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BackgroundHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive form of the disease, and ultimately progresses in patients with metastases on standard therapies. Anthracyclines, such as doxorubicin, are an effective treatment for HER2-positive breast cancer, particularly when administered in combination with trastuzumab - however, doxorubicin-related cardiotoxicity has limited its use. Many patients are therefore never treated with anthracyclines, even upon disease progression, despite the potential for benefit. MM-302 is a novel, HER2-targeted antibody-liposomal doxorubicin conjugate that specifically targets HER2-overexpressing cells. Preclinical and Phase 1 data suggest that MM-302, as a monotherapy or in combination with trastuzumab, could be effective for managing previously treated, anthracycline-naïve, HER2-positive breast cancer, without the cardiotoxicity observed with free doxorubicin formulations.Methods/designHERMIONE is an open-label, multicenter, randomized (1:1) Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice (gemcitabine, capecitabine, or vinorelbine) plus trastuzumab planned to enroll 250 anthracycline-naïve patients with locally advanced/metastatic HER2-positive breast cancer. Key inclusion criteria are: previous treatment with trastuzumab (with or without pertuzumab) in any setting; refractory or intolerant to pertuzumab (refractory to pertuzumab defined as progression in the locally advanced or metastatic setting, or disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy); and disease progression on, or intolerant to, ado-trastuzumab emtansine for locally advanced or metastatic disease. The trial is currently being conducted at sites in the USA, Canada, and Western Europe. Treatment will be administered in 21-day cycles, and will be continued until disease progression or unacceptable toxicity. The primary endpoint is independently assessed progression-free survival (PFS). Tumor response will be assessed every 6 weeks, and defined according to RECIST v1.1. Secondary endpoints include investigator-assessed PFS, overall survival (OS), OS rates at 6 months and 1 year, objective response rates, safety and tolerability, quality of life, and the pharmacokinetic profile of MM-302 plus trastuzumab.DiscussionThe HERMIONE study will evaluate the efficacy and safety of MM-302 plus trastuzumab in patients with refractory HER2-positive advanced/metastatic breast cancer for whom there are no standard of care therapies with a proven survival advantage.Trial registrationClinicaltrials.gov identifier: NCT02213744 . Registration date: 06AUG2014.

[3M.sup.b] Triticum aestivum L. (Mv9kr1)- Aegilops biuncialis Vis. (MvGB642) addition lines were crossed with the Chinese Spring ph1b mutant genotype (CSph1b) to produce [3M.sup.b]-wheat chromosome rearrangements. In the [F.sub.3] generation, [3M.sup.b](4B) substitution lines and [3M.sup.b].4BS centric fusions were identified with in situ hybridization using repetitive and genomic DNA probes, and with SSR markers. Grain micronutrient analysis showed that the investigated Ae. biuncialis accession MvGB382 and the parental line MvGB642 are suitable gene sources for improving the grain micronutrient content of wheat, as they have higher K, Zn, Fe, and Mn contents. The results suggested that the Ae. biuncialis chromosome [3M.sup.b] carries genes determining the grain micronutrient content, as the [3M.sup.b].4BS centric fusion had significantly higher Zn and Mn contents compared with the recipient wheat cultivar. As yield-related traits, such as the number of tillers, the length of main spike, and spikelets per main spike, were similar in the [3M.sup.b].4BS centric fusion and the parental wheat genotype, it can be concluded that this line could be used in pre-breeding programs aimed at enriching elite wheat cultivars with essential micronutrients. Key words: Triticum aestivum, Aegilops biuncialis, [3M.sup.b](4B) substitution, [3M.sup.b].4BS centric fusion, sequential FISH and GISH, grain micronutrient content. Des lignees d'addition [3M.sup.b] Triticum aestivum L. (Mv9kr1)--Aegilops biuncialis Vis. (MvGB642) ont ete croisees avec le mutant Chinese Springph1b (CSph1b) afin de produire des rearrangements chromosomiques [3M.sup.b]-ble. Au sein de la generation [F.sub.3], des lignees de substitution [3M.sup.b](4B) et des fusions centriques [3M.sup.b].4BS ont ete identifiees par hybridation in situ au moyen de sondes d'ADN repete ou genomique ainsi qu'avec des marqueurs SSR. Une analyse de la composition du grain en matiere de micronutriments a montre que l'accession etudiee de l'Ae. biuncialis (MvGB382) et la lignee parentale MvGB642 constituent des sources valables pour ameliorer le contenu en micronutriments chez le ble, du fait qu'elles ont une teneur accrue en K, Zn, Fe et Mn. Ces resultats suggerent que le chromosome [3M.sup.b] de l'Ae. biuncialis porte des genes contribuant a determiner le contenu en micronutriments puisque la fusion centrique [3M.sup.b].4BS presentait un contenu en Zn et en Mn significativement superieur a la variete de ble receptrice. Puisque les composantes de rendement comme le nombre de talles, la longueur de la tige principale et le nombre d'epillets par epi etaient semblables chez la fusion centrique [3M.sup.b].4BS et chez le genotype de ble parental, les auteurs en concluent que cette lignee pourrait s'averer utile dans des programmes de pre-selection visant a accroitre la teneur en micronutriments essentiels chez les cultivars elites de ble. [Traduit par la Redaction] Mots-cles: Triticum aestivum, Aegilops biuncialis, substitution [3M.sup.b](4B), fusion centrique [3M.sup.b].4BS, analyses FISH et GISH sequentielles, teneur en micronutriments chez le grain., Introduction Micronutrients are essential parts of the human diet, and in some cases the alimentary disorders caused by an insufficient daily intake may lead to serious illnesses. Zinc (Zn) is [...]

The frequency and pattern of irradiation-induced intergenomic chromosome rearrangements were analysed in the mutagenized ([M.sub.0]) and the first selfed ([M.sub.1]) generations of Triticum aestivum L.--Aegilops biuncialis Vis. amphiploids (2n = 70, AABBDD[U.sup.b][U.sup.b][M.sup.b]][M.sup.b]) by multicolour genomic in situ hybridization (mcGISH). mcGISH allowed the simultaneous discrimination of individual Ae. biuncialis genomes and wheat chromosomes. Dicentric chromosomes, fragments, and terminal translocations were most frequently induced by [gamma]-irradiation, but centric fusions and internal exchanges were also more abundant in the treated plants than in control amphiploids. Rearrangements involving the [M.sup.b] genome ([M.sup.b]-type aberrations) were more frequent than those involving the [M.sup.b] genome ([M.sup.b]-type aberrations). This irradiation sensitivity of the [U.sup.b] chromosomes was attributed to their centromeric or near-centromeric regions, since [M.sup.b]-type centric fusions were significantly more abundant than [U.sup.b]-type centric fusions at all irradiation doses. Dicentrics completely disappeared, but centric fusions and translocations were well transmitted from [M.sub.0] to [M.sub.1]. Identification of specific chromosomes involved in some rearrangements was attempted by sequential fluorescence in situ hybridization with a mix of repeated DNA probes and GISH on the same slide. The irradiated amphiploids formed fewer seeds than untreated plants, but normal levels of fertility were recovered in their offspring. The irradiation-induced wheat--Ae. biuncialis intergenomic translocations will facilitate the successful introgression of drought tolerance and other alien traits into bread wheat. Key words: Triticum aestivum, Aegilops biuncialis, amphiploid, [gamma]-irradiation, intergenomic translocations, mcGISH. La frequence et la nature des rearrangements chromosomiques intergenomiques induits par irradiation ont ete analyses au sein de la generation irradiee (Mo) et de la generation suivante ([M.sub.1]) d'amphidiploides Triticum aestivum L.--Aegilops biuncialis Vis. (2n = 70, AABBDD[U.sup.b][U.sup.b][M.sup.b][M.sup.b]) par hybridation genomique in situ multicolore (mcGISH). L'hybridation mcGISH a permis de simultanement identifier les genomes de l'Ae. biuncialis et les chromosomes individuels du ble. Des chromosomes dicentriques, des fragments et des translocations terminales etaient les plus frequemment induits par irradiation [gamma], mais des fusions centriques et des echanges internes etaient egalement plus abondants chez les plantes traitees que chez les amphidiploides temoins. Des rearrangements impliquant le genome [U.sup.b] (aberrations de type [U.sup.b]) etaient plus frequentes que celles impliquant le genome [M.sup.b] (aberrations de type [M.sup.b]). Cette sensibilite a l'irradiation des chromosomes [U.sup.b] a ete attribuee a leurs regions centromeriques ou pericentromeriques puisque des fusions centriques de type [U.sup.b] etaient significativement plus abondantes que les fusions centriques de type [M.sup.b] a toutes les doses d'irradiation. Les chromosomes dicentriques ont totalement disparu tandis que les fusions centriques et les translocations etaient bien transmises de la [M.sub.0] a la [M.sub.1]. L'identification de chromosomes specifiques impliques dans certains rearrangements a ete tentee par hybridation in situ en fluorescence sequentielle avec une combinaison de plusieurs sondes d'ADN repetitif et d'hybridation GISH sur la meme lame. Les amphidiploides irradies ont forme moins de graines que les plantes temoins, mais des niveaux normaux de fecondite ont ete retrouves au sein de leur descendance. Les translocations intergenomiques ble--Ae. biuncialis induites par irradiation faciliteront l'introgression de la resistance a la secheresse et d'autres caracteres d'interet de l'espece exotique vers le ble. Mots-cles: Triticum aestivum, Aegilops biuncialis, amphiploide, irradiation y, translocations intergenomiques, mcGISH. [Traduit par la Redaction], Introduction Aegilops biuncialis Vis. (2n = 4x = 28, [U.sup.b][U.sup.b][M.sup.b][M.sup.b]) is an allotetraploid species having good tolerance against biotic (Damania and Pecetti 1990; Makkouk et al. 1994) and abiotic stresses [...]

Abstract: The short interspersed nuclear element (SINE), Au, was used to develop sequence-specific amplified polymorphism (S-SAP) markers for U- and M-genome chromosomes. The markers were localized using Triticum aestivum (wheat)--Aegilops [...]

The antifungal polyketide soraphen A is produced by the myxobacterium Sorangium cellulosum So ce26. The slow growth, swarming motility and general intransigence of the strain for genetic manipulations make industrial strain development, large-scale fermentation and combinatorial biosynthetic manipulation of the soraphen producer very challenging. To provide a better host for soraphen A production and molecular engineering, the biosynthetic gene cluster for this secondary metabolite was integrated into the chromosome of Streptomyces lividans ZX7. The upstream border of the gene cluster in Sor. cellulosum was defined by disrupting sorC, which is proposed to take part in the biosynthesis of methoxymalonyl-coenzyme A, to yield a Sor. cellulosum strain with abolished soraphen A production. Insertional inactivation of orf2 further upstream of sore had no effect on soraphen A production. The genes sorR, C, D, F and E thus implicated in soraphen biosynthesis were then introduced into an engineered Str. lividans strain that carried the polyketide synthase genes sorA and sorB, and the methyltransferase gene sorM integrated into its chromosome. A benzoate-coenzyme A ligase from Rhodopseudomonas palustris was also included in some constructs. Fermentations with the engineered Str. lividans strains in the presence of benzoate and/or cinnamate yielded soraphen A. Further feeding experiments were used to delineate the biosynthesis of the benzoyl-coenzyme A starter unit of soraphen A in the heterologous host.