The OMERACT Giant cell arteritis Ultrasonography Score: a potential predictive outcome to assess the risk of relapse during follow-up.

OBJECTIVE: To determine whether the OMERACT giant cell arteritis (GCA) Ultrasonography (US) Score (OGUS) change after treatment can be used for assessing the probability of relapse. METHODS: Multicenter retrospective study of GCA patients referred to two US GCA fast-track clinics over 2 years. Patients underwent US evaluation at baseline, 3 and 6 months. EULAR definitions for remission and relapse were checked at 3 and 6 months. OGUS changes at 0-3 months and 0-6 months were compared among patients with and without relapse at 6 months, as well as those with and without remission at 6 months. RESULTS: A total of 76 patients were included (mean age 77.2 years, 55.3% females). Nineteen (26%) patients relapsed at 6-months, of whom 14(19.1%) showed a minor relapse. EULAR remission at 6 months was achieved by 32(43.8%) patients. The standardized mean difference of OGUS between baseline and 3 and 6 months was -0.25 and -0.38, respectively. OGUS significantly improved between baseline and 6 months (1.18 vs 0.99,p=0.004) and from 3-6 months (1.08 vs 0.99,p=0.04) in non-relapsing patients, whereas no significant changes at 3 (1.17 vs 1.17;p=0.736) and 6 (1.17 vs 1.21;p=0.343) months were observed in those who experienced relapse. Mean 0-6-month OGUS improvement was lower in patients who relapsed (-0.1 vs 0.16,p=0.037). Mean 0-6-month OGUS improvement was greater in patients who achieved remission at 6 months (0.28vs -0.07,p=0.001). CONCLUSIONS: The absence of OGUS improvement during follow-up in GCA may be used to assess the probability of relapse and the absence of remission at 6 months.

Low-dose ionizing γ-radiation elicits the extrusion of neutrophil extracellular traps.

PURPOSE: Cancer patients frequently undergo radiotherapy in their clinical management with unintended irradiation of blood vessels and copiously irrigated organs in which polymorphonuclear leukocytes circulate. Following the observation that such low doses of ionizing radiation are able to induce neutrophils to extrude neutrophil extracellular traps (NETs), we have investigated the mechanisms, consequences and the occurrence of such phenomena in patients undergoing radiotherapy. EXPERIMENTAL DESIGN: NETosis was analyzed in cultures of neutrophils isolated from healthy donors, cancer patients and cancer-bearing mice under confocal microscopy. Cocultures of radiation-induced NETs, immune effector lymphocytes and tumor cells were used to study the effects of irradiation-induced NETs on immune cytotoxicity. Radiation-induced NETs were intravenously injected to mice assessing their effects on metastasis. Circulating NETs in irradiated cancer patients were measured by ELISA methods detecting MPO-DNA complexes and citrullinated H3. RESULTS: Very low γ-radiation doses (0.5-1 Gy) given to neutrophils elicit NET formation in a manner dependent on oxidative stress, NADPH oxidase activity and autocrine interleukin-8. Radiation-induced NETs interfere with NK- and T-cell cytotoxicity. As a consequence, pre-injection of irradiation-induced NETs increases the number of successful metastases in mouse tumor models. Increases in circulating NETs were readily detected in two prospective series of patients following the first fraction of their radiotherapy courses. CONCLUSIONS: NETosis is induced by low-dose ionizing irradiation in a neutrophil-intrinsic fashion and radiation-induced NETs are able to interfere with immune-mediated cytotoxicity. Radiation-induced NETs foster metastasis in mouse models and can be detected in the circulation of patients undergoing conventional radiotherapy treatments.

Electronic isomerism in a heterometallic nickel-iron-sulfur cluster models substrate binding and cyanide inhibition of carbon monoxide dehydrogenase.

The nickel-iron carbon monoxide dehydrogenase (CODH) enzyme uses a heterometallic nickel-iron-sulfur ([NiFe4S4]) cluster to catalyze the reversible interconversion of carbon dioxide (CO2) and carbon monoxide (CO). These reactions are essential for maintaining the global carbon cycle and offer a route towards sustainable greenhouse gas conversion but have not been successfully replicated in synthetic models, in part due to a poor understanding of the natural system. Though the general protein architecture of CODH is known, the electronic structure of the active site is not well-understood, and the mechanism of catalysis remains unresolved. To better understand the CODH enzyme, we have developed a protein-based model containing a heterometallic [NiFe3S4] cluster in the Pyrococcus furiosus (Pf) ferredoxin (Fd). This model binds small molecules such as carbon monoxide and cyanide, analogous to CODH. Multiple redox- and ligand-bound states of [NiFe3S4] Fd (NiFd) have been investigated using a suite of spectroscopic techniques, including resonance Raman, Ni and Fe K-edge X-ray absorption spectroscopy, and electron paramagnetic resonance, to resolve charge and spin delocalization across the cluster, site-specific electron density, and ligand activation. The facile movement of charge through the cluster highlights the fluidity of electron density within iron-sulfur clusters and suggests an electronic basis by which CN- inhibits the native system while the CO-bound state continues to elude isolation in CODH. The detailed characterization of isolable states that are accessible in our CODH model system provides valuable insight into unresolved enzymatic intermediates and offers design principles towards developing functional mimics of CODH.

Dendritic Cells in Cancer Immunology and Immunotherapy.

Cancer immunotherapy modulates the immune system, overcomes immune escape and stimulates immune defenses against tumors. Dendritic cells (DCs) are professional promoters of immune responses against tumor antigens with the outstanding ability to coordinate the innate and adaptive immune systems. Evidence suggests that there is a decrease in both the number and function of DCs in cancer patients. Therefore, they represent a strong scaffold for therapeutic interventions. DC vaccination (DCV) is safe, and the antitumoral responses induced are well established in solid tumors. Although the addition of checkpoint inhibitors (CPIs) to chemotherapy has provided new options in the treatment of cancer, they have shown no clinical benefit in immune desert tumors or in those tumors with dysfunctional or exhausted T-cells. In this way, DC-based therapy has demonstrated the ability to modify the tumor microenvironment for immune enriched tumors and to potentiate systemic host immune responses as an active approach to treating cancer patients. Application of DCV in cancer seeks to obtain long-term antitumor responses through an improved T-cell priming by enhancing previous or generating de novo immune responses. To date, DCV has induced immune responses in the peripheral blood of patients without a significant clinical impact on outcome. Thus, improvements in vaccines formulations, selection of patients based on biomarkers and combinations with other antitumoral therapies are needed to enhance patient survival. In this work, we review the role of DCV in different solid tumors with their strengths and weaknesses, and we finally mention new trends to improve the efficacy of this immune strategy.

Case–control study assessing the impact of COVID19 in advanced kidney cancer patients treated with antiangiogenics or immunotherapy: the COVID-REN study

Background Cancer is a risk factor for developing severe COVID19. Additionally, SARS-CoV2 has a special tropism for renal cells and complications like thrombosis or cytokine storm could be enhanced by standard treatments in kidney cancer (i.e., antiangiogenics or immunotherapy). Thus, understanding the impact of COVID19 in patients with this tumor is key for their correct management. Methods We designed a retrospective case–control study comparing the outcome of three groups of advanced kidney cancer patients on systemic treatment: cohort A (developed COVID19 while on antiangiogenics), cohort B (developed COVID19 while on immunotherapy) and cohort C (non-infected). Matching factors were age, gender, and treatment. Results 95 patients were recruited in 16 centers in Spain from September 2020 to May 2021. Finally, 85 were deemed as eligible (23 cohort A, 21 cohort B, 41 cohort C). Patients with COVID required more dose interruptions (25 vs. six) and hospitalizations (10 vs. none) than those without COVID (both p = 0.001). No difference between cohorts A and B was observed regarding hospitalization or length of stay. No ICU admission was registered and one patient in cohort B died due to COVID19. Regarding cancer evolution, three patients in cohort A presented progressive disease after COVID19 compared to two in cohort B. One case in cohort B, initially deemed as stable disease, achieved a partial response after COVID19. Conclusions Kidney cancer patients who developed COVID19 while on systemic therapy required more treatment interruptions and hospitalizations than those non-infected. However, no significant impact on cancer outcome was observed. Also, no difference was seen between cases on antiangiogenics or immunotherapy (AU)

Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma.

BACKGROUND: Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at a young age, other heavy smokers never develop it, even at an advanced age, suggesting a remarkable variability in the individual susceptibility to the carcinogenic effects of tobacco. We characterized the germline profile of subjects presenting these extreme phenotypes with Whole Exome Sequencing (WES) and Machine Learning (ML). METHODS: We sequenced germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age (extreme cases) or who did not develop lung cancer at an advanced age (extreme controls), selected from databases including over 6600 subjects. We selected individual coding genetic variants and variant-rich genes showing a significantly different distribution between extreme cases and controls. We validated the results from our discovery cohort, in which we analysed by WES extreme cases and controls presenting similar phenotypes. We developed ML models using both cohorts. FINDINGS: Mean age for extreme cases and controls was 50.7 and 79.1 years respectively, and mean tobacco consumption was 34.6 and 62.3 pack-years. We validated 16 individual variants and 33 variant-rich genes. The gene harbouring the most validated variants was HLA-A in extreme controls (4 variants in the discovery cohort, p = 3.46E-07; and 4 in the validation cohort, p = 1.67E-06). We trained ML models using as input the 16 individual variants in the discovery cohort and tested them on the validation cohort, obtaining an accuracy of 76.5% and an AUC-ROC of 83.6%. Functions of validated genes included candidate oncogenes, tumour-suppressors, DNA repair, HLA-mediated antigen presentation and regulation of proliferation, apoptosis, inflammation and immune response. INTERPRETATION: Individuals presenting extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma show different germline profiles. Our strategy may allow the identification of high-risk subjects and the development of new therapeutic approaches. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

SIN3A histone deacetylase action counteracts MUS81 to promote stalled fork stability.

During genome duplication, replication forks (RFs) can be stalled by different obstacles or by depletion of replication factors or nucleotides. A limited number of histone post-translational modifications at stalled RFs are involved in RF protection and restart. Provided the recent observation that the SIN3A histone deacetylase complex reduces transcription-replication conflicts, we explore the role of the SIN3A complex in protecting RFs under stressed conditions. We observe that Sin3A protein is enriched at replicating DNA in the presence of hydroxyurea. In this situation, Sin3A-depleted cells show increased RF stalling, H3 acetylation, and DNA breaks at stalled RFs. Under Sin3A depletion, RF recovery is impaired, and DNA damage accumulates. Importantly, these effects are partially dependent on the MUS81 endonuclease, which promotes DNA breaks and MRE11-dependent DNA degradation of such breaks. We propose that chromatin deacetylation triggered by the SIN3A complex limits MUS81 cleavage of stalled RFs, promoting genome stability when DNA replication is challenged.

Experimental Evidences on Magnetism-Covalent Bonding Interplay in Structural Properties of Solids and during Chemisorption.

Valence electrons are one of the main players in solid catalysts and in catalytic reactions, since they are involved in several correlated phenomena like chemical bonding, magnetism, chemisorption, and bond activation. This is particularly true in the case of solid catalysts containing d-transition metals, which exhibit a wide range of magnetic phenomena, from paramagnetism to collective behaviour. Indeed, the electrons of the outer d-shells are, on one hand, involved in the formation of bonds within the structure of a catalyst and on its surface, and, on the other, they are accountable for the magnetic properties of the material. For this reason, the relationship between magnetism and heterogeneous catalysis has been a source of great interest since the mid-20th century. The subject has gained a lot of attention in the last decade, thanks to the orbital engineering of quantum spin-exchange interactions and to the widespread application of external magnetic fields as boosting tools in several catalytic reactions. The topic is discussed here through experimental examples and evidences of the interplay between magnetism and covalent bonding in the structure of solids and during the chemisorption process. Covalent bonding is discussed since it represents one of the strongest contributions to bonds encountered in materials.

Opioids and fibromyalgia: frequency of use and factors associated with increased consumption in patients remitted to a tertiary care center.

BACKGROUND: Opioids are not recommended for fibromyalgia. OBJECTIVE: To investigate the frequency of opioid use in a large cohort of fibromyalgia patients and to identify factors associated with opioid consumption. METHODS: A retrospective, observational study of a large fibromyalgia cohort in a tertiary care center. We assessed fibromyalgia severity, functional capacity, anxiety, depression, drugs consumption and the patient's impression of change. We compared strong opioid consumers (SOC) and non-SOC. Inferential statistical and logistic regression analysis were used to identify factors associated with opioid consumption, and ANOVA for repeated measurements. RESULTS: We found a prevalence of 9.2% of SOC (100 patients) among 1087 patients in the cohort. During the last four years there was a significant increase on the incidence of SOC up to 12.8% (p = 0.004). There were no differences in demographic variables between SOC and non-SOC. Clinical variables were significantly more severe in SOC, and they consumed more non-opioid drugs (p < 0.0001). Opioid consumption was independently associated with other non-opioid drugs (Odds ratio 1.25, CI: 1.13-1.38), but not with the fibromyalgia severity. At three months, 62% of the patients had opioid withdrawal. There were no statistical differences in the fibromyalgia severity at the initial evaluation, or the patient's impression of change compared with those patients who continued opioids. Coping strategies were better in those patients who withdrew opioids (p = 0.044). CONCLUSIONS: We observed an increase in opioid prescriptions during the last four years. Opioid consumption was associated with concomitant use of non-opioid drugs, but it was not associated with fibromyalgia severity.

Obinutuzumab Pretreatment as a Novel Approach to Mitigate Formation of Anti-Drug Antibodies Against Cergutuzumab Amunaleukin in Patients with Solid Tumors.

PURPOSE: The immunocytokine cergutuzumab amunaleukin (CEA-IL2v) showed manageable safety and favorable pharmacodynamics in phase I/Ib trials in patients with advanced/metastatic carcinoembryonic antigen-positive (CEA+) solid tumors, but this was accompanied by a high incidence of anti-drug antibodies (ADA). We examined B-cell depletion with obinutuzumab as a potential mitigation strategy. EXPERIMENTAL DESIGN: Preclinical data comparing B-cell depletion with rituximab versus obinutuzumab are summarized. Substudies of phase I/Ib trials investigated the effect of obinutuzumab pretreatment on ADA development, safety, pharmacodynamics, and antitumor activity of CEA-IL2v ± atezolizumab in patients with advanced/metastatic or unresectable CEA+ solid tumors who had progressed on standard of care. RESULTS: Preclinical data showed superior B-cell depletion with obinutuzumab versus rituximab. In clinical studies, patients received CEA-IL2v monotherapy with (n = 16) or without (n = 6) obinutuzumab pretreatment (monotherapy study), or CEA-IL2v + atezolizumab + obinutuzumab pretreatment (n = 5; combination study). In the monotherapy study, after four cycles (every 2 weeks treatment), 0/15 evaluable patients administered obinutuzumab pretreatment had ADAs versus 4/6 patients without obinutuzumab. Obinutuzumab pretreatment with CEA-IL2v monotherapy showed no new safety signals and pharmacodynamic data suggested minimal impact on T cells and natural killer cells. Conversely, increased liver toxicity was observed in the combination study (CEA-IL2v + atezolizumab + obinutuzumab pretreatment). CONCLUSIONS: These preliminary findings suggest that obinutuzumab pretreatment before CEA-IL2v administration in patients with CEA+ solid tumors may be a feasible and potent ADA mitigation strategy, with an acceptable safety profile, supporting broader investigation of obinutuzumab pretreatment for ADA mitigation in other settings.

First-line Management of Metastatic Urothelial Cancer: Current and Future Perspectives After the EV-302 and CheckMate-901 Studies.

The standard of care for the first-line management of metastatic urothelial carcinoma has been recently challenged, with the combination of pembrolizumab and enfortumab vedotin (P-EV) strongly arising as a practice-changing option from classical platinum-based chemotherapies. With this paradigm shift on the horizon new questions, including the most suitable second line of treatment for these patients, and the role that the molecular characterization of these tumours will have when selecting these therapies will inevitably arise. Furthermore, after the negative results of the Keynote 361 and IMvigor 130 trials, the combination of nivolumab with platinum-based chemotherapy followed by nivolumab maintenance (Nivo GC-Nivo) has also shown positive results when compared with chemotherapy alone. Translational studies at a molecular, cellular, and functional level will be key to better explain these discordant results. In this Current Perspective, we discuss the potential impact of these results in clinical practice and propose specific guidance for prospective translational research.

Biophysical effects of a natural peloid on normal skin.

A protocol study was designed to examine cutaneous behavior after continuous application of a peloid in the dry mineral residue of Lanjarón-Capuchina natural mineral water. This study aims to analyze the biomechanical behavior of normal skin using various non-invasive bioengineering techniques after the application of this peloid. We determine the effects of its application for 3 months on 38 healthy volunteers (41.4 ± 5.9 years, range 32-58) without a previous history of skin diseases by courtmetry, sebumetry, pH-metry, reviscometry, and tewametry. It was shown that the production of cutaneous sebum is significantly reduced by 6%, trans epidermal skin loss (TEWL) by 21%, skin fatigue by 30%, elasticity increased by 19%, firmness by 5%, and a skin redensification by 6% was obtained under these experimental conditions. Disparate and non-significant results were obtained concerning pH and viscoelasticity. Continuous skin care with the Lanjarón-Capuchina natural peloid modifies skin behavior, normalizing sebaceous secretion, favoring the biomechanical properties of the skin and the skin barrier function without modifying skin homeostasis.

Case-control study assessing the impact of COVID19 in advanced kidney cancer patients treated with antiangiogenics or immunotherapy: the COVID-REN study.

BACKGROUND: Cancer is a risk factor for developing severe COVID19. Additionally, SARS-CoV2 has a special tropism for renal cells and complications like thrombosis or cytokine storm could be enhanced by standard treatments in kidney cancer (i.e., antiangiogenics or immunotherapy). Thus, understanding the impact of COVID19 in patients with this tumor is key for their correct management. METHODS: We designed a retrospective case-control study comparing the outcome of three groups of advanced kidney cancer patients on systemic treatment: cohort A (developed COVID19 while on antiangiogenics), cohort B (developed COVID19 while on immunotherapy) and cohort C (non-infected). Matching factors were age, gender, and treatment. RESULTS: 95 patients were recruited in 16 centers in Spain from September 2020 to May 2021. Finally, 85 were deemed as eligible (23 cohort A, 21 cohort B, 41 cohort C). Patients with COVID required more dose interruptions (25 vs. six) and hospitalizations (10 vs. none) than those without COVID (both p = 0.001). No difference between cohorts A and B was observed regarding hospitalization or length of stay. No ICU admission was registered and one patient in cohort B died due to COVID19. Regarding cancer evolution, three patients in cohort A presented progressive disease after COVID19 compared to two in cohort B. One case in cohort B, initially deemed as stable disease, achieved a partial response after COVID19. CONCLUSIONS: Kidney cancer patients who developed COVID19 while on systemic therapy required more treatment interruptions and hospitalizations than those non-infected. However, no significant impact on cancer outcome was observed. Also, no difference was seen between cases on antiangiogenics or immunotherapy.

Cancer risk with biologic and targeted synthetic DMARDs in patients with rheumatic diseases and previous malignancies: Results from the BIOBADASER register.

OBJECTIVE: to investigate the occurrence and relative risk of incident malignancy in patients with rheumatic diseases and previous malignancies treated with biologic and targeted synthetic DMARDs (b/tsDMARDs). METHODS: Cohort study of patients included in BIOBADASER 3.0 up to 2021, treated with b/tsDMARDs and history of a previous malignancy. Incident cancer was defined as any cancer (new primary, local recurrence or metastases) during the drug exposure. Incidence rate ratios of cancer per 1,000 patients-year (PY) and 95 % confidence interval (CI) were estimated. Rates of incident cancer in tsDMARDs and other bDMARDs versus TNFi were compared. RESULTS: A total of 352 patients from over 9,129 patients recorded in BIOBADASER 3.0 had a history of a previous malignancy. Overall, there were 47 incident malignancies (28 solid cancers, 18 non-melanoma skin cancers and 1 melanoma). The overall rate of incident malignancy was 47.4 (95 % CI 35.6-63.1) events/1,000 PY, ranging between 24.5 events/1000 PY in the anti-CD20 group to 93 events/1000 PY in the anti-CTLA-4 group. We did not find differences in the adjusted rate of incident cancer in patients exposed to JAKi [0.5 (95 % CI 0.2-1.7)], anti-CD20 [0.4(95 % CI 0.1-1)], or anti-IL6 [1.1(95 % CI 0.5-2.4)], anti-CTLA-4 [1.5 (95 % CI 0.7-3.1) or anti-IL17 [0.7 (95 % CI 0.2-2.4) versus TNFi therapy. CONCLUSIONS: We did not find differences in the risk of incident cancer in patients with rheumatic diseases and a previous malignancy between TNFi and other b/tsDMARDs. While incident cancers in our cohort were limited, our data is reassuring, awaiting validation in future studies.

Sequential vaccinations with divergent H1N1 influenza virus strains induce multi-H1 clade neutralizing antibodies in swine.

Vaccines that protect against any H1N1 influenza A virus strain would be advantageous for use in pigs and humans. Here, we try to induce a pan-H1N1 antibody response in pigs by sequential vaccination with antigenically divergent H1N1 strains. Adjuvanted whole inactivated vaccines are given intramuscularly in various two- and three-dose regimens. Three doses of heterologous monovalent H1N1 vaccine result in seroprotective neutralizing antibodies against 71% of a diverse panel of human and swine H1 strains, detectable antibodies against 88% of strains, and sterile cross-clade immunity against two heterologous challenge strains. This strategy outperforms any two-dose regimen and is as good or better than giving three doses of matched trivalent vaccine. Neutralizing antibodies are H1-specific, and the second heterologous booster enhances reactivity with conserved epitopes in the HA head. We show that even the most traditional influenza vaccines can offer surprisingly broad protection if they are administered in an alternative way.

Impact of ultrasound limitation to assess aortitis in patients with giant cell arteritis: comparative study with FDG-PET/CT.

OBJECTIVE: To determine the impact of ultrasound (US) intrinsic limitation to assess aortitis versus FDG-PET/CT in patients with US-proven giant cell arteritis (GCA) and to identify factors associated with aortic involvement. METHODS: Retrospective observational study of patients referred to US fast-track clinics at two academic centres over a 4-year period. Only patients with GCA confirmed by US were included. Temporal arteries (TA) and extracranial arteries US were performed at baseline. FDG-PET/CT was performed according to clinician's criteria. An FDG artery uptake at the aorta higher than liver uptake was considered positive for aortitis. RESULTS: Seventy-two of 186 patients with US-proven GCA underwent an FDG-PET/CT; 29 (40.3%) had a positive FDG-PET/CT and 24 (33.3%) presented aortitis. Only 6 (20.7%) patients with positive FDG-PET/CT had negative US findings of large vessel (LV)-GCA. Among patients with aortitis in FDG-PET/CT, only two (8.3%) had negative US findings of LV-GCA. Patients with aortitis were younger (68.9 vs 81;p<0.001), more frequently females (79.2% vs 39.6%;p=0.002) and had higher platelets count (413.4 vs 311.1;p=0014). Patients with aortitis presented positive TA US less frequently (41.7% vs 83.3%;p<0.001), but more LV US involvement (91.7% vs 41.7%; p<0.001) versus patients without aortitis. None of the patients with aortitis exhibited visual symptoms (0% vs 31.2%;p=0.001). CONCLUSIONS: FDG-PET/CT can detect aortitis in one out of every three patients with US-proven GCA. However, a negative US examination for LV-GCA suggests a low risk of aortitis. Younger and female GCA patients with thrombocytosis, absence of visual manifestations and LV-GCA on US may more frequently present aortitis by FDG-PET/CT.

CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects.

CD137 (4-1BB) is a member of the TNFR family that mediates potent T cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies (mAbs). CD137 agonists attain immunotherapeutic antitumor effects in cancer mouse models, and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137 signaling complex. Moreover, cIAPs are required for CD137 signaling toward the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC mimetics that trigger cIAP degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models, and cIAPs are also required for signaling from CARs encompassing CD137's cytoplasmic tail.

Spin-Polarization Strategy for Enhanced Acidic Oxygen Evolution Activity.

Spin-polarization is known as a promising way to promote the anodic oxygen evolution reaction (OER), since the intermediates and products endow spin-dependent behaviors, yet it is rarely reported for ferromagnetic catalysts toward acidic OER practically used in industry. Herein, the first spin-polarization-mediated strategy is reported to create a net ferromagnetic moment in antiferromagnetic RuO2 via dilute manganese (Mn2+ ) (S = 5/2) doping for enhancing OER activity in acidic electrolyte. Element-selective X-ray magnetic circular dichroism reveals the ferromagnetic coupling between Mn and Ru ions, fulfilling the Goodenough-Kanamori rule. The ferromagnetism behavior at room temperature can be well interpreted by first principles calculations as the interaction between the Mn2+ impurity and Ru ions. Indeed, Mn-RuO2 nanoflakes exhibit a strongly magnetic field enhanced OER activity, with the lowest overpotential of 143 mV at 10 mA cmgeo -2 and negligible activity decay in 480 h stability (vs 200 mV/195 h without magnetic field) as known for magnetic effects in the literature. The intrinsic turnover frequency is also improved to reach 5.5 s-1 at 1.45 VRHE . This work highlights an important avenue of spin-engineering strategy for designing efficient acidic oxygen evolution catalysts.