (OVA) by specific SIgA1 and have analyzed local T-cell activation. Transgenic DO11.10 mice were grafted with a hybridoma-secreting OVA-specific humanized IgA1, which could bind mouse CD71 and which were released in the intestinal lumen as SIgA. CD71 expression was induced at the gut apical surface by treating the mice with tyrphostin A8. Following gavage of the mice with OVA, OVA-specific CD4⁺ T cells isolated from the mesenteric lymph nodes displayed higher expression of the activation marker CD69 and produced more interferon gamma in mice bearing the hybridoma-secreting OVA-specific IgA1, than in ungrafted mice or in mice grafted with an irrelevant hybridoma. These results indicate that the protective role of SIgA1 might be jeopardized in human pathological conditions associated with ectopic expression of CD71 at the gut surface.

[Occupational physicians and occupational cancers: attitudes, opinions, practices. A qualitative study in South Eastern France]. / Médecins du travail et cancers professionnels : attitudes, opinions et pratiques. Une recherche qualitative dans le Sud-Est de la France.

BACKGROUND: A qualitative study was conducted in 2008 of occupational physicians (OPs) in south-eastern France to document their attitudes, opinions and practices on prevention and screening of occupational cancers. This was done to provide elements to prepare the questionnaire of a quantitative study in 2009. METHODS: Semi-structured interviews were conducted using a structured interview guide with 20 OPs. The data collected were subjected to an analysis of thematic content type. RESULTS: The analysis revealed that OPs face many difficulties when preventing occupational cancers. For most of OPs, these difficulties appeared related to "external factors": lack of involvement of employers and minimization of risks by employers and employees. Lack of time, overload and, for some OPs, perceived lack of independence towards employers, were also mentioned as barriers to cancer prevention. This study also suggested hypotheses related to OPs themselves (internal factors): perceived lack of effectiveness and, trend to minimize the risks of occupational cancer in their geographical area. Finally, the results suggest a significant heterogeneity of OPs' practices regarding occupational cancer screening. CONCLUSION: These results raise several hypotheses that will be addressed further in the quantitative survey. They warn about the difficulties of a profession that seems to encounter a demographic and identity crisis.

A high-density genetic map of hexaploid wheat (Triticum aestivum L.) from the cross Chinese Spring x SQ1 and its use to compare QTLs for grain yield across a range of environments.

A population of 96 doubled haploid lines (DHLs) was prepared from F1 plants of the hexaploid wheat cross Chinese Spring x SQ1 (a high abscisic acid-expressing breeding line) and was mapped with 567 RFLP, AFLP, SSR, morphological and biochemical markers covering all 21 chromosomes, with a total map length of 3,522 cM. Although the map lengths for each genome were very similar, the D genome had only half the markers of the other two genomes. The map was used to identify quantitative trait loci (QTLs) for yield and yield components from a combination of 24 site x treatment x year combinations, including nutrient stress, drought stress and salt stress treatments. Although yield QTLs were widely distributed around the genome, 17 clusters of yield QTLs from five or more trials were identified: two on group 1 chromosomes, one each on group 2 and group 3, five on group 4, four on group 5, one on group 6 and three on group 7. The strongest yield QTL effects were on chromosomes 7AL and 7BL, due mainly to variation in grain numbers per ear. Three of the yield QTL clusters were largely site-specific, while four clusters were largely associated with one or other of the stress treatments. Three of the yield QTL clusters were coincident with the dwarfing gene Rht-B1 on 4BS and with the vernalisation genes Vrn-A1 on 5AL and Vrn-D1 on 5DL. Yields of each DHL were calculated for trial mean yields of 6 g plant(-1) and 2 g plant(-1) (equivalent to about 8 t ha(-1) and 2.5 t ha(-1), respectively), representing optimum and moderately stressed conditions. Analyses of these yield estimates using interval mapping confirmed the group-7 effects on yield and, at 2 g plant(-1), identified two additional major yield QTLs on chromosomes 1D and 5A. Many of the yield QTL clusters corresponded with QTLs already reported in wheat and, on the basis of comparative genetics, also in rice. The implications of these results for improving wheat yield stability are discussed.

Indium- or Zinc-Mediated One-Pot Synthesis of Homoallylamines, beta-Amino Esters, and beta-Amino Nitriles.

Homoallylamines, beta-amino esters, and beta-amino nitriles were obtained in a one-pot synthesis directly from an aldehyde and a secondary amine such as dibenzylamine or diallylamine. Their condensation with titanium(IV) isopropoxide generates an intermediate aminoalkoxy titanium complex. Further reaction in THF with nucleophilic organometallic species, generated in situ from indium or zinc and a reactive halide (allyl bromide, alkyl bromo- or iodoacetate, iodoacetonitrile), furnished the corresponding amines.

Neuropathic arthropathy: a forgotten diagnosis? Two recent cases involving the hip.

Two cases of neuropathic arthropathy of the hip are reported. One was the first manifestation of tabes dorsalis in a 74-year-old man, whereas the second occurred in a 47-year-old woman with a history of spina bifida and L2-L5 epidural lipoma. Radiographic joint destruction occurred within five and three months, respectively. The main clinical and radiological features of neuropathic arthropathy are reviewed, and diagnostic pitfalls are discussed. There are no specific laboratory tests or histologic findings. This now rare condition should be routinely considered in patients with severe joint destruction contrasting with minimal pain. The reasons for the decision to use trochanteric-iliac coaptation in one of our patients and a wait-and-see approach in the other are explained. The literature is reviewed. Ten cases treated by joint replacement have been reported. However, neither joint replacement nor arthrodesis seem capable of restoring satisfactory hip function.

A nonparametric bootstrap method for testing close linkage vs. pleiotropy of coincident quantitative trait loci.

A novel method using the nonparametric bootstrap is proposed for testing whether a quantitative trait locus (QTL) at one chromosomal position could explain effects on two separate traits. If the single-QTL hypothesis is accepted, pleiotropy could explain the effect on two traits. If it is rejected, then the effects on two traits are due to linked QTLs. The method can be used in conjunction with several QTL mapping methods as long as they provide a straightforward estimate of the number of QTLs detectable from the data set. A selection step was introduced in the bootstrap procedure to reduce the conservativeness of the test of close linkage vs. pleiotropy, so that the erroneous rejection of the null hypothesis of pleiotropy only happens at a frequency equal to the nominal type I error risk specified by the user. The approach was assessed using computer simulations and proved to be relatively unbiased and robust over the range of genetic situations tested. An example of its application on a real data set from a saline stress experiment performed on a recombinant population of wheat (Triticum aestivum L. ) doubled haploid lines is also provided.

[Intramedullary metastases of bronchogenic carcinoma. Two cases]. / Métastases intramédullaires d'un cancer bronchique. Deux observations.

Intramedullary metastases are uncommon. We report two cases in patients with small cell bronchogenic cancer. The clinical diagnosis was supported by T1 magnetic resonance imaging after gadolinium injection. A unique medullary metastasis associated with other metastatic localizations was observed in the first patient and multiple intramedullary metastases alone in the second. These secondary intramedullary localizations were highly sensitive to chemotherapy after the first monthly cure in the first patient and after the third in the second patient. We emphasize the importance of chemotherapy in such cases, usually associated with focal radiotherapy.

Non-coherent near infrared radiation protects normal human dermal fibroblasts from solar ultraviolet toxicity.

The sun is the most important and universal source of non-ionizing radiation shed on human populations. Life evolved on Earth bathed by this radiation. Solar UV damages cells, leading to deleterious conditions such as photoaging and carcinogenesis in human skin. During the process of evolution, the cells selected dark- and light-dependent repair mechanisms as a defence against these hazardous effects. This study describes the induction by non-coherent infrared radiation (700-2000 nm), in the absence of rising temperature, of a strong cellular defense against solar UV cytotoxicity as well as induction of cell mitosis. Blocking mitoses with arabinoside-cytosine or protein synthesis with cycloheximide did not abolish the protection, leading to the conclusion that this protection is independent of cell division and of protein neosynthesis. The protection provided by infrared radiation against solar UV radiation is shown to be a long-lasting (at least 24 h) and cumulatif phenomenon. Infrared radiation does not protect the lipids in cellular membranes against UVA induced peroxidation. The protection is not mediated by heat shock proteins. Living organisms on the Earth's surface are bathed by infrared radiation every day, before being submitted to solar UV. Thus, we propose that this as yet undescribed natural process of cell protection against solar UV, acquired and preserved through evolutional selection, plays an important role in life maintenance. Understanding and controlling this mechanism could provide important keys to the prevention of solar UV damage of human skin.

Empirical nonparametric bootstrap strategies in quantitative trait loci mapping: conditioning on the genetic model.

Several nonparametric bootstrap methods are tested to obtain better confidence intervals for the quantitative trait loci (QTL) positions, i.e., with minimal width and unbiased coverage probability. Two selective resampling schemes are proposed as a means of conditioning the bootstrap on the number of genetic factors in our model inferred from the original data. The selection is based on criteria related to the estimated number of genetic factors, and only the retained bootstrapped samples will contribute a value to the empirically estimated distribution of the QTL position estimate. These schemes are compared with a nonselective scheme across a range of simple configurations of one QTL on a one-chromosome genome. In particular, the effect of the chromosome length and the relative position of the QTL are examined for a given experimental power, which determines the confidence interval size. With the test protocol used, it appears that the selective resampling schemes are either unbiased or least biased when the QTL is situated near the middle of the chromosome. When the QTL is closer to one end, the likelihood curve of its position along the chromosome becomes truncated, and the nonselective scheme then performs better inasmuch as the percentage of estimated confidence intervals that actually contain the real QTL's position is closer to expectation. The nonselective method, however, produces larger confidence intervals. Hence, we advocate use of the selective methods, regardless of the QTL position along the chromosome (to reduce confidence interval sizes), but we leave the problem open as to how the method should be altered to take into account the bias of the original estimate of the QTL's position.

QTL analysis to study the association between leaf size and abscisic acid accumulation in droughted rice leaves and comparisons across cereals.

Plants accumulate abscisic acid (ABA) under droughted conditions. Genetic variation in the accumulation of ABA in deteched and partially dehydrated leaves of rice has previously been reported, and this was found to be associated with variation in leaf size (smaller leaves made more ABA). Correlation analysis failed to distinguish clearly between a causal relationship between the two traits and close genetic between loci controlling the traits. Here we present a detailed genetic analysis of ABA accumulation in detached and partially dehydrated rice leaves. using a population of F2 plants generated from the lowland x upland cross IR20 (high-ABA) x 63-83 (low-ABA) which was mapped with RFLP and AFLP markers. Several highly significant quantitative trait loci (QTLs) for ABA accumulation and leaf weight were identified. Only one of the minor QTLs for ABA accumulation (accounting for only 4% of the phenotypic variance) was coincident with any QTLs for leaf size such that the high-ABA allele was associated with smaller leaves. This analysis, therefore, showed that the association previously found between ABA accumulation and leaf size was probably largely due to genetic linkage and not to a direct effect of leaf size on ABA accumulation or vice versa. Because of the importance of ABA accumulation in regulating responses of plants to drought stress and the effects of plant size on the rate of development of stress, QTLs for drought-induced ABA accumulation, leaf size and tiller number were compared between rice and wheat. In particular, a possible location in rice was sought for a homoeologue of the major wheat vernalization responsive gene, Vrn1, as this gene is also associated with major effects on leaf size, tiller number and ABA accumulation in wheat. The likelihood of homoeologous loci regulating ABA accumulation, leaf size and tiller number in the two crops is discussed.

UVA-induced oxidative damage in fibroblasts cultured in a 3-dimensional collagen matrix.

The exposure of dermal equivalent, i.e., fibroblasts cultured in a 3-dimensional collagen matrix to realistic doses of UVA (< or = 200 kJ/m2), results in a lipid peroxidation process as evidenced by the release of thiobarbituric acid-reactive substances in the supernatant. This peroxidative process is shown to be associated with the presence of fibroblasts and is inhibited by preincubation with vitamin E, the well-known chain-breaking antioxidant. Moreover, the UVA irradiation triggers cytotoxic effects which can also be reversed by preincubation with vitamin E. While the peroxidation extent is similar for fibroblasts cultured in monolayers or in dermal equivalent, the cytotoxic response to UVA is more pronounced in dermal equivalent.