First-in-Human Phase 1 Study of a B Cell- and Monocyte-Based Immunotherapeutic Vaccine against HER2-Positive Advanced Gastric Cancer.

PURPOSE: BVAC-B is an autologous B cell- and monocyte-based immunotherapeutic vaccine that contains cells transfected with a recombinant human epidermal growth factor receptor 2 (HER2) gene and loaded with the natural killer T cell ligand alpha-galactosylceramide. Here, we report the first BVAC-B study in patients with HER2-positive advanced gastric cancer. MATERIALS AND METHODS: Patients with advanced gastric cancer refractory to standard treatment with HER2+ immunohistochemistry ≥ 1 were eligible for treatment. Patients were administered low (2.5×107 cells/dose), medium (5.0×107 cells/dose), or high dose (1.0×108 cells/dose) of BVAC-B intravenously four times every 4 weeks. Primary endpoints included safety and maximum tolerated BVAC-B dose. Secondary endpoints included preliminary clinical efficacy and BVAC-B-induced immune responses. RESULTS: Eight patients were treated with BVAC-B at low (n=1), medium (n=1), and high doses (n=6). No dose-limiting toxicity was observed, while treatment-related adverse events (TRAEs) were observed in patients treated with medium and high doses. The most common TRAEs were grade 1 (n=2) and grade 2 (n=2) fever. Out of the six patients treated with high-dose BVAC-B, three had stable disease with no response. Interferon gamma, tumor necrosis factor-α, and interleukin-6 increased after BVAC-B treatment in all patients with medium and high dose, and HER2-specific antibody was detected in some patients. CONCLUSION: BVAC-B monotherapy had a safe toxicity profile with limited clinical activity; however, it activated immune cells in heavily pretreated patients with HER2-positive gastric cancer. Earlier treatment with BVAC-B and combination therapy is warranted for evaluation of clinical efficacy.

Continuous Measurement of Lactate Concentration in Human Subjects through Direct Electron Transfer from Enzymes to Microneedle Electrodes.

Microneedle lactate sensors may be used to continuously measure lactate concentration in the interstitial fluid in a minimally invasive and pain-free manner. First- and second-generation enzymatic sensors produce a redox-active product that is electrochemically sensed at the electrode surface. Direct electron transfer enzymes produce electrons directly as the product of enzymatic action; in this study, a direct electron transfer enzyme specific to lactate has been immobilized onto a microneedle surface to create lactate-sensing devices that function at low applied voltages (0.2 V). These devices have been validated in a small study of human volunteers; lactate concentrations were raised and lowered through physical exercise and subsequent rest. Lactazyme microneedle devices show good agreement with concurrently obtained and analyzed serum lactate levels.

Geophilosophies: towards another sense of the earth.

The relationship between 'philosophy' and the 'geo' has received renewed attention with the rise of the terrestrial and the planetary as leitmotifs for thinking about the collective subjectivation of particular kinds of world. In some of these conversations, this relationship is developed to consider how social collectives emerge with the production of particular kinds of territorial abstraction. Three decades since Gilles Deleuze and Félix Guattari published What is Philosophy?, book that has a lasting legacy in developing geophilosophy as a particular mode of transcendental empirical enquiry, this special issue revisits the relationship between geophilosophy and the production of an alternative sense of the earth. In this introduction, we approach geophilosophy in its pluralism by showing how the concept does not only concern the question of how to retain a sense of difference and contingency in thought, but also concerns a mode of enquiry that presents opportunities to experiment with alternative forms of collective subjectivation. Assaying the legacy of Deleuze and Guattari's geophilosophy on contemporary forms of earth-thinking, the article identifies the unique demands and geophilosophical possibilities taken up by the contributors to this issue that question how to recuperate another sense of the earth.

First-in-Man trial of a drug-free bioresorbable stent designed to minimize the duration of coronary artery scaffolding.

For the last two decades, various degradable stents have been proposed to treat coronary artery diseases and replace metallic stents to avoid residual foreign material after healing. To date, the right balance between suitable scaffolding and loss of radial strength soon after endothelium restoration is still an unmet need. The present article reports on the First-in-Man trial of a drug-free bioresorbable stent based on a lactic acid stereocopolymer composed of 98% l-lactyl units selected to release stress shielding earlier than in the case of homopoly(l-lactic acid). Thirty patients with single de novo coronary lesions were included in the trial. The fate of scaffolds was monitored by clinical and imaging follow-ups to assess rate of adverse events, acute recoil, late luminal loss, and late lumen recovery. There was no death, no myocardial infarction, and no stent thrombosis observed over the 36 months trial. Dismantling occurred about 3 months after implantation. Bioresorption was almost completed at 2 years. The late lumen loss observed at the end of the first year was partly compensated one year later by enlarging remodeling. At one year, a neointimal hyperplasia slightly greater than for drug-eluting metallic and bioresorbable stents was shown using optical coherence tomography. The excess of hyperplasia was discussed relative to struts thickness, absence of anti-proliferative drug, and release of degradation by-products.

Walking the Line: Balancing Access to Research and Protecting Prisoners.

Prisoners are often excluded from participating in clinical research (ie clinical trials and clinical investigations related to medicinal products and medical devices) due to the historical precedent of their abuse and exploitation. The exclusion of prisoners from clinical research is often deemed necessary to guarantee their protection from such abuse and exploitation. However, in this article, we argue that the right to science, which encompasses the right to access the benefits of science and research participation, is an emerging human right that is applicable to prisoners and may only be limited when this is necessary and proportionate. Whether this is necessary depends in part on the validity of a prisoner's informed consent. We discuss the importance of prison conditions for voluntary consent and examine the relationship between prison overcrowding and sub-par prison conditions by analysing the jurisprudence of the European Court of Human Rights on Article 3 of the European Convention on Human Rights on the prohibition of torture and inhuman treatment. We contend that the special circumstances of being in prison warrant additional protective measures, concurring with the Belgian Advisory Committee on Bioethics that research without the explicit aim of improving the situation of the individual prisoner or the prison community should be excluded. Given the complexity of the question of whether prisoners can give valid informed consent, rigorous oversight by an ethics committee with expertise concerning the prison system is necessary to provide a proportional balance between offering prisoners access to research and protection from abuse and exploitation.

A validated ultra-HPLC-MS/MS method for determination of honokiol in human plasma and its application to a clinical pharmacokinetic study.

Aim: To investigate pharmacokinetics of honokiol after administration of honokiol liposome injection (HKLI) and support the clinical studies of HKLI; it is crucial to determine the concentration of honokiol in human biological samples. Experimental method & results: Human plasma samples were extracted by protein precipitation and analyzed by a new ultra-HPLC-MS/MS (UPLC-MS/MS) method with LLOQ of 0.5 ng/ml. The method was validated according to bioanalytical guidelines from the US FDA and EMA. Successful method validation proved that the method was sensitive and selective, and was suitable for determination of honokiol in clinical plasma samples. Conclusion: The method was successfully applied to evaluate the pharmacokinetics of honokiol after administration of HKLI to Chinese subjects with advanced non-small-cell lung cancer in a first in-human study.

Mente fascista / Fascist mind / Mente fascista / L'esprit fasciste

O artigo discute o estado de mente fascista a partir da contribuição de Christopher Bollas. Dialoga também com filósofos que se interessaram pelo tema: Hannah Arendt e Giorgio Agamben. A mente fascista não é parlamentar (com vários pontos de vista em confronto, em diálogo), mas imperial: com um único ponto de vista fixo. Torna-se inumana. Para chegar a isso os fascistas desencadeiam uma guerra permanente primeiro contra si - por meio de múltiplos assassinatos contra as partes de seu self amoroso, reparador, compassivo - e depois contra os outros, eleitos para esse fim. Para eliminar toda a oposição interna, a mente fascista conta com a ideologia, crença, convicção - antídotos da dúvida, da hesitação -, convergindo para um campo de certezas. Projeções de partes do seu self serão lançadas para o outro: partes más, preconceituosas, desdenhadoras. Também se valem da introjeção extrativa, como defesa letal: roubando do outro - o inimigo eleito - partes de seu self.

The article discusses the state of the fascist mind, taking into account Christopher Bollas' contribution. It also establishes a fruitful dialogue with other philosophers who are interested in the subject: Hannah Arendt and Giorgio Agamben. The fascist mind is not parliamentary (with several conflicting points of view, in dialogue) but imperial: with a single fixed viewpoint. It becomes inhuman. In order to do that, fascists unleash an ongoing war, first against themselves - through multiple murderous actions against the parts of their loving, repairing, compassionate self - and, then, against the "others" chosen for that end. To eliminate all internal opposition, the fascist mind relies on ideology, belief, conviction - antidotes to doubt, hesitation - converging to a field of certainties. Projections of parts of her self will be thrown at the other: evil, biased, scornful parts. They also use extractive introjection, as a lethal defense: stealing from the other - the elect enemy - parts of their selves.

El artículo discute el estado de la mente fascista a partir de la contribución de Christopher Bollas. Dialoga también con otros filósofos que se interesaron por el tema: Hannah Arendt y Giorgio Agamben. La mente fascista no es parlamentaria (con varios puntos de vista en confrontación, en diálogo) pero si imperial: con un único punto de vista fijo. Se convierte en inhumana. Para llegar a eso los fascistas desencadenan una guerra permanente primero contra sí mismos - a través de múltiples asesinatos contra las partes de su propio self amoroso, reparador, compasivo - y luego contra los otros, elegidos para ese fin. Para eliminar toda la oposición interna, la mente fascista cuenta con la ideología, creencia, convicción - antídotos de la duda, de la vacilación - convergiendo hacia un campo de certezas. Las proyecciones de partes de su self serán lanzadas para el otro: partes malas, preconcebidas, despreciadoras. Se valen también de la introyección extractiva, como defensa letal: robando del otro - el enemigo elegido - partes de su self.

L'article discute l'état d'esprit fasciste à partir de la contribution de Christopher Bollas. Il dialogue également avec d'autres philosophes qui s'intéressent à cette thématique: Hannah Arendt et Giorgio Agamben. L'esprit fasciste n'est pas parlementaire (avec plusieurs points de vue en confrontation, en dialogue), mais impérial (avec un seul point de vue fixe). Il devient ainsi inhumain. Pour y arriver, les fascistes développent une guerre permanente, d'abord contre eux-mêmes - par des multiples assassinats contre de parts de leur self amoureux, réparateur, compatissant - et puis contre les autres, élus pour cette fin. Pour supprimer toute opposition interne, l'esprit fasciste compte sur l'idéologie, la croyance, la conviction - antidotes du doute, de l'hésitation - de façon à converger vers un champ de certitudes. Projections de parts de son self seront lancées vers l'autre: des parts méchantes, pleines de préjugés, méprisantes. Il s'utilise également de l'introjection extractive, en tant que défense létale: il vole de l'autre - l'ennemi élu - des parts de son self.

Operation evaluation in-human of a novel remote-controlled vascular interventional robot.

Remote-controlled vascular interventional robots (RVIRs) are being developed to increase the accuracy of surgical operations and reduce the number of occupational risks sustained by intervening physicians, such as radiation exposure and chronic neck/back pain. However, complex control of the RVIRs improves the doctor's operation difficulty and reduces the operation efficiency. Furthermore, incomplete sterilization of the RVIRs will increase the risk of infection, or even cause medical accidents. In this study, we introduced a novel method that provides higher operation efficiency than a previous prototype and allows for complete robot sterilization. A prototype was fabricated and validated through laboratory setting experiments and an in-human experiment. The results illustrated that the proposed RVIR has better performance compared with the previous prototype, and preliminarily demonstrated that the proposed RVIR has good safety and reliability and can be used in clinical surgeries.

Urgently awaiting implementation: The right to be free from exploitation, violence and abuse in Article 16 of the Convention on the Rights of Persons with Disabilities (CRPD).

The Convention on the Rights of Persons with Disabilities (CRPD) enshrines the freedom from exploitation, violence and abuse, a provision, which has hitherto received little attention. Exploring the contents of Article 16, this paper seeks to unpack both the potential for violence prevention as well as the implementation challenges. It situates violence protection within related treaty provisions and touches on specific challenges in institutional care as well as the private realm.

Liberdade e natureza (in)humana (Zizek versus Habermas) / Freedom and nature (in)human (Zizek versus Habermas)

O presente trabalho tem como objetivo problematizar a relação entre o princípio de liberdade e a ideia de natureza humana. Defendemos a tese de que o verdadeiro conceito de liberdade só pode ser pensado além dos limites (naturalmente) estabelecidos pela espécie humana. Logo, liberdade tem a ver com o domínio do inumano, não com o do humano. Desse modo, convém contrapor duas perspectivas contemporâneas que divergem radicalmente sobre o conceito de modernidade: a pragmática formal de Jürgen Habermas e o materialismo dialético de Slavoj Zizek. Tomamos como fio condutor, portanto, a polêmica sobre o tema da biogenética, e, a partir daí, procuramos demonstrar como a concepção de modernidade para Zizek - apoiado principalmente em Hegel e Lacan - revela-se ainda mais radical do que o projeto de uma modernidade inacabada de Habermas.

This paper aims to discuss the relationship between the principle of freedom and the idea of human nature. We seek to argue that the very concept of freedom can only be thought beyond the limits of course set by the human species. I.e. freedom has to do with the domain of the inhumane, not of the human. Therefore, it is essential to oppose two contemporary perspectives that differ radically about the concept of modernity: the Habermas' formal pragmatics and Slavoj Zizek's dialectical materialism. We must take, therefore, as a guide the controversy on the subject of biogenetic, and, from there, to demonstrate how the concept of modernity to Zizek proves to be even more radical than the Habermas' project of modernity unfinished.

Developing a novel comprehensive framework for the investigation of cellular and whole heart electrophysiology in the in situ human heart: historical perspectives, current progress and future prospects.

Understanding the mechanisms of fatal ventricular arrhythmias is of great importance. In view of the many electrophysiological differences that exist between animal species and humans, the acquisition of basic electrophysiological data in the intact human heart is essential to drive and complement experimental work in animal and in-silico models. Over the years techniques have been developed to obtain basic electrophysiological signals directly from the patients by incorporating these measurements into routine clinical procedures which access the heart such as cardiac catheterisation and cardiac surgery. Early recordings with monophasic action potentials provided valuable information including normal values for the in vivo human heart, cycle length dependent properties, the effect of ischaemia, autonomic nervous system activity, and mechano-electric interaction. Transmural recordings addressed the controversial issue of the mid myocardial "M" cell. More recently, the technique of multielectrode mapping (256 electrodes) developed in animal models has been extended to humans, enabling mapping of activation and repolarisation on the entire left and right ventricular epicardium in patients during cardiac surgery. Studies have examined the issue of whether ventricular fibrillation was driven by a "mother" rotor with inhomogeneous and fragmented conduction as in some animal models, or by multiple wavelets as in other animal studies; results showed that both mechanisms are operative in humans. The simpler spatial organisation of human VF has important implications for treatment and prevention. To link in-vivo human electrophysiological mapping with cellular biophysics, multielectrode mapping is now being combined with myocardial biopsies. This technique enables region-specific electrophysiology changes to be related to underlying cellular biology, for example: APD alternans, which is a precursor of VF and sudden death. The mechanism is incompletely understood but related to calcium cycling and APD restitution. Multielectrode sock mapping during incremental pacing enables epicardial sites to be identified which exhibit marked APD alternans and sites where APD alternans is absent. Whole heart electrophysiology is assessed by activation repolarisation mapping and analysis is performed immediately on-site in order to guide biopsies to specific myocardial sites. Samples are analysed for ion channel expression, Ca(2+)-handling proteins, gap junctions and extracellular matrix. This new comprehensive approach to bridge cellular and whole heart electrophysiology allowed to identify 20 significant changes in mRNA for ion channels Ca(2+)-handling proteins, a gap junction channel, a Na(+)-K(+) pump subunit and receptors (particularly Kir 2.1) between the positive and negative alternans sites.

Contesting the cruel treatment of abortion-seeking women.

This article draws on legal arguments made by civil society organisations to challenge the legal reasoning that apparently produced the decision in the Ms Y case in Ireland in August 2014. I show how legal standards of reasonableness and practicality ought to be interpreted in ways that are respectful of the patient's wishes and rights. The case concerned a decision by the Health Service Executive, the Irish public health authority, to refuse an abortion to a pregnant asylum seeker and rape survivor on the grounds that a caesarean section and early live delivery were practicable and reasonable alternatives justified by the need to protect fetal life. I argue that the abortion refusal may not have been a reasonable decision, as required by the terms of relevant legislation, for four different reasons. First, the alternative of a caesarean section and early live delivery was not likely to avert the risk of suicide, and in fact did not do so. Second, the consent to the caesarean section alternative may not have been a real consent in the legal sense if it was not voluntary. Third, an abortion refusal and forcible treatment fall below the norms of good medical practice as interpreted through a patient-centred perspective. Fourth, an abortion refusal that entails forms of cruel, inhumane and degrading treatment ought not to be a reasonable action under the legislation.