The protein barrier-to-autointegration factor (BAF) and its interaction partners, the LEM (LAP2B, emerin, MAN1)-domain proteins, constitute a powerful cytoplasmic DNA defense mechanism. invading DnA molecules are quickly bound by the BAf system and trapped in membrane compartments. This decreases the nuclear uptake of DNA from the cytoplasm. Inhibition of the BAF system is therefore expected to enhance the efficacy of non-viral DNA transfection agents. In this study, we introduced a protocol for the recombinant expression of soluble BAf and developed two eLiSA-type assays to discover small molecule inhibitors of BAf-dependent DnA retention by high throughput screening (HTS). The proton pump inhibitor rabeprazole as well as three compounds of the Maybridge library were identified as inhibitors of the LEM-BAF-DNA interaction chain. The inhibition was based on adduct formation with BAF cysteine residues. An enhancing effect of the compounds on cell culture transfection, however, was not observed, which may be attributed to the reducing environment of the cytoplasm that prevents the adduct formation with BAF cysteine residues. The novel assays developed here can provide new tools to further study the biological functions of the BAf system, and may lead to the identification of suitable BAF inhibitors in future HTS campaigns.

The recent success achieved by immune checkpoint inhibitors in the field of immuno-oncology has been less evident for the treatment of metastatic colorectal cancer (mCRC) patients. To date, cancer immunotherapy has been efficacious only in few patients bearing high mutational burden (less than 25%) mCRCs. In this Communication, we report the generation of a novel antibody cytokine fusion protein (termed Sm3E-mIL12) targeting the CRC-associated carcinoembryonic antigen (CEA). The antibody moiety bound avidly to CEA when immobilized on solid supports, and selectively stained C51 tumor cells transfected with the antigen (C51-CEA). The cytokine payload retained full activity in vitro, as compared to the parental recombinant interleukin-12 (IL12). Ex vivo microscopic analyses revealed a homogenous distribution of Sm3E-mIL12 in the neoplastic mass upon intravenous administration. In vivo, Sm3E-mIL12 was well tolerated up to 180 µg per mouse. The targeted delivery of IL12 to CEA-expressing C51 carcinomas led to durable complete responses in 60% of the treated mice. The intratumoral density of immune effector cells was markedly increased after the third injection of Sm3E-mIL12, in keeping with the progressive regression of the neoplastic mass. The data suggest that a fully human analogue may be considered for the treatment of patients with mCRC.

Dans le cadre des traitements de la dépendance à l’héroïne, des tests urinaires réguliers sont imposés dans certains cantons, même si pas recommandés par la société de discipline. Dans notre contribution nous examinons la justification médicale et sociale de ces tests et leur fondement éthique. Sous l’angle juridique, nous sommes d’avis qu’ils constituent une atteinte à la sphère privée et à la liberté personnelle de la personne soignée. Pareille ingérence lorsqu’imposée par l’Etat nécessite une base légale qui, aujourd’hui, à notre avis, fait défaut. Lorsque le médecin ordonne le test, il doit se fonder sur le consentement libre et éclairé de son mandant, condition rarement remplie. Nous recommandons que ces tests soient limités aux seules situations où la personne en traitement en fait la demande. -- Bei der Behandlung der Heroinabhängigkeit werden in gewissen Kantonen regelmässige Urintests vorgeschrieben, obwohl dies von der Fachgesellschaft nicht empfohlen wird. In unserem Beitrag untersuchen wir die medizinische und soziale Rechtfertigung für diese Tests sowie ihre ethische Begründung. Aus rechtlicher Sicht sind wir der Meinung, dass sie einen Eingriff in die Privatsphäre und die persönliche Freiheit der behandelten Person darstellen. Solche Eingriffe durch den Staat bedürfen einer gesetzlichen Grundlage, die unseres Erachtens zurzeit nicht gegeben ist. Wenn der Arzt den Test anordnet, muss er sich auf die freie und informierte Zustimmung des Patienten stützen – eine Bedingung, die selten erfüllt ist. Wir empfehlen, solche Tests auf Situationen zu beschränken, in denen die zu behandelnde Person sie wünscht.

Prescrire des médicaments contenant des substances soumises à contrôle (SSC : stupéfiants et substances psychotropes) peut avoir des conséquences en matière de circulation routière. Nous présentons ici les devoirs du médecin et les risques encourus par la personne en traitement, avant de plaider pour une clarification s'agissant de médicaments pouvant influer sur la capacité ou l'aptitude à la conduite. Driving under the influence…Prescribing medicines containing controlled substances (SSC : narco tics and psychotropic substances) can have legal consequences as per the Road Traffic Act. We set forth the physician's duties as well as the risks incurred by the patient. We recommend that rules regarding SSC, which can influence the capacity or the ability to drive, be clarified. VIGNETTE CLINIQUE : DISCUSSIONDans le cas de la vignette, si le médecin a informé la personne traitée du risque spécifique lié à la prise de chacun des médica-

The word “narcotic” is often first associated with “illicit drugs”. Yet, many “narcotic” and psychotropic substances are, in fact, medicines. Controlled medicines (CM) are products that meet the legal definition of both a “narcotic” under the Swiss Narcotics Act and of a medicine under the Therapeutic Products Act. We aim to examine how similar and how different, respectively, the implementation of CM regulations is throughout French-speaking Switzerland. Based on a legal analysis of the cantonal regulations, we conducted semi-structured interviews with cantonal pharmacists and cantonal physicians. We asked them how they perceive and implement the federal legal requirements. We find that some of these requirements have fallen into disuse, notably the federal duty to notify off-label use of CM. We observe that counterfoil prescriptions in their current paper format are a veritable data graveyard in the sense that they are not actively used to monitor or supervise the market. Moreover, we detect different conditions for opioid agonist treatment authorization. Some cantons require additional physicians’ training or written commitments by the person treated. Our mapping of the CM regulation implementation can serve as a basis for cantons to review their practices.