Dissection of a metastatic gene expression signature into distinct components

BACKGROUND: Metastasis, the process whereby cancer cells spread, is in part caused by an incompletely understood interplay between cancer cells and the surrounding stroma. Gene expression studies typically analyze samples containing tumor cells and stroma. Samples with less than 50% tumor cells are generally excluded, thereby reducing the number of patients that can benefit from clinically relevant signatures. RESULTS: For a head-neck squamous cell carcinoma (HNSCC) primary tumor expression signature that predicts the presence of lymph node metastasis, we first show that reduced proportions of tumor cells results in decreased predictive accuracy. To determine the influence of stroma on the predictive signature and to investigate the interaction between tumor cells and the surrounding microenvironment, we used laser capture microdissection to divide the metastatic signature into six distinct components based on tumor versus stroma expression and on association with the metastatic phenotype. A strikingly skewed distribution of metastasis associated genes is revealed. CONCLUSION: Dissection of predictive signatures into different components has implications for design of expression signatures and for our understanding of the metastatic process. Compared to primary tumors that have not formed metastases, primary HNSCC tumors that have metastasized are characterized by predominant down-regulation of tumor cell specific genes and exclusive up-regulation of stromal cell specific genes. The skewed distribution agrees with poor signature performance on samples that contain less than 50% tumor cells. Methods for reducing tumor composition bias that lead to greater predictive accuracy and an increase in the types of samples that can be included are presented

Implementing population health managemen

Purpose The purpose of this paper is to gain insight into how population health management (PHM) strategies can successfully integrate and reorganize public health, health care, social care and community services to improve population health and quality of care while reducing costs growth, this study compared four large-scale transformation programs: Greater Manchester Devolution, Vancouver Healthy City Strategy, Gen-H Cincinnati and Gesundes Kinzigtal. Design/methodology/approach Following the realist methodology, this explorative comparative case-study investigated PHM initiatives' key features and participants' experiences of developing such initiatives. A semi-structured interview guideline based on a theoretical framework for PHM guided the interviews with stakeholders (20) from different sectors. Findings Five initial program theories important to the development of PHM were formulated: (1) create trust in a shared vision and understanding of the PHM rationale to establish stakeholders' commitment to the partnership; (2) create shared ownership for achieving the initiative's goals; (3) create shared financial interest that reduces perceived financial risks to provide financial sustainability; (4) create a learning environment to secure initiative's credibility and (5) create citizens' and professionals' awareness of the required attitudes and behaviours. Originality/value The study highlights initial program theories for the implementation of PHM including different strategies and structures underpinning the initiatives. These insights provide a deeper understanding of how large-scale transformation could be developed

До мінералогії сезонних сульфатів мису Фіолент (Південно-Західний Крим)

Комплексом методів вивчено колекцію зразків вторинних мінералів одного з узбережних відслонень зони окиснення сульфідної мінералізації мису Фіолент (Південно-Західний Крим). Установлено, що всі досліджені зразки є полімінеральними утвореннями, в яких одночасно співіснують у різних пропорціях сульфати Mg, Al, Fe²⁺, Fe³⁺, Ca тощо: пікерингіт (найпоширеніший), пікерингіт залізистий, гексагідрит, старкіїт, епсоміт, алуноген, ботріоген, копіапіт, ярозит, гіпс та ін. Старкіїт і ботріоген у Криму виявлено вперше.The collection of secondary minerals from one of littoral occurrences of sulphide zone of oxidation of the Fiolent Cape (South-Western Crimea) is studied by different methods. It was established that all studied samples were polymineral formations which consisted of sulphates of Mg, Al, Fe²⁺, Fe³⁺, Ca, etc. in different proportions: pickeringite (the most wide-spread), ferropickeringite, hexahydrite, starkeyite, epsomite, alunogen, botryogen, copiapite, jarosite, gypsum etc. Starkeyite and botryogen are detected in the Crimea for the first time

Late Miocene contourite channel system reveals intermittent overflow behavior

Paleoceanographic information from submarine overflows in the vicinity of oceanic gateways is of major importance for resolving the role of ocean circulation in modulating Earth’s climate. Earth system models are currently the favored way to study the impact of gateways on global-scale processes, but studies on overflow-related deposits are more suitable to understand the detailed changes. Such deposits, however, had not yet been documented in outcrop. Here, we present a unique late Miocene contourite channel system from the Rifian Corridor (Morocco) related to the initiation of Mediterranean Outflow Water (MOW). Two channel branches were identified consisting of three vertically stacked channelized sandstone units encased in muddy deposits. Both branches have different channel-fill characteristics. Our findings provide strong evidence for intermittent behavior of overflow controlled by tectonic processes and regional climatic change. These fluctuations in paleo-MOW intermittently influenced global ocean circulation

Epidermal growth factor receptor expression in pancreatic lesions induced in the rat by azaserine.

In the present study, the expression of the epidermal growth factor receptor (EGFR) was investigated in putative preneoplastic and neoplastic acinar cell lesions induced in the rat pancreas by azaserine, using Northern blotting, in situ hybridisation (ISH) and immunohistochemistry. EGFR protein levels were decreased in putative preneoplastic eosinophilic acinar cell lesions (atypical acinar cell nodules, AACN) in comparison with normal acinar cells of the pancreas. However, EGFR mRNA expression correlated positively with the volume of AACN in pancreatic homogenates and ISH showed equal or stronger EGFR mRNA expression in AACN than in the surrounding normal acinar cells. Neither EGFR protein nor EGFR mRNA was detected in more advanced lesions such as acinar adenocarcinomas (in situ). Moreover, EGFR protein expression showed an inverse relationship with the mitotic rate of the acinar cells. These findings suggest that down-regulation of EGFR at the protein level may abrogate negative constraints on cell growth, which may stimulate the development of putative preneoplastic AACN to more advanced lesions and, ultimately, acinar adenocarcinomas

Treatment decision for transcatheter aortic valve implantation: the role of the heart team: Position statement paper of the Dutch Working Group of Transcatheter Heart Interventions

The current paper presents a position statement of the Dutch Working Group of Transcatheter Heart Valve Interventions that describes which patients with aortic stenosis should be considered for transcatheter aortic valve implantation and how this treatment proposal/decision should be made. Given the complexity of the disease and the assessment of its severity, in particular in combination with the continuous emergence of new clinical insights and evidence from physiological and randomised clinical studies plus the introduction of novel innovative treatment modalities, the gatekeeper of the treatment proposal/decision and, thus, of qualification for cost reimbursement is the heart team, which consists of dedicated professionals working in specialised centres

Sandy contourite drift in the late Miocene Rifian Corridor (Morocco):Reconstruction of depositional environments in a foreland-basin seaway

The Rifian Corridor was a seaway between the Atlantic Ocean and the Mediterranean Sea during the late Miocene. The seaway progressively closed, leading to the Messinian Salinity Crisis in the Mediterranean Sea. Despite the key palaeogeographic importance of the Rifian Corridor, patterns of sediment transport within the seaway have not been thoroughly studied. In this study, we investigated the upper Miocene sedimentation and bottom current pathways in the South Rifian Corridor. The planktic and benthic foraminifera of the upper Tortonian and lower Messinian successions allow us to constrain the age and palaeo-environment of deposition. Encased in silty marls deposited at 150–300 m depth, there are (i) 5 to 50 m thick, mainly clastic sandstone bodies with unidirectional cross-bedding; and (ii) 50 cm thick, mainly clastic, tabular sandstone beds with bioturbation, mottled silt, lack of clear base or top, and bi-gradational sequences. Furthermore, seismic facies representing elongated mounded drifts and associated moat are present at the western mouth of the seaway. We interpret these facies as contourites: the products of a westward sedimentary drift in the South Rifian Corridor. The contourites are found only on the northern margin of the seaway, thus suggesting a geostrophic current flowing westward along slope and then northward. This geostrophic current may have been modulated by tides. By comparing these fossil examples with the modern Gulf of Cadiz, we interpret these current-dominated deposits as evidence of late Miocene Mediterranean overflow into the Atlantic Ocean, through the Rifian Corridor. This overflow may have affected late Miocene ocean circulation and climate, and the overflow deposits may represent one of the first examples of mainly clastic contourites exposed on land