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Bacteriophage therapy, which uses lytic viruses as antimicrobials, has received renewed interest to address the emerging antimicrobial resistance (AMR) crisis. Cystic fibrosis (CF), a disease complicated by recurrentP. aeruginosapulmonary infections that cause lung function decline, is an example where AMR is already a clinical problem. While bacteria evolve bacteriophage resistance, we developed a strategy to select bacteriophages that target bacterial cell surface receptors that contribute to antibiotic resistance or virulence. Thus, in addition to killing bacteria, these phages steer surviving, evolved bacteria to antibiotic re-sensitivity or attenuated virulence. Here, we present outcomes from nine CF adults treated with nebulized bacteriophage therapy for AMRP. aeruginosausing this personalized approach. Results showed that phage therapy: 1) reduced sputumP. aeruginosa, 2) showed evidence for predicted trade-offs in most subjects, and 3) improved lung function, which may reflect the combined effects of decreased bacterial sputum density and phage-driven evolved trade-offs.

Background: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These ‘RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown. Methods: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry. Results: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4–18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4. Conclusions: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.

From an economic point of view Underground Coal Gasification (UCG) is a promising technology that can be used to reach coal resources that are difficult or expensive to by conventional mining methods. Furthermore, the process addresses safety concerns, by avoiding the presence of workers underground. An optimal UCG process requires the integration of various scientific fields (chemistry, geochemistry, geomechanics) and the demonstration of limited of environmental impacts. This paper focuses on the mechanical component of the UCG operation and its impact on the surrounding environment in terms of stability and land subsidence. The mechanical components are also considered. Underground mining by coal combustion UCG challenges include the mechanical behavior of the site and of stability of the overburden rock layers. By studying the underground reactor, its inlet and outlet, we confirm the key role played by mechanical damage and thermo-mechanical phenomena are identified. Deformation or collapse above the cavity may cause a collapse in the overlying layers or subsidence at the surface level. These phenomena are highly dependent on the thermoporomechanical behavior of the rock surrounding the cavity (the host rocks). Unlike conventional methods, the UCG technology introduces an additional variable into the physical problem: the high temperatures, which evolve with time and space. In this framework, we performed numerical analyses of the coal site that could be exploited using this method. The numerical results presented in this paper are derived from models based on different assumptions describing a raw geological background. Several 3D (3 dimensional) and 2D (2 dimensional, plane) nonlinear finite element modelings are performed based on two methods. The first assumes a rock medium as a perfect thermo-elastoplastic continuum. In the second, in order to simulate large space scale crack propagation explicitly, we develop a method based upon finite element deactivation. This method is built on a finite element mesh refinement and uses Mohr-Coulomb failure criterion. Based on the analysis of the numerical results, we can highlight two main factors influencing the behavior and the mechanical stability of the overburden, and consequently the UCG process evolution. The first is the size of the cavity. This geometrical parameter, which is common to all types of coal exploitation, is best controlled using the classic exploitation method. We show that in the case of UCG, the shape of the cavity and its evolution over time can be modified considerably by the thermomechanical behavior of the host rocks. The second is the presence of a heat source whose location and intensity evolve over time. Even if thermal diffusivity of the rock is low and only a small distance from the coal reactor is thermally affected, we show that the induced mechanical changes extend significantly in the overburden, and that subsidence can therefore be estimated at the surface. We conclude the integration of the mechanical analysis into a risk analysis process mechanical analysis can be integrated in a thorough risk analysis.

An underground research laboratory (URL) is being constructed by Andra in eastern France, in Callovo-Oxfordian claystone (COx) in which various in situ geomechanical experiments are being undertaken or are to be carried out. The aim of this URL is to characterize the in situ properties of COx claystone and to test disposal technologies in a realistic way in order to assess the short- and long-term safety of a deep radioactive waste repository. In parallel, theoretical and numerical models able to reproduce the phenomena observed under different types of loading paths must be developed. The phenomenological elastic-visco-plastic model developed by Souley et al. (2011) has been enhanced to reflect recent advances in understanding of the mechanical and hydromechanical behavior of COx claystone and the modification of the mechanical and hydraulic properties in the EDZ (Excavation Damage Zone). In particular, the influence of induced damage and fracturing on the delayed strains and strain rates of the COx claystone and the permeability changes observed at the site scale, as well as hydro-mechanical couplings, are discussed and incorporated in a new model. This model is implemented into the commercial code FLAC 3D . Short- and long-term test data (Armand et al., 2016) can be used to identify possible key parameters for the model. These tests were also used to identify certain parameters of our model. Some tests were simulated to verify the numerical implementation of the proposed model. Finally, the simulation of the GCS drift excavation (Seyedi et al., 2016) has been performed. Comparisons to in situ measurements are discussed and some accordance and discrepancies were observed.

We study the existence and some properties of travelling waves in partially degenerate reaction-difiusion systems. Such systems may for example describe intracellular calcium dynamics in the presence of immobile bufiers. In order to prove the wave existence, we flrst consider the non degenerate case and then pass to the limit as some of the difiusion coe-cient converge to zero. The passage to the limit is based on a priori estimates of solutions independent of the values of the difiusion coe-cients. The wave uniqueness is also proved.

By means of the Conley connection index theory we prove existence of travelling wave solutions to a system of equations in a two temperature model of laser maintained plasma. These solutions describe locally the motion of plasma boundaries.

The scope of this paper is to provide several findings relating to the question : Does the initial excavation phase of cast in situ panel using a bentonite supporting fluid have an effect on the ultimate behavior of the soil and supported structures ? This study was performed using the Finite Difference Method and considering a three-dimensional geometry and a dual phase coupled behavior. The numerical results were compared to the measurements made on-site. The study demonstrated that a 3D approach is suitable for evaluating the displacements, stresses and pore water pressures. On the other hand, it was also show that the three-dimensional model could be replaced by a more simple axisymmetrical analysis.

We use the implicit function theorem to prove an existence of a heteroclinic orbit to a system of two non-linear second-order ODEs. The perturbation is carried out around infinite value of a 'coupling parameter'. The form of the system which is considered in this paper is related to the system defining travelling wave solutions in a two temperature model of the laser sustained plasma.

In this paper we construct two approximating sequences for heteroclinic solution to a scalar ODE. These sequences do not ‘intersect’ and bound a unique real solution from below and above, thus enabling us to estimate this solution with any accuracy.

Anorectal malformations (ARM) encompass a broad clinical spectrum which ranges from mild anal stenosis to severe anorectal anomalies such as complex cloacal malformations. The overall incidence of ARM is around 1 in every 2,500 live births. Although causative genes for a few syndromic forms have been identified, the molecular genetic background of most ARM remains unknown. The present report describes a patient with a de novo 13.2-Mb deletion of chromosome 18q22.3–qter and a 2.2-Mb de novo duplication of chromosomal region 18pter–p11.32 located at the telomeric end of chromosome 18q. The patient presented with ARM and the typical features of 18q– syndrome (De-Grouchy syndrome). The combination of a partial duplication of the short arm and a partial deletion of the long arm of chromosome 18 has been described in 16 previous cases. However, this is the first report of an association between this complex chromosomal rearrangement and ARM.

Les tunnels sont de plus en plus realises en pleine section, ce qui conduit a des hauteurs du front de taille parfois tres importantes. C’est pourquoi les ingenieurs sont frequemment appeles a examiner la tenue du front, et a prevoir son renforcement par des boulons longitudinaux en fibre de verre. Les approches actuelles privilegient les analyses en stabilite, mais ne permettent guere une evaluation des deformations du front, sauf a utiliser des methodes numeriques, dans lesquelles la prise en compte des renforcements conduit a des modeles tres lourds et peu utilisables en pratique courante. Cet article presente une nouvelle approche analytique en contraintes-deformations, basee sur un principe de symetrie spherique, et permettant d’evaluer les deformations d’extrusion du front, et ce meme lorsque le front est renforce par des boulons. Nous presentons en premier lieu les principes de la methode ainsi que sa validation, puis differentes etudes parametriques, ainsi que quelques cas possibles d’utilisation : evaluation d’un coefficient de securite, dimensionnement d’un renforcement par boulonnage, effet de la pression de confinement sur l’extrusion lors de l’utilisation de boucliers.

The high frequency of the t(3;12)(q27-28;q14-15) in lipomas and pulmonary chondroid hamartomas (PCHs) makes the HMGIC-LPP fusion gene the most common fusion gene in a human tumor known so far. Nevertheless, there is no in-depth molecular analysis of the HMGIC-LPP fusion transcripts in PCHs. Certainly, a possible molecular variability of the HMGIC-LPP fusion may contribute to a better understanding of the histologic differences between lipomas and PCHs and the intratumoral histologic heterogeneity of PCHs. By RT-PCR and restriction analysis, we have investigated the HMGIC-LPP fusion transcripts in a series of 13 PCHs with t(3;12)(q27-28;q14-q15). HMGIC-LPP fusion transcripts of identical size were found in all PCHs tested. In all tumors investigated, the fusion transcripts had the same structure, i.e., exons 1 to 3 of HMGIC and exons 9 to 11 of LPP encoding a protein composed of three AT-hooks and two LIM-domains. Our results clearly show that neither the histologic differences between lipomas and PCHs nor the histologic heterogeneity of PCHs can be explained by a molecular diversity of the HMGIC-LPP fusion transcript.

In a totally benign endometrial polyp, double minute chromosomes were shown to contain an amplified and apparently nonrearranged HMGIC gene, expressed in the tumor cells, suggesting amplification of HMGIC through double minute chromosome formation as another hitherto unreported mechanism associated with the development of some mesenchymal tumors.

The HMGIC gene, located in chromosome band 12q15, is rearranged in many different benign human tumors, often resulting in its fusion to ectopic sequences from other genes. The t(3;12)(q27;q14-q15) fuses HMGIC with the LPP gene and has so far been described exclusively in lipomas. Thus, it can be hypothesized that this particular gene fusion determines the adipocytic differentiation. We studied five pulmonary chondroid hamartomas all showing a t(3;12)(q27;q14-q15) that apparently was identical to the one observed in lipomas. By fluorescence in situ hybridization we found that both HMGIC and LPP are disrupted by this translocation. By RT-PCR the existence of a HMGIC/LPP fusion gene was confirmed. These results show that the fusion is not specific for lipomas. We favor the hypothesis that it is an ectopic sequence fused to HMGIC that is responsible for a cell shift to an embryogenic stage. Following this hypothesis the phenotype of the tumor may be induced by extracellular signal transduction.

Aberrations of the HMGIC gene, encoding an architectural transcription factor and located in the chromosomal region 12q15, are very frequent among benign mesenchymal tumors, such as lipomas, uterine leiomyomas, or pulmonary chondroid hamartomas. These HMGIC aberrations are caused by characteristic structural chromosomal aberrations, either visible by conventional cytogenetics or as cryptic abnormalities. Some of these aberrations of chromosome 12 are not specific for particular tumor entities but can occur in a variety of tumors with HMGIC abnormalities. One such example is the pericentric inversion inv(12)(p11.2q15). Starting from the ectopic sequence derived from an HMGIC fusion transcript of an aggressive angiomyxoma with such an inversion we established three PAC clones covering the breakpoint region 12p11 and cloned part of a yet unknown gene in 12p11.2, which is fused to the third exon of HMGIC. Using fluorescence in situ hybridization with these PACs we were able to show that the same region was involved by 12p11.2 aberrations in lipomas, aggressive angiomyxomas, and pulmonary chondroid hamartomas.

The first description of involvement of 6p21 and rearrangement of HMGIY in a hamartoma of the breast is in keeping with the emerging role of HMG genes in benign mesenchymal tumors.

Uterine leiomyoma cytogenetically exhibits at least six chromosomally abnormal subgroups. The largest subgroup is characterized by deletions of the long arm of chromosome 7. Few molecular and fluorescence in situ hybridization data are available that have aimed at a better definition of the lesion. Here, we report the results of a partial molecular cytogenetic characterization of two del(7q) chromosomes that were derived from cell lines established from two uterine leiomyomas with del(7)(q22q32). By using a large series of ordered 7q markers, we were able to identify the most proximal and the most distal conserved markers, which delineate the size of the deletion and which allow for a more targeted approach to the nature and function of genes that are possibly relevant for the pathogenesis of the disorder.

Akin to the HMGI-C rearrangements observed in benign solid tumors with 12q14-15 abnormalities, the HMGI(Y) gene has been assumed to play a crucial role in tumors with 6p21 abnormalities. Fluorescence in situ hybridization (FISH) studies using a PAC clone containing the HMGI(Y) gene as a molecular probe have been performed on a cell line from a uterine leiomyoma with a complex translocation involving chromosomal band 6p21.3. The results revealed that the breakpoint mapped within the PAC clone as reflected by signals on the normal chromosome 6 and both derivative chromosomes 1 and 14. Thus, the breakpoint was located within the HMGI(Y) gene or its close vicinity. These findings support the idea that HMGI(Y) rearrangements are causally related to the origin of uterine leiomyomas with 6p21 abnormalities.

Pulmonary chondroid hamartomas (PCH) are benign tumors of the lung characterized by a more or less high degree of mesenchymal metaplasia. In our series we investigated 30 PCH by a combination of cytogenetic and molecular methods. 18 tumors (60%) had cytogenetically detectable aberrations involving either 12q14-15 or 6p21 with a clear predominance of chromosomal abnormalities involving 12q14-15 (15 tumors). As in subgroups of pleomorphic adenomas of the salivary glands, leiomyomas of the uterus, and lipomas with 12q14-15 abnormalities the HMGI-C gene is frequently rearranged we tested PCH with either 12q14-15 abnormalities or normal karyotype by FISH and 3' RACE experiments for rearrangements of HMGI-C. Rearrangements were found in all cases with chromosomal 12q14-15 abnormalities and further six cases with an apparently normal karyotype. By the combination of cytogenetics with molecular techniques the percentage of cases with intragenic rearrangements of HMGI-C or rearrangements of its immediate surrounding was thus increased to 70% (21/30 cases). Considering all types of aberrations within this series 80% (24/30) of all PCH were aberrant. This is the first report on a combined molecular and cytogenetic analysis of a large series of pulmonary chondroid hamartomas indicating that rearrangements of HMGI-C, a member of the high mobility group protein gene family, are the leading molecular events in the genesis of PCH.

Aberrations involving the chromosomal region 12q24 are a nonrandom cytogenetic abnormality in frequent benign tumors mainly of mesenchymal origin, e.g., uterine leiomyomas, pleomorphic adenomas of the salivary gland, lipomas, or hamartomas of the lung. Mostly, these 12q24 abnormalities occur as a result of inversions also affecting chromosomal region 12q14-15. In addition to the frequent tumors mentioned above, these abnormalities have also been found in rare mesenchymal tumors, e.g., hemangiopericytomas. Although recently the molecular basis of the aberrations of chromosomal region 12q14-15, i.e., a rearrangement of the HMGI-C gene has been identified, the molecular roots of the 12q24 changes still remain to be elucidated. Herein we report on 3' rapid amplification of cDNA ends PCR results on cDNA from a primary uterine leiomyoma. As an ectopic sequence fused to exon 3 of the HMGI-C gene, we have identified a cDNA sequence that revealed 100% homology to exon 13 of the human mitochondrial aldehyde dehydrogenase gene (ALDH 2). Because ALDH 2 maps to 12q24.1, this fusion transcript is a good candidate underlying the chromosomal rearrangements involving 12q24.

Aggressive angiomyxoma is a rare mesenchymal tumor occurring mainly in the vulvar region extending into the paravaginal and perirectal region. Histologically, this tumor is rich in vascular structures and in collagen fibers and is of myxoid appearance. Cytogenetic and molecular analysis was performed on a case of an aggressive angiomyxoma and revealed clonal karyotypic abnormalities. All 50 metaphases analyzed showed a translocation involving the chromosomal region 12q14-15. Chromosomal aberrations involving the breakpoint region 12q14-15 are frequently seen in a variety of other mesenchymal tumors as uterine leiomyomas, lipomas, hamartomas of the lung, liposarcomas, or hemangiopericytomas. Therefore, this breakpoint region seems to be the most frequent chromosomal abnormality associated with the initiation of human mesenchymal neoplasms. To narrow down the breakpoint region on a molecular level in the cells of the angiomyxoma we performed FISH analysis with different cosmid clones originating from a yeast artificial chromosome and cosmid contig overspanning parts of the region 12q14-15. We were able to narrow down the region to approximately 70-80 kb belonging to an area designated a multiple aberration region, because it also includes the breakpoints of leiomyomas, lipomas, and pleomorphic adenomas with 12q13-15 abnormalities. Our molecular and cytogenic data suggest that angiomyxomas or at least a subset of them molecularly belong to the benign group of mesenchymal tumors showing multiple aberration region involvement.

Chromosomal aberrations involving the chromosomal breakpoint region 12q14-15 are frequently seen in a variety of mesenchymal tumors as uterine leiomyomas, lipomas, myxoid liposarcomas, enchondromas, or hemangiopericytomas. Therefore, this breakpoint region seems to be one of the most frequent chromosomal abnormality associated with the initiation of human mesenchymal neoplasms. To narrow down the breakpoint region on a molecular level in cells of three pulmonary chondroid hamartomas with 12q14-15 aberrations, we performed fluorescence in situ hybridization analysis with different cosmid clones originating from a YAC and cosmid contig overspanning parts of the region 12q14-15. We were able to narrow down the breakpoint to a region of 175 kb belonging to an area designated multiple aberration region because it also includes the breakpoints of leiomyomas, lipomas, and pleomorphic adenomas with 12q14-15 abnormalities. Our molecular and cytogenetic data suggest that hamartomas of the lung molecularly belong to the benign group of mesenchymal tumors showing multiple aberration region involvement.

Three pelves and eight innominate bones belonging to the fossil species, Australopithecus africanus, Australopithecus robustus, Homo erectus, and Homo sapiens, have been studied biometrically and compared with those of recent humans and apes. A new method of logarithmic factorial analysis suppresses both the size effects and the size reference on pelvic proportions. In combination with principal component analysis it allows specializations to be dissociated from allometrical variations. Some morphological differences on the hominid pelvis prove to be mainly allometric. However, the pelvic morphology of australopithecines is clearly differentiated from that of the genus Homo (including H. erectus, OH 28, KNMER 3227). A. africanus (Sts 14, MLD 7, AL 288) is nearer the humans than is A. robustus (SK 50, SK 3155), which appears to be more specialized in the australopithecine lineage. The pelvic morphology of A. africanus, as integrated with the articular pelvic-femoral link, appears to be biometrically equivalent to that of humans.

We report a case of Richter transformation of a chronic lymphocytic leukemia with a 22q13 translocation involving the HMGI-C gene. Fluorescence in situ hybridization analysis with the use of two different cosmid pools spanning the entire HMGI-C region showed that the breakpoint on chromosome 12 was located in the HMGI-C gene, presumably within intron 3. In fact, the 3' region of HMGI-C had been translocated to a derivative chromosome 6. This translocation was not visible at the cytogenetic level. Immunohistochemical analysis performed on the bone marrow smear demonstrated the expression of the HMGI-C protein specifically in the blasts, suggesting that the aberrant expression of the HMGI-C gene might have an important role in the process of leukemogenesis. (C) 2000 Elsevier Science Inc. All rights reserved.

In an attempt to identify the target gene of specific translocations involving chromosomal band 19q13 in benign follicular thyroid tumors, we have used two cell lines derived from benign thyroid tumors showing translocations with 19q13 breakpoints for fluorescence in situ hybridization mapping studies with cosmid and PAC clones located in a 400-kbp region. The breakpoints of the chromosome 19 abnormalities mapped within a 140-kb segment covered by a single PAC clone. Sequencing of part of this PAC clone allowed us to establish the cDNA sequence and the genomic structure of a candidate gene located in close vicinity to the breakpoints. The gene that we tentatively refer to as RITA (rearranged in thyroid adenomas) belongs to the KRAB zinc finger protein coding genes. From our results we have concluded that in the two cell lines investigated the breaks have occurred either within the 5' untranslated region of RITA or in its close 5' vicinity. By Northern blot analyses two transcripts of about 4.7 kbp and 5 kbp were detected in normal thyroid tissue as well as in other normal tissues tested. An additional 2.1-kbp transcript was found only in testicular tissue. In contrast to all normal tissues, both cell lines with 19q aberrations expressed larger transcripts of approximately 5.5 kbp and 6.2 kbp. From the close vicinity to the breakpoint region, the expression patterns of the gene, and its type, we consider RITA a strong candidate target gene of the specific 19q aberrations in benign thyroid tumors.

Specific chromosomal abnormalities of chromosomal region 6p21.3 have been described in subsets of many benign mesenchymal tumors. In the presented study, we investigated a series of 36 such cases by FISH, and Southern blot analyses for HMGIY rearrangements. FISH results revealed that the chromosomal breakpoints of I I pulmonary chondroid hamartomas (PCHs), 12 endometrial polyps (EPs), one lipoma, and two uterine leiomyomas (ULs) were located within a 80 kb region surrounding the HMGIY gene. In 11 PCHs and one UL the breakpoints were located 3' of HMGIY, and one PCH showed a breakpoint 5' of HMGIY. Southern blot analyses with intra- and extragenic probes were performed of primary tumor material or cell lines from one UL, three PCHs, and five EPs. In none of these cases was an intragenic rearrangement found. Finally, we were able to detect expression of truncated HMGIY transcripts by 3'-RACE FOR. Our data clearly show the role of a further member of the HMGI family in the development of benign mesenchymal tumors. Although most of the breakpoints of the chromosomal translocations involving HMGIY are located outside the gene, aberrant transcripts resembling the structure of those observed in the case of HMGIC have been found. Our molecular investigations thus led to the identification of the molecular mechanism by which rearrangements of either of two closely related genes lead to the development of frequent benign mesenchymal tumors in humans. Genes Chromosomes Cancer 23:279-285, 1998. (C) 1998 Wiley-Liss, Inc.