bluuebunny/crossref_metadata_2025 huggingface dataset:
Lemierre's Syndrome – A rare cause of disseminated sepsis requiring multi-organ support
Authors: Rae John , Misselbrook Katie
Published: March 2017

Lemierre's syndrome is a rare complication of acute pharyngitis characterised by septicaemia with infective thrombophlebitis of the internal jugular vein, most commonly due to Fusobacterium necrophorum. It characteristically affects healthy young adults causing persistent pyrexia and systemic sepsis presenting several days after an initial pharyngitis. Septic emboli seed via the bloodstream to distant sites including the lung, joints, skin, liver, spleen and brain. Prolonged antimicrobial therapy is required and admission to intensive care common. This once rare condition is increasing in incidence but awareness amongst clinicians is low. We present a classic case in a young man who developed multi-organ failure requiring intensive care support and describe the epidemiology, pathophysiology, microbiology, clinical features and management of the disease.
A Pathology of Business Cartels: Original Sin or the Child of Regulation?
Authors: Harding Christopher
Published: March 2017

Over the last 10 to 15 years there has been a significant movement towards criminalisation of involvement in business cartels in a number of jurisdictions around the world, outside of the US and Canada where such conduct has been a criminal offence since the end of the nineteenth century. In particular there is now an emphasis on individual or personal as distinct from corporate liability and on the use of severe sanctions such as imprisonment. For European jurisdictions, this represents a significant shift in enforcement strategy and the perception of activities such as price fixing, market sharing and bid rigging. Observation of these legal developments inevitably gives rise to the question: what is so bad about cartel conduct as to merit censure and sanctioning through the processes of criminal law? However, a clear consensus on the specific nature of cartel delinquency remains elusive. The American approach has been to identify an element of conspiracy in the criminality of what are now commonly referred to as hard core cartels. Elsewhere, there are ill-thought out analogies put forward with theft, fraud and dishonesty. The argument in this paper seeks a justification for criminalisation in the upward spiral of enforcement activity and consequent cartel defensiveness, turning cartelists into ‘cognisant, contumacious and covert’ actors who are evolving an increasingly determined outlaw identity in the face of an increasingly assertive global enforcement enterprise.
The EU's Accession to the Convention on Human Rights: A New Era of Closer Cooperation between the Council of Europe and the EU?
Authors: White Simone
Published: March 2017

The sound development of EU criminal law depends on the adoption of human rights standards at EU level. The EU's accession to the Convention on Human Rights has been described as ‘mission impossible’ because of the number and complexity of issues to be negotiated. Yet the stakes are high and there is a political will to build a coherent human rights system at European level. The author argues that the working link between the European Union and the Council of Europe needs to be further strengthened and that a ‘Greater Europe’ criminal law/human rights regime will be made possible by the accession of the European Union to ECHR.
The European Investigation Order
Authors: Blackstock Jodie
Published: March 2017

This article presents a critical evaluation of the latest EU proposal in the area of judicial cooperation in criminal proceedings. Whilst a framework decision on requests for evidence was adopted in 2008, which aimed to streamline the evidence gathering mechanisms across EU borders, the majority of Member States now agree that the instrument is in fact unworkable, since it fails to cover all forms of requests. As such, conventions on mutual legal assistance, which are hampered by slow and uncertain responses, continue to be the mechanism through which evidence is requested, gathered and transferred in the EU. The proposed Member State initiative of a European investigation order has greater ambition. However, this article seeks to show that in attempting to provide a more efficient instrument adhering strictly to the principle of mutual recognition, much of the protection for suspects, and therefore the cornerstone of equality of arms, is lost.
Ne Bis in Idem as a Defence Right and Procedural Safeguard in the EU
Authors: Bravo Teresa
Published: March 2017

This paper will focus on the ne bis in idem principle, in the AFSJ as a defence right and argues that emancipating this principle from the conflict of jurisdictions debate will increase the status of defence rights in the EU and enhance its dimension as a procedural safeguard.

Article 82(2), b) of the TFEU paves the way to harmonisation of procedural safeguards, on an EU level, and can also be understood as a means to create a “common legal grammar” between Member States. Consequently, European legislation regarding ne bis in idem would not only bring legal certainty but it also contributes to diminishing the grounds of refusal as far as mutual recognition legal instruments are concerned. The need for a deontic European model regarding defence rights and procedural safeguards is also in discussion as it would serve as a counterweight between the two dimensions of European integration, in the AFSJ: freedom and security.
Historical Development of Penitentiary Legislation in Albania
Authors: Gashi Rexhep
Published: March 2017

This paper presents and analyzes the historical development of penitentiary legislation in Albania during the communist dictatorship and the period after the establishment of political pluralism and the victory of democracy in Albania.

During the communist dictatorship from 1944–1991, the legal regulation of the system of imprisonment for crimes committed was defective, and this led to arbitrary and abusive conduct on the part of the authorities. Where there was regulation it was largely politicized and ideologized and was therefore a powerful weapon in the hands of the proletarian dictatorship.

Also, during this time and up to the advance to democracy in Albania, a large number of prisons and labour camps were operated whose inmates were predominantly political prisoners.

In the period after the establishment of political pluralism and the advent in 1991 of Albania's fragile democracy until today, a considerable number of legal acts governing incarceration as a punishment have been approved. Also several conventions and other international acts in the field of fundamental freedoms and human rights, including rights of convicted persons have been ratified. But despite some tangible results this legislation has not led to acceptable penitentiary practices.
The Criminalisation Power of the European Union after Lisbon and the Principle of Democratic Legitimacy
Authors: Simon Perrine
Published: March 2017

This article proposes to scrutinise the process of enacting substantive criminal law under the new competence of the Lisbon Treaty, namely under article 83 in light of the notion of legitimacy as endorsed by the principle of legality. The article focuses in a first part on the scope of the competence under article 83 TFEU and concludes that this criminal law competence is broad and still tainted by uncertainty. In a second part, the paper looks at the theoretical implementation of the competence regarding subsidiarity and proportionality tests and concludes that these principles seem to play as an insufficient safeguard. However proportionality could constitute an adequate safeguard to the use of criminal law competence if rearticulated to incorporate the principle of ‘ultima ratio’.
The European Union's Response to Irregular Migration and the Problem of Criminalisation
Authors: Kramo Yvonne Afia
Published: March 2017

The global approach to migration adopted by the European Union (EU) has been heavily criticised for its control-based measures which fail to incorporate a rights-based approach to migration governance. This paper considers how irregular migration has emerged as a policy priority at the supranational level and how this has resulted in the convergence of administrative and criminal legal regimes to deal with the migration ‘problem’. It considers the burgeoning case law of the Court of Justice of the European Union concerning the interpretation of the 2008 Returns Directive to examine the emerging link between EU law and the criminalisation of irregular migrants, a practice that has developed in line with the ‘crimmigration’ trend seen in other Western jurisdictions. By engaging with the relevant criminological and criminal law literature, this paper illustrates the practical and normative challenges which arise from this punitive approach to migration and the manner in which EU law is implicated in the criminalisation trend. In so doing, it concludes that the use of criminal law for immigration enforcement not only challenges key values which underpin EU law, but also constitutes a violation of liberal criminal law principles.
Enforcing the Market Abuse Regime: Towards an Integrated Model of Criminal and Administrative Law Enforcement in the European Union?
Authors: Luchtman Michiel , Vervaele John
Published: March 2017

The European Union has long been an important driver for the integration of financial markets in Europe. The goal of this article is to map how the current and future legal infrastructure in respect of the investigation, prosecution and punishment of market abuse rules supports the central assumption of the EU legislature that, in order to offer a comprehensive package in the fight against market abuse, a level playing field throughout the EU is necessary. Although good progress has been made with the proposals for a new regulation and directive on market abuse, it is our opinion that these proposals still do not sufficiently take account of the fact that highly integrated financial markets also need highly integrated law enforcement structures and powers, regardless of the organizational statute of the national authorities involved (criminal or administrative).
The Contribution of the Court of Justice to the Structuring of the European Space of Fundamental Rights
Authors: Ritleng Dominique
Published: March 2017

With the Melloni and Akerberg Fransson judgments, the Court of Justice has greatly helped to define the articulation of the different systems of legal protection of fundamental rights in the European Union, by providing useful guidance on the scope of application of the Charter, the concurring application of the different standards of protection and the convergence of the EU Charter and of the European Convention on human rights.
Ne Bis in Idem and the Enforcement Condition: Balancing Freedom, Security and Justice?
Authors: Wasmeier Martin
Published: March 2017

A transnational ne bis in idem rule (or: prohibition of double jeopardy) is a core element of the area of freedom, security and justice. It has been given different expressions in Article 50 of the Charter and Article 54 of the Convention Implementing the Schengen Convention (CISA). In its judgment of 27 May 2014, the Court dealt with the relation between these provisions. This article critically discusses the judgment's reasoning and its conclusion that the “enforcement clause” (which subjects ne bis in idem to additional conditions regarding the enforcement of a penalty) is fully compatible with the Charter. It is submitted that additional elements should be taken into account in the necessity and proportionality test under Article 52(1) of the Charter, such as: a clarification of the right's rationale, possible alternatives to the enforcement clause and a thorough balancing between security concerns, free movement, procedural fairness and material justice. The Court's core argument, according to which the existing framework for judicial cooperation in criminal matters is insufficient to prevent risks of impunity is put under particular scrutiny. Furthermore, in the light of the previous case law on double jeopardy and the judgment in Case “M” of 5 June 2014, the article underlines the need to ensure consistency in the reasoning.
To Continue or Not: Who Shall Be in Control of the European Public Prosecutor's Dismissal Decisions?
Authors: Göhler Johanna
Published: March 2017

This article intends to present a comprehensive framework for a regime of judicial review on dismissal decisions taken by a future European Public Prosecutor's Office (EPPO). To clearly outline the process of this judicial review the article poses and analyses several underlying issues. First, will a supranational solution be superior to the application of the Member States' individual review systems? If a supranational solution is approved, which legal basis can serve as the foundation for this supranational regime and on which theoretical foundation should it be based? Finally, who should be granted standing to request a review?

It is suggested that judicial review might be enacted on a supranational level. Standing should be granted to EU citizens with an identifiable status in a particular case and to defined groups with a recognised status. The review shall confirm the legality of prosecutorial decisions and maintain public confidence in the EPPO.
Typology of Pre-Lisbon Acts and Their Legal Effects According to Protocol No. 36
Authors: Zeder Fritz
Published: March 2017

The legal effects of acts in the field of police cooperation and judicial cooperation in criminal matters, adopted on the basis of the TEU prior to the entry into force of the Treaty of Lisbon, are preserved until those acts are repealed, annulled or amended. There is still a considerable number of such acts in force. The article looks into what exactly these legal effects are today, distinguishing between four categories of such acts (framework decisions, decisions, implementing decisions and conventions); one of the legal effects looked at is the possibility of infringement procedures. Reference is made to a recent ECJ judgment which clarifies the legal effects of implementing decisions and rules that such decisions can still be adopted today, under certain procedural requirements.
The Instruments of Harmonisation of National Criminal Law, Their Enforcement and the Role of the Court of Justice
Authors: Grasso Giovanni
Published: March 2017

One of the main innovations of the Treaty of Lisbon relating to criminal justice matters is the abolition of the division into pillars that had featured within the previous institutional structure. This institutional change will have an effect on the legal instruments of the Area of Freedom, Security and Justice, adopted since the entry into force of the Treaty of Lisbon. As far as the acts adopted in the past, the transitional regime enshrined in Articles 9 and 10 of Protocol no. 36 (devoted to transitional provisions) needs to be carefully examined. According to Article 9, the third pillar acts adopted before the entry into force of the Treaty of Lisbon keep their proper effects unchanged ‘until those acts are repealed, annulled or amended in implementation of the Treaties’; in the field of harmonisation or approximation of national sanctioning rules, this means that third pillar harmonising legal instruments (usually framework decisions) will continue to have their legal effects. Such effects differ in several respects from those of the directives. Article 10 of Protocol no. 36 is especially devoted to the competence of the European Court of Justice. In particular, it states that in relation to the third pillar acts adopted before the entry into force of the Treaty of Lisbon, the previous provisions of Title VI of the original version of the Treaty on European Union, and especially Article 35, continue to apply. This transitional regime meets two limitations. First of all, the new provisions on the competence of the Court will apply in case of amendment of a third pillar act and for those Member States to which that amended act shall apply (Article 10 (2)). Secondly, after the transitional period of five years, the new provisions will apply (Article 10 (3)). This article will carefully examine these provisions through some examples based on several measures adopted after the entry into force of the Treaty of Lisbon.
Exchanging Information on Road Traffic Offences: A Measure of Police Cooperation or Transport Policy? Case Note on C-43/12 Commission v Parliament and Council
Authors: Vavoula Niovi
Published: March 2017

The present case note examines the judgment of the CJEU concerning the legal basis of an EU instrument establishing an information exchange system for road-traffic offences (C-43/12 Commission v Parliament and Council). The case arose from the interinstitutional battle between the Commission on the one hand and the Parliament and Council on the other, whereby the former considered that such a scheme forms part of the EU transport policy, while the latter opined that it constitutes a standard police cooperation measure. In this context, this case note maps the historical background behind the case from the release of proposal for a directive by the Commission to the adoption of a Framework Decision instead and the institution of infringement proceedings before the CJEU. Then, the conflicting opinions of the parties, the Advocate General and the Grand Chamber are analysed, followed by commentary.
The Judge and Citizenship of the Union
Authors: Jaeger Marc
Published: March 2017

This article provides an overview of the role of the judge in safeguarding the rights of the Union citizen in an area of freedom, security and justice. It is first the Courts of the Union who have provided the necessary impetus to give legal effectiveness to a concept that could have remained a mere political instrument. It is then the Courts of the Union who have ensured the protection of the rights of the citizen of the Union against challenges by Member States and institutions and bodies of the Union, while maintaining the balance with the prerogatives of the Member States and of the institutions and bodies subject to its judicial review. It is now also the national judge that is directly tasked with ensuring the implementation of the rights of the Union citizen in everyday life and who has truly become an ordinary judge of EU law.
Crossed fused renal ectopia in a Persian cat
Authors: Seo Sang-Hyuk , Lee Hyun-A , Suh Sang-Il , Choi Ran , Park In-Chul , Hyun Changbaig
Published: March 2017

Case summary

This report describes a rare case of crossed fused renal ectopia (CFRE) in a cat. A mature intact male Persian cat presented with bloody nasal discharge and ascites. Diagnostic studies revealed an ectopic left kidney fused with an orthotopic right kidney and a concurrent feline infectious peritonitis (FIP) infection. The FIP was responsible for clinical signs in this cat, while clinical signs associated with CFRE were not obvious. Despite receiving intensive treatment, the cat died. A post-mortem examination was not performed because the owners declined approval.

Relevance and novel information

To the best of our knowledge, this is the first report of L-shaped CFRE in a cat. In addition, this report describes the CT features of L-shaped CFRE in a cat.
The h-Index of Editorial Board Members Correlates Positively With the Impact Factor of Sports Medicine Journals
Authors: Kay Jeffrey , Memon Muzammil , de SA Darren , Simunovic Nicole , Duong Andrew , Karlsson Jon , Ayeni Olufemi Rolland
Published: March 2017

Background:

The h-index is a metric widely used to present both the productivity and impact of an author’s previous publications.

Purpose:

To evaluate and observe any correlations among the h-indices of 2015 editorial board members from 8 top sports medicine journals.

Study Design:

Systematic review.

Methods:

The sex, country of residence, degree, and faculty position of the editorial board members were identified using their respective scientific publication profiles. The h-index and other bibliometric indicators of these editorial board members were obtained using both the Web of Science (WoS) and Google Scholar (GS) databases. Nonparametric statistics were used to analyze differences in h-index values, and regression models were used to assess the ability of the editorial board member’s h-index to predict their journal’s impact factor (IF).

Results:

A total of 422 editorial board members were evaluated. The median h-index of all editors was 20 (interquartile range [IQR], 19) using GS and 15 (IQR, 15) using WoS. GS h-index values were 1.19 times higher than WoS, with significant correlation between these values ( r2 = 0.88, P = .0001). Editorial board members with a PhD had significantly higher h-indices than those without (GS, P = .0007; WoS, P = .0002), and full professors had higher h-indices than associate and assistant professors (GS, P = .0001; WoS, P = .0001). Overall, there were significant differences in the distribution of the GS ( P < .0001) and WoS ( P < .0001) h-indices of the editorial board members by 2014 IF of the journals. Both the GS h-index (β coefficient, 0.01228; 95% CI, 0.01035-0.01423; P < .0001) as well as the WoS h-index (β coefficient, 0.01507; 95% CI, 0.01265-0.01749; P < .0001) of editorial board members were significant predictors of the 2014 IF of their journal.

Conclusion:

The h-indices of editorial board members of top sports medicine journals are significant predictors of the IF of their respective journals.
Surgical treatment algorithms for post-burn contractures
Authors: Hayashida Kenji , Akita Sadanori
Published: March 2017

Burn contractures produce restrictions in motion and unacceptable aesthetic results, frequently with persistent wounds. Proper planning and tissue selection are essential to minimize donor site morbidity optimizing outcomes. The principle of burn reconstructive surgery requires that the defects after release should be replaced with donor tissues which have matching texture and color as well as enough pliability. Autologous skin grafting or flap surgeries meet these criteria to replace scar tissues and resurface the subsequent to post-released scar defects. Despite the benefits, the use of flaps is often limited in burn patients for many reasons. If a surgeon intends to release completely and reconstruct in one-stage operation, a large defect may result in large donor site morbidity, necessitating flap surgery including free flap surgery. A lot of different methods and procedures are available for resurfacing the defects, and these are reviewed. In this article, algorithms for the release of burn contractures and reconstructive methods are presented. These treatment algorithms should aid in achieving significant improvement in both joint motions and aesthetic deformities.
Ultrasound Molecular Imaging With BR55 in Patients With Breast and Ovarian Lesions: First-in-Human Results
Authors: Willmann Jürgen K. , Bonomo Lorenzo , Testa Antonia Carla , Rinaldi Pierluigi , Rindi Guido , Valluru Keerthi S. , Petrone Gianluigi , Martini Maurizio , Lutz Amelie M. , Gambhir Sanjiv S.
Published: March 2017

Purpose

We performed a first-in-human clinical trial on ultrasound molecular imaging (USMI) in patients with breast and ovarian lesions using a clinical-grade contrast agent (kinase insert domain receptor [KDR] –targeted contrast microbubble [MBKDR]) that is targeted at the KDR, one of the key regulators of neoangiogenesis in cancer. The aim of this study was to assess whether USMI using MBKDR is safe and allows assessment of KDR expression using immunohistochemistry (IHC) as the gold standard.

Methods

Twenty-four women (age 48 to 79 years) with focal ovarian lesions and 21 women (age 34 to 66 years) with focal breast lesions were injected intravenously with MBKDR (0.03 to 0.08 mL/kg of body weight), and USMI of the lesions was performed starting 5 minutes after injection up to 29 minutes. Blood pressure, ECG, oxygen levels, heart rate, CBC, and metabolic panel were obtained before and after MBKDR administration. Persistent focal MBKDR binding on USMI was assessed. Patients underwent surgical resection of the target lesions, and tissues were stained for CD31 and KDR by IHC.

Results

USMI with MBKDR was well tolerated by all patients without safety concerns. Among the 40 patients included in the analysis, KDR expression on IHC matched well with imaging signal on USMI in 93% of breast and 85% of ovarian malignant lesions. Strong KDR-targeted USMI signal was present in 77% of malignant ovarian lesions, with no targeted signal seen in 78% of benign ovarian lesions. Similarly, strong targeted signal was seen in 93% of malignant breast lesions with no targeted signal present in 67% of benign breast lesions.

Conclusion

USMI with MBKDR is clinically feasible and safe, and KDR-targeted USMI signal matches well with KDR expression on IHC. This study lays the foundation for a new field of clinical USMI in cancer.
Cost Implications of an Evidence-Based Approach to Radiation Treatment After Lumpectomy for Early-Stage Breast Cancer
Authors: Greenup Rachel A. , Blitzblau Rachel C. , Houck Kevin L. , Sosa Julie Ann , Horton Janet , Peppercorn Jeffrey M. , Taghian Alphonse G. , Smith Barbara L. , Hwang E. Shelley
Published: March 2017

Introduction:

Breast cancer treatment costs are rising, and identification of high-value oncology treatment strategies is increasingly needed. We sought to determine the potential cost savings associated with an evidence-based radiation treatment (RT) approach among women with early-stage breast cancer treated in the United States.

Patients and Methods:

Using the National Cancer Database, we identified women with T1-T2 N0 invasive breast cancers treated with lumpectomy during 2011. Adjuvant RT regimens were categorized as conventionally fractionated whole-breast irradiation, hypofractionated whole-breast irradiation, and omission of RT. National RT patterns were determined, and RT costs were estimated using the Medicare Physician Fee Schedule.

Results:

Within the 43,247 patient cohort, 64% (n = 27,697) received conventional RT, 13.3% (n = 5,724) received hypofractionated RT, 1.1% (n = 477) received accelerated partial-breast irradiation, and 21.6% (n = 9,349) received no RT. Among patients who were eligible for shorter RT or omission of RT, 57% underwent treatment with longer, more costly regimens. Estimated RT expenditures of the national cohort approximated $420.2 million during 2011, compared with $256.2 million had women been treated with the least expensive regimens for which they were safely eligible. This demonstrated a potential annual savings of $164.0 million, a 39% reduction in associated treatment costs.

Conclusion:

Among women with early-stage breast cancer after lumpectomy, use of an evidence-based approach illustrates an example of high-value care within oncology. Identification of high-value cancer treatment strategies is critically important to maintaining excellence in cancer care while reducing health care expenditures.
Mycobacterium tuberculosis Cpn60.2 (GroEL2) blocks macrophage apoptosis via interaction with mitochondrial mortalin
Authors: Joseph Sunil , Yuen Alex , Singh Vijender , Hmama Zakaria
Published: March 2017

Earlier studies suggested that Mycobacterium tuberculosis (Mtb) proteins exported within the host macrophage play an essential role in tuberculosis pathogenesis. In fact, Mtb proteins interact with and deactivate key regulators of many macrophage functions such as phago-lysosome fusion and antigen presentation, resulting in the intracellular persistence of pathogenic mycobacteria. Cpn60.2 is an abundant Mtb chaperone protein, restricted to cell cytoplasm and surface, that was reported to be essential for bacterial growth. Here, we provide evidence that once Mtb is ingested by the macrophage, Cpn60.2 is able to detach from the bacterial surface and crosses the phagosomal membrane towards mitochondria organelles. Once there, Cpn60.2 interacts with host mortalin, a member of HSP 70 gene family that contributes to apoptosis modulation. In this regard, we showed that Cpn60.2 blocks macrophage apoptosis, a phenotype that is reversed when cells are pretreated with a specific mortalin inhibitor. Our findings have extended the current knowledge of the Mtb Cpn60.2 functions to add a strong anti-apoptotic activity dependent on its interaction with mitochondrial mortalin, which otherwise promotes Mtb survival in the hostile macrophage environment.
In-air hearing of the great cormorant (Phalacrocorax carbo)
Authors: Maxwell Alyssa , Hansen Kirstin Anderson , Ortiz Sara Torres , Larsen Ole Næsbye , Siebert Ursula , Wahlberg Magnus
Published: March 2017

Many aquatic birds use sounds extensively for in-air communication. Regardless of this, we know very little about their hearing abilities. The in-air audiogram of a male adult great cormorant (Phalacrocorax carbo) was determined using psychophysical methods (method of constants). Hearing thresholds were derived using pure tones of five different frequencies. The lowest threshold was at 2 kHz: 18 dB re 20 µPa rms. Thresholds derived using signal detection theory were within 2 dB of the ones derived using classical psychophysics. The great cormorant is more sensitive to in-air sounds than previously believed and its hearing abilities are comparable to several other species of birds of similar size. This knowledge is important for our understanding of the hearing abilities of other species of sea birds. It can also be used to develop cormorant deterrent devices for fisheries, as well as to assess the impact of increasing in-air anthropogenic noise levels on cormorants and other aquatic birds.
Estrogen modulates mesenchyme-epidermis interactions in the adult nipple
Authors: Wu Hsing-Jung , Oh Ji Won , Spandau Dan F. , Tholpady Sunil , Diaz Jesus , Schroeder Laura J. , Offutt Carlos D. , Glick Adam B. , Plikus Maksim V. , Koyama Sachiko , Foley John
Published: March 2017

Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, the specific pathways involved remain to be identified. By recombining cells from the ventral skin of the K14-PTHrP transgenic mice [which overexpress parathyroid hormone-related protein (PTHrP) in their developing epidermis and mammary glands] with those from wild type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipple-like epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventral K14-PTHrP and wild-type fibroblasts, identifying differentially expressed transcripts that are involved in WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling. Considering that some of the growth factor pathways are targets for estrogen regulation, we examined the upstream role of this hormone in maintaining the nipple. Ablation of estrogen signaling through ovariectomy produced nipples with abnormally thin epidermis, and we identified TGFβ as a negatively regulated target of estrogen signaling. Estrogen treatment represses Tgfβ1 at the transcript and protein levels in K14-PTHrP fibroblasts in vitro, while ovariectomy increases Tgfb1 levels in K14-PTHrP ventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, these results show that specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts.
Human umbilical cord blood-borne fibroblasts contain marrow niche precursors that form a bone/marrow organoid in vivo
Authors: Pievani Alice , Sacchetti Benedetto , Corsi Alessandro , Rambaldi Benedetta , Donsante Samantha , Scagliotti Valeria , Vergani Patrizia , Remoli Cristina , Biondi Andrea , Robey Pamela G. , Riminucci Mara , Serafini Marta
Published: March 2017

Human umbilical cord blood (CB) has attracted much attention as a reservoir for functional hematopoietic stem and progenitor cells, and, recently, as a source of blood-borne fibroblasts (CB-BFs). Previously, we demonstrated that bone marrow stromal cell (BMSC) and CB-BF pellet cultures make cartilage in vitro. Furthermore, upon in vivo transplantation, BMSC pellets remodelled into miniature bone/marrow organoids. Using this in vivo model, we asked whether CB-BF populations that express characteristics of the hematopoietic stem cell (HSC) niche contain precursors that reform the niche. CB ossicles were regularly observed upon transplantation. Compared with BM ossicles, CB ossicles showed a predominance of red marrow over yellow marrow, as demonstrated by histomorphological analyses and the number of hematopoietic cells isolated within ossicles. Marrow cavities from CB and BM ossicles included donor-derived CD146-expressing osteoprogenitors and host-derived mature hematopoietic cells, clonogenic lineage-committed progenitors and HSCs. Furthermore, human CD34+ cells transplanted into ossicle-bearing mice engrafted and maintained human HSCs in the niche. Our data indicate that CB-BFs are able to recapitulate the conditions by which the bone marrow microenvironment is formed and establish complete HSC niches, which are functionally supportive of hematopoietic tissue.
Hox-mediated endodermal identity patterns the pharyngeal muscle formation in the chordate pharynx
Authors: Yoshida Keita , Nakahata Azusa , Treen Nicholas , Sakuma Tetsushi , Yamamoto Takashi , Sasakura Yasunori
Published: March 2017

The pharynx, possessing gill slits and the endostyle, is a characteristic of chordates that is a complex of multiple tissues well organized along the anterior-posterior (AP) axis. Although Hox genes show AP coordinated expression in the pharyngeal endoderm, tissue specific roles of these factors for establishing the regional identities within this tissue is largely unknown. Here, we show that Hox1 is essential for the establishment of AP axial identity of the endostyle, a major structure of the pharyngeal endoderm, in the ascidian Ciona intestinalis. We found that Hox1 knockout causes posterior to anterior transformation of the endostyle identity, and Hox1 represses Otx expression and anterior identity, and vice versa. Furthermore, alteration of the regional identity of the endostyle disrupts the formation of body wall muscles, suggesting that the endodermal axial identity is essential for the coordinated pharyngeal development. Our results reveal an essential role of Hox genes for establishment of the AP regional identity in the pharyngeal endoderm and crosstalk between endoderm and mesoderm for the development of chordate pharynx.
O método do caso
Authors: Curado Isabela Baleeiro
Published: March 2017

O caso não é apenas uma boa história. O artigo reflete sobre os demais requisitos de um bom caso (e de uma boa nota de enino).
Systematic assessment of multi-gene predictors of pan-cancer cell line sensitivity to drugs exploiting gene expression data
Authors: Nguyen Linh , Dang Cuong C , Ballester Pedro J.
Published: March 2017

Background:Selected gene mutations are routinely used to guide the selection of cancer drugs for a given patient tumour. Large pharmacogenomic data sets, such as those by Genomics of Drug Sensitivity in Cancer (GDSC) consortium, were introduced to discover more of these single-gene markers of drug sensitivity. Very recently, machine learning regression has been used to investigate how well cancer cell line sensitivity to drugs is predicted depending on the type of molecular profile. The latter has revealed that gene expression data is the most predictive profile in the pan-cancer setting. However, no study to date has exploited GDSC data to systematically compare the performance of machine learning models based on multi-gene expression data against that of widely-used single-gene markers based on genomics data.Methods:Here we present this systematic comparison using Random Forest (RF) classifiers exploiting the expression levels of 13,321 genes and an average of 501 tested cell lines per drug. To account for time-dependent batch effects in IC50measurements, we employ independent test sets generated with more recent GDSC data than that used to train the predictors and show that this is a more realistic validation than standard k-fold cross-validation.Results and Discussion:Across 127 GDSC drugs, our results show that the single-gene markers unveiled by the MANOVA analysis tend to achieve higher precision than these RF-based multi-gene models, at the cost of generally having a poor recall (i.e. correctly detecting only a small part of the cell lines sensitive to the drug). Regarding overall classification performance, about two thirds of the drugs are better predicted by the multi-gene RF classifiers. Among the drugs with the most predictive of these models, we found pyrimethamine, sunitinib and 17-AAG.Conclusions:Thanks to this unbiased validation, we now know that this type of models can predictin vitrotumour response to some of these drugs. These models can thus be further investigated onin vivotumour models. R code to facilitate the construction of alternative machine learning models and their validation in the presented benchmark is available athttp://ballester.marseille.inserm.fr/gdsc.transcriptomicDatav2.tar.gz.
Recent advances in understanding and preventing human papillomavirus-related disease
Authors: Hellner Karin , Dorrell Lucy
Published: March 2017

High-risk human papillomaviruses (hrHPV) are responsible for anogenital and oropharyngeal cancers, which together account for at least 5% of cancers worldwide. Industrialised nations have benefitted from highly effective screening for the prevention of cervical cancer in recent decades, yet this vital intervention remains inaccessible to millions of women in low- and middle-income countries (LMICs), who bear the greatest burden of HPV disease. While there is an urgent need to increase investment in basic health infrastructure and rollout of prophylactic vaccination, there are now unprecedented opportunities to exploit recent scientific and technological advances in screening and treatment of pre-invasive hrHPV lesions and to adapt them for delivery at scale in resource-limited settings. In addition, non-surgical approaches to the treatment of cervical intraepithelial neoplasia and other hrHPV lesions are showing encouraging results in clinical trials of therapeutic vaccines and antiviral agents. Finally, the use of next-generation sequencing to characterise the vaginal microbial environment is beginning to shed light on host factors that may influence the natural history of HPV infections. In this article, we focus on recent advances in these areas and discuss their potential for impact on HPV disease.
Lifetime Risk of Lung Cancer Death for Inhalation 239Pu
Authors: Василенко  , Vasilenko E. , Ефимов  , Efimov A. , Востротин  , Vostrotin V. , Сокольников  , Sokolnikov M. , Романов  , Romanov S.
Published: March 2017

Aim of the study: Assessment of reliability of radiation safety standards after inhalation intake of Pu-239. Material and methods: Using results of epidemiological study of lung cancer mortality in Mayak workers cohort and statistical data on all causes and lung cancer mortality in Russia the excess lifetime risk of lung cancer death was calculated. Results: Current radiation safety standards restrict annual intake of Pu-239 class “S” at 1300 Bq/year level. The annual limit of intake is calculated in a way that the level of committed effective dose in 50 years after intake should not exceed 20 mSv. At the same time radiation safety standards restrict the level of the excess lifetime risk of cancer death at the level of 0.05 (for category A personnel) and/or annual increment of excess lifetime risk at the level 0.001. The equivalent dose of alpha-particles to the lung after 50 years of inhalation intake of Pu class “S” when calculated according to DOSE-2008 model will be 7 Sv. Given the pattern of dose accumulation over time after this scenario of Pu class “S” inhalation intake we calculated excess relative risk of lung cancer death, lifetime excess risk of lung cancer death and annual increment of excess lifetime risk. In 50 years of exposure to inhalation intake of Pu-239 class “S” the excess lifetime risk of lung cancer death will be 0.08, i.e. will exceed the 0.05 limit provided in radiation safety standards. The annual increment of the lifetime risk will exceed limit of 0.001, provided by the radiation safety standards, at age 45 and older. These results demonstrate that the protection of personnel working with Pu-239 class “S” is insufficient in current radiation safety standards. One of the potential reasons is that lung contribution to total detriment for organism provided by ionizing radiation is averaged for all ages whereas for people of working age who contact to Pu at work this detriment doubles.
Safety of Salvage Cystectomy after the Faolure of Organ Preserving Treatment in Patients with Muscle Invasive Bladder Cancer
Authors: Панахов  , Panakhov A. , Романов  , Romanov V. , Евсюкова  , Evsyukova O. , Петерс  , Peters M. , Калинин  , Kalinin S. , Фигурин  , Figurin K. , Черняев  , Chernyaev V. , Тхакохов  , Tkhakokhov M. , Волкова  , Volkova M. , Матвеев  , Matveev V.
Published: March 2017

Purpose: To prove the safety of the salvage cystectomy after organ preserving treatment in patients with muscle invasive bladder cancer.

Material and methods: In the research retrospective data of 130 patients with muscle invasive transitional cell carcinoma of the bladder were selected. In the main group 66 patients undergoing of the salvage cystectomy after radiotherapy were included, in the control group – 64 patients who underwent of radical cystectomy without prior treatment. The main and control groups were matched by age, gender, category with cN (p > 0.05 for all). In the main group tumors which were beyond the bladder wall, hydronephrosis were more frequently diagnosed; during the salvage operations pelvic lymph node dissection rarely performed (p = 0.03) and orthotopic bladder substitution was made (p = 0.027).

Results: The median of duration of the salvage cystectomy was 310 min, which was not significantly different from 300 minutes in the control group (p = 0.711). The median of amount of bleeding of the patients undergoing surgery after irradiation, was not significantly lower than that the patients who had cystectomy which performed without prior radiation therapy (1329 and 1802 ml respectively, p = 0.118). The frequency of intraoperative complications of saving cystectomy was 10.6 %, which did not differ from 7.8 % in the control group (p = 0.300). Only one kind of complication of cystectomy after radiation therapy was difficult to control the bleeding in 6 cases (9.1 %). The frequency of postoperative complications – 42.7 % in the main and control group 42.2 % (p = 0.530). The perioperative mortality was equal to 6.1 %. The operating time, blood loss, frequency, structure and severity of complications i did not differ significantly n the main and control groups (p > 0.05 for all).

Conclusion: The salvage cystectomy is indicated to a sick muscle-invasive bladder cancer with an incomplete effect, relapse or intolerable toxicity, organ-preserving treatment, including radiation therapy. Desmoplastic reactions of the irradiated tissue cause the technical complexity of the interference and worsen the conditions for reparation. The most common intraoperative complication of salvage cystectomy is bleeding, in the structure of postoperative complications infections, intestinal obstruction and complications of the urinary anastomoses dominate. The accumulation of surgical experience make the frequency and severity complications of the salvage radical cystectomy comparable, offsetting an increase of operational risk in previously irradiated patients.
Evaluation of Therapeutic Gain \factor in Neutron Therapy Based on the Linear Quadratic Model
Authors: Лисин  , Lisin V.
Published: March 2017

Purpose: To study the dependencies of therapeutic gain factor (TGF) on dose of cyclotron-produced fast neutron beams using the linear-quadratic model (LQM) parameters characterizing radiation response in tumor and normal tissues.

Material and methods: The TGF in neutron therapy was calculated as the ratio of the relative biological effectiveness of neutrons for tumor (RBE tumor) to relative biological effectiveness for normal tissue (RBE normal tissue). The LQM was used to calculate the dependencies of neutron RBE on the dose and therapeutic gain factor. We considered two cases: 1) neutron therapy for 3 types of tumors with different radiation response, where the same normal tissue was critical; 2) neutron therapy for the same tumor, when 3 types of normal tissues were taken as critical.

Results: Based on calculations and analysis of published data, the dependencies of neutron RBE on dose for selected types of tumors and normal tissues were obtained. The following variants were considered: 1) RBE tumor > RBE normal tissue; 2) RBE tumor < RBE normal tissue, in both two variants, the dependen-

cies in the therapeutic dose rate were convergent; 3) the dependencies of RBE tumor and RBE normal tissue on dose are crossed. The dependencies of TGF for neutron therapy on single boost doses and quantitative ratios between the LQM parameters characterizing radiation response of tumor and normal tissues were found. A multivariate ratio between the dependencies on dose of RBE tumor and RBE normal tissue was the cause of variety in the dependencies of TGF on dose. In the first case, the TGF increased with increasing (α/β)γ ratio and decreasing single dose, and the maximum value of TGF was equal to ~ 1.4. In the second case, TGF was < 1, i.e. the effectiveness of neutron therapy was lower than the effectiveness of gamma irradiation, but it was increased with higher single dose and lower radiosensitivity of normal tissue. In the third case, the dose at the intersection point (Di) was the boundary, and TGF was > 1 to the left of the boundary, and TPV was <1 to the right of the boundary, provided that D  OBEnormal tissue.

Conclusion: The obtained results with known parameters of the LQM for tumor and normal tissues allowed us to make an appropriate choice between neutron and gamma- ray therapy in order to increase the effectiveness of treatment for cancer patients. It was shown that in the case of neutron therapy, the analysis of dependencies of TGF on dose allowed the optimal dose fractionation regimen to be selected.
Epistemological Naturalness: What is a good heuristic strategy good for?
Authors: Drobňák Matej
Published: March 2017

According to the standard interpretation of Lewis’s theory of predicate meaning (the U&N theory), the naturalness of meaning candidates should be stated metaphysically  as a length of definition in terms of fundamental properties. Recently, Weatherson has criticized the U&N theory and argued that the criterion of naturalness should be stated epistemologically  as the amount of evidence needed to form a belief. Despite the criticism, his attitude towards the U&N theory is quite relaxed. According to Weatherson, the U&N theory can be used as a good heuristic for delivering the correct verdicts when doing applied semantics, i.e., when we try to determine the best meaning candidate for a particular predicate.In this paper, I try to show that the “good heuristic strategy” is of no use because A) there is no guarantee that the epistemological and the metaphysical criteria of naturalness deliver the same verdicts and B) even if they deliver the same verdicts, the difference in their theoretical backgrounds may affect arguments which rely on the verdicts. The difference will be shown by drawing on the example of Theodore Sider and his use of the U&N theory.
Flowers that help us to flourish
Authors: Francis-Pester Dawn
Published: March 2017

Flower growing can be a magical activity for children. In this article, we take a look at four early years favourites, along with tips on how to grow them, and some potential uses.
Getting them settled in
Authors: Martland Rebecca
Published: March 2017

Children may arrive in a new childminder setting distraught and inconsolable, after all, it is a difficult time for both them and their parents, but we can help smooth the process.