PARP Inhibitors in Prostate Cancer-the Preclinical Rationale and Current Clinical Development

Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. However, recent studies have proposed therapeutic potential for PARP inhibitors in tumors with a variety of vulnerabilities generating dependence on PARP beyond the synthetic lethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initially thought. Importantly, PARP-associated DNA repair pathways are also closely connected to androgen receptor (AR) signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer. In this review, we provide an extensive overview of published and ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss the underlying biology. Several clinical trials are currently studying PARP inhibitor mono-and combination therapies in the treatment of prostate cancer. Integration of drugs targeting DNA repair pathways in prostate cancer treatment modalities allows developing of more personalized care taking also into account the genetic makeup of individual tumors

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder with unclear underlying mechanisms. Here, the authors unravel the contribution of a stress-responsive pathway to RSTS where impaired HSF2 acetylation, due to RSTS-associated CBP/EP300 mutations, alters the expression of neurodevelopmental players, in keeping with hallmarks of cell-cell adhesion defects.Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.</p

Human-Multi-Drone Interaction in Search and Rescue Systems under High Cognitive Workload

Unmanned Aerial Vehicles (UAV), often referred to as drones, have seen increased use in search and rescue (SAR) missions. Traditionally, these missions involve manual control of each drone for aerial surveillance. As UAV autonomy progresses, the next phase in drone technology consists of a shift to autonomous collaborative multi-drone operations, where drones function collectively in swarms. A significant challenge lies in designing user interfaces that can effectively support UAV pilots in their mission without an overload of information from each drone and of their surroundings. This thesis evaluates important human factors, such as situational awareness (SA) and cognitive workload, within complex search and rescue scenarios, with the goal of increasing trust in multi-drone systems through the design and testing of various components. Conducting these user studies aims to generate insights for the future design of multi-drone systems. Two prototypes were developed with a multi-drone user interface, and simulated a stressful search and rescue mission with high cognitive workload. In the second prototype, a heatmap guided UAV pilots based on the lost person model. The prototypes were tested in a conducted user study with experienced UAV pilots in different SAR organizations across Sweden. The results showed variability in SA while monitoring drone swarms, depending on user interface components and SA levels. The prototypes caused significant cognitive workload, slightly reduced in the heatmap-equipped prototype. Furthermore, there was a marginal increase in trust observed in the prototype with the heatmap. Notably, a lack of manual control raised challenges for the majority of participants and many desired features were suggested by participants. These early expert insights can serve as a starting point for future development of multi-drone systems.The HERD project, supported by the Innovation Fund Denmark for the DIREC project (9142-00001B

The Nurse anesthesia’s experience of using endotracheal tube and laryngeal mask in case of sudden cardiac arrest

Introduktion: Anestesisjuksköterskor arbetar inom flera olika delar av sjukvården. Tack vare deras kunskaper om luftvägar och omhändertagande av kritiskt sjuka patienter så anställs anestesisjuksköterskor inom olika prehospitala verksamheter så som exempelvis resursenheter. Vid plötsliga hjärtstopp är upprättandet av en fri luftväg kritiskt. Detta görs vanligen genom användandet av olika medicintekniska hjälpmedel som larynxmask eller endotrachealtub. De respektive hjälpmedlen har olika styrkor och svagheter som är väl studerade, men upplevelser av att använda dessa metoder finns det lite forskning om. Syfte: Syftet med studien var att studera anestesisjuksköterskans upplevelser av att använda larynxmask och endotrachealtub vid plötsliga hjärtstopp utanför sjukhuset. Metod: En kvalitativ induktiv enkätstudie med öppna semistrukturerade frågor genomfördes för att fånga användarnas upplevelser av skillnader mellan dessa metoder av luftvägshantering. 14 anestesisjuksköterskor med minst två års erfarenhet samt erfarenhet av att arbeta prehospitalt deltog i studien. Deltagarna arbetar i tre regioner vilka har stora skillnader i resurser och arbetsrutiner. Resultat: Larynxmask var mest använt, trots att nästan alla deltagare föredrog att ha patienten intuberad. Orsaken till att laynxmasken användes trots att deltagarna föredrog att patienten skulle ha en endotrachealtub varierade något men hade flera gemensamma faktorer så som tidsåtgång och enkel användning. Introduction: Nurse anesthesias work in different parts of healthcare. In various prehospital activities and different resource units these specialist nurses are often hired for their knowledge of the airways and critical patients. In case of sudden cardiac arrest, the establishment of a free airway is critical. This is usually done using various medical aids such as a laryngeal mask or endotracheal tube. These have their different strengths and weaknesses that are well studied, but there is little research on experiences of using these methods. Aim: The aim of the study was to study anesthesia nurses' experiences of using a laryngeal mask and endotracheal tube in sudden cardiac arrest outside the hospital. Method: A qualitative inductive survey with open semistructural questions, was done to capture the users’ experiences of the differences between these methods of airway management. This study included 14 nurse anesthetists, with at least 2 years of experience and experience of working in a prehospital setting. Participants from three regions participated, those regions differ in resources and ways of working routines. Result: The laryngeal mask is most commonly used, even though almost all participants prefer to have an intubated patient. The reasons for that varies between the participants but have several common factors such as time of application and ease of use

The Nurse anesthesia’s experience of using endotracheal tube and laryngeal mask in case of sudden cardiac arrest

Introduktion: Anestesisjuksköterskor arbetar inom flera olika delar av sjukvården. Tack vare deras kunskaper om luftvägar och omhändertagande av kritiskt sjuka patienter så anställs anestesisjuksköterskor inom olika prehospitala verksamheter så som exempelvis resursenheter. Vid plötsliga hjärtstopp är upprättandet av en fri luftväg kritiskt. Detta görs vanligen genom användandet av olika medicintekniska hjälpmedel som larynxmask eller endotrachealtub. De respektive hjälpmedlen har olika styrkor och svagheter som är väl studerade, men upplevelser av att använda dessa metoder finns det lite forskning om. Syfte: Syftet med studien var att studera anestesisjuksköterskans upplevelser av att använda larynxmask och endotrachealtub vid plötsliga hjärtstopp utanför sjukhuset. Metod: En kvalitativ induktiv enkätstudie med öppna semistrukturerade frågor genomfördes för att fånga användarnas upplevelser av skillnader mellan dessa metoder av luftvägshantering. 14 anestesisjuksköterskor med minst två års erfarenhet samt erfarenhet av att arbeta prehospitalt deltog i studien. Deltagarna arbetar i tre regioner vilka har stora skillnader i resurser och arbetsrutiner. Resultat: Larynxmask var mest använt, trots att nästan alla deltagare föredrog att ha patienten intuberad. Orsaken till att laynxmasken användes trots att deltagarna föredrog att patienten skulle ha en endotrachealtub varierade något men hade flera gemensamma faktorer så som tidsåtgång och enkel användning. Introduction: Nurse anesthesias work in different parts of healthcare. In various prehospital activities and different resource units these specialist nurses are often hired for their knowledge of the airways and critical patients. In case of sudden cardiac arrest, the establishment of a free airway is critical. This is usually done using various medical aids such as a laryngeal mask or endotracheal tube. These have their different strengths and weaknesses that are well studied, but there is little research on experiences of using these methods. Aim: The aim of the study was to study anesthesia nurses' experiences of using a laryngeal mask and endotracheal tube in sudden cardiac arrest outside the hospital. Method: A qualitative inductive survey with open semistructural questions, was done to capture the users’ experiences of the differences between these methods of airway management. This study included 14 nurse anesthetists, with at least 2 years of experience and experience of working in a prehospital setting. Participants from three regions participated, those regions differ in resources and ways of working routines. Result: The laryngeal mask is most commonly used, even though almost all participants prefer to have an intubated patient. The reasons for that varies between the participants but have several common factors such as time of application and ease of use

ATM/ATR-mediated phosphorylation of PALB2 promotes RAD51 function

DNA damage activates the ATM and ATR kinases that coordinate checkpoint and DNA repair pathways. An essential step in homology‐directed repair (HDR) of DNA breaks is the formation of RAD51 nucleofilaments mediated by PALB2–BRCA2; however, roles of ATM and ATR in this critical step of HDR are poorly understood. Here, we show that PALB2 is markedly phosphorylated in response to genotoxic stresses such as ionizing radiation and hydroxyurea. This response is mediated by the ATM and ATR kinases through three N‐terminal S/Q‐sites in PALB2, the consensus target sites for ATM and ATR. Importantly, a phospho‐deficient PALB2 mutant is unable to support proper RAD51 foci formation, a key PALB2 regulated repair event, whereas a phospho‐mimicking PALB2 version supports RAD51 foci formation. Moreover, phospho‐deficient PALB2 is less potent in HDR than wild‐type PALB2. Further, this mutation reveals a separation in PALB2 function, as the PALB2‐dependent checkpoint response is normal in cells expressing the phospho‐deficient PALB2 mutant. Collectively, our findings highlight a critical importance of PALB2 phosphorylation as a novel regulatory step in genome maintenance after genotoxic stress

Anaphase-Promoting Complex/Cyclosome Participates in the Acute Response to Protein-Damaging Stress ▿

The ubiquitin E3 ligase anaphase-promoting complex/cyclosome (APC/C) drives degradation of cell cycle regulators in cycling cells by associating with the coactivators Cdc20 and Cdh1. Although a plethora of APC/C substrates have been identified, only a few transcriptional regulators are described as direct targets of APC/C-dependent ubiquitination. Here we show that APC/C, through substrate recognition by both Cdc20 and Cdh1, mediates ubiquitination and degradation of heat shock factor 2 (HSF2), a transcription factor that binds to the Hsp70 promoter. The interaction between HSF2 and the APC/C subunit Cdc27 and coactivator Cdc20 is enhanced by moderate heat stress, and the degradation of HSF2 is induced during the acute phase of the heat shock response, leading to clearance of HSF2 from the Hsp70 promoter. Remarkably, Cdc20 and the proteasome 20S core α2 subunit are recruited to the Hsp70 promoter in a heat shock-inducible manner. Moreover, the heat shock-induced expression of Hsp70 is increased when Cdc20 is silenced by a specific small interfering RNA (siRNA). Our results provide the first evidence for participation of APC/C in the acute response to protein-damaging stress