Recognizing Members of the Tournament Equilibrium Set is NP-hard

A recurring theme in the mathematical social sciences is how to select the "most desirable" elements given a binary dominance relation on a set of alternatives. Schwartz's tournament equilibrium set (TEQ) ranks among the most intriguing, but also among the most enigmatic, tournament solutions that have been proposed so far in this context. Due to its unwieldy recursive definition, little is known about TEQ. In particular, its monotonicity remains an open problem up to date. Yet, if TEQ were to satisfy monotonicity, it would be a very attractive tournament solution concept refining both the Banks set and Dutta's minimal covering set. We show that the problem of deciding whether a given alternative is contained in TEQ is NP-hard.Comment: 9 pages, 3 figure

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

VACCELERATE Webinar - Humoral immune responses after SARS-CoV-2 vaccination in patients with cancer

Patients with cancer are at high risk for severe COVID-19 diseases and show impaired immune responses after vaccination. Specifically, levels of neutralizing antibodies against variants of concern, including Delta and Omicron, are lower in cancer patients. Fourth vaccination dose or administration of monoclonal neutralizing antibodies, such as tixagevimab and cilgavimab, is being considered, although data supporting this strategy are limited, especially for currently circulating variants, such as BA.4. The Medical University Vienna analyzed the variant-specific humoral immunity after active and passive SARS-CoV-2 immunization in 72 patients with haemato-oncological diseases by comparing antibody levels after the third and fourth vaccinations or administration of tixagevimab and cilgavimab in patients with cancer

Neurological complications of cancer immunotherapy

Immunotherapy has emerged as a powerful therapeutic approach in many areas of clinical oncology and hematology. The approval of ipilimumab, a monoclonal antibody targeting the immune cell receptor CTLA-4, has marked the beginning of the era of immune checkpoint inhibitors. In the meantime, numerous antibodies targeting the PD-1 pathway have expanded the class of clinically approved immune checkpoint inhibitors. Furthermore, novel antibodies directed against other immune checkpoints are currently in clinical evaluation. More recently, bispecific antibodies, which link T cells directly to tumor cells as well as adoptive T cell transfer with immune cells engineered to express a chimeric antigen receptor, have been approved in certain indications. Neurological complications associated with the use of these novel immunotherapeutic concepts have been recognized more and more frequently. Immune checkpoint inhibitors may cause various neurological deficits mainly by alterations of the peripheral nervous system's integrity. These include radiculopathies, neuropathies, myopathies as well as myasthenic syndromes. Side effects involving the central nervous system are less frequent but may result in severe clinical symptoms and syndromes. The administration of chimeric antigen receptor (CAR) T cell is subject to rigorous patient selection and their use is frequently associated with neurological complications including encephalopathy and seizures, which require immediate action and appropriate therapeutic measures. Close clinical monitoring for neurological symptoms is key for early recognition of immunotherapy-related side effects. Comprehensive diagnostic work-up and adequate therapeutic measures are essential to avoid further clinical deterioration and residual neurological deficits