bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial
Authors: Aggarwal Charu , Prawira Amy , Antonia Scott , Rahma Osama , Tolcher Anthony , Cohen Roger B , Lou Yanyan , Hauke Ralph , Vogelzang Nicholas , P Zandberg Dan , Kalebasty Arash Rezazadeh , Atkinson Victoria , Adjei Alex A , Seetharam Mahesh , Birnbaum Ariel , Weickhardt Andrew , Ganju Vinod , Joshua Anthony M , Cavallo Rosetta , Peng Linda , Zhang Xiaoyu , Kaul Sanjeev , Baughman Jan , Bonvini Ezio , Moore Paul A , Goldberg Stacie M , Arnaldez Fernanda I , Ferris Robert L , Lakhani Nehal J 
Published: April 2022

BackgroundAvailability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone.MethodsIn this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts.ResultsOverall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC.ConclusionsCheckpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC.Trial registration numberNCT02475213.
Immunogenicity and safety of COVID-19 vaccination in patients with primary Sjögren’s syndrome
Authors: Verstappen Gwenny M , de Wolff Liseth , Arends Suzanne , Heiermann Hella-Marie , van Sleen Yannick , Visser Annie , Terpstra Janneke H , Diavatopoulos Dimitri A , van der Heiden Marieke , Vissink Arjan , van Baarle Debbie , Kroese Frans G M , Bootsma Hendrika 
Published: April 2022

ObjectivesTo evaluate humoral and cellular immune responses and adverse events (AEs) after COVID-19 vaccination in patients with primary Sjögren’s syndrome (pSS) compared to healthy controls (HC), and disease activity following vaccination in patients with pSS.Methods67 patients with pSS and 33 HC (ratio 2:1) received COVID-19 vaccinations following the Dutch vaccination programme. Patients with pSS did not use immunomodulatory drugs, except hydroxychloroquine. Anti-spike 1 receptor binding domain IgG serum antibody levels were measured 28 days after complete vaccination. AEs were collected 7 days after vaccination. In a subgroup, salivary anti-SARS-CoV-2 antibodies and T-cell response by interferon-γ enzyme-linked immune absorbent spot was measured.Results47 patients with pSS (70%) and 14 HC (42%) received BNT162b2 (Pfizer-BioNtech), 13 (19%) and 5 (15%) received ChAdOx1 nCoV-19 (AstraZeneca), 6 (9%) and 8 (24%) received mRNA-1273 (Moderna), and 1 (1%) and 6 (18%) received Ad.26.COV2.S (Janssen). All participants had positive anti-SARS-CoV-2 antibody levels (>2500 AU/mL) postvaccination. No differences in anti-SARS-CoV-2 antibody levels were observed between patients with pSS and HC, for each vaccine type. Salivary anti-SARS-CoV-2 IgG antibodies also increased, and a T-cell response was observed in patients with pSS and HC. Frequencies of systemic AEs were comparable between patients with pSS and HC (first vaccination: 34/67 (51%) vs 16/33 (48%), p=0.83; second: 41/66 (62%) vs 14/25 (56%), p=0.59). No significant worsening was observed in patient-reported and systemic disease activity, including auto-antibodies.ConclusionsPatients with pSS had similar humoral and cellular immune responses as HC, suggesting COVID-19 vaccination is effective in patients with pSS. AEs were also comparable, and no increase in disease activity was seen in patients with pSS.
The implementation of transcranial Doppler ultrasonography for preclinical study of migraine
Authors: Dolgorukova Antonina , Potapenko Anastasiia V. , Murzina Anna A. , Lyubashina Olga A. , Y. Sokolov Alexey 
Published: April 2022

Transcranial Doppler ultrasonography is used to study intracranial blood flow changes associated with migraine in humans, but whether this method is helpful in preclinical settings is yet unknown. To identify changes in rat intracranial blood flow specific to trigeminovascular activation—a key process in migraine pathophysiology—we measured Doppler indices in the middle cerebral artery and basilar artery before, during, and after dural or somatosensory electrical stimulation. Hemodynamic changes specific to dural stimulation were tested further in separate experiments. After baseline recordings, the animals received cumulative infusions of valproate (100 mg/kg, trice), sumatriptan (0.3, 1, and 3 mg/kg), or saline, and dural stimulation with measurement of Doppler indices was repeated every 10 min for 1 h. Several parameters of blood flow in the rat middle cerebral artery underwent alterations specific to trigeminovascular activation. These changes, however, were insensitive to valproate and sumatriptan and diminished over time. These findings question the reliability of blood flow velocity variations in large intracranial vessels as biological markers of migraine-related processes and do not support the idea of using transcranial Doppler ultrasonography for preclinical screening of antimigraine treatments, at least in the model of acute trigeminovascular activation in rats.
Circadian Regulator CLOCK Drives Immunosuppression in Glioblastoma
Authors: Xuan Wenjing , Hsu Wen-Hao , Khan Fatima , Dunterman Madeline , Pang Lizhi , Wainwright Derek A. , Ahmed Atique U. , Heimberger Amy B. , Lesniak Maciej S. , Chen Peiwen 
Published: April 2022

Abstract

The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for tumor progression. However, the molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) and its heterodimeric partner brain and muscle ARNT-like 1 (BMAL1) in glioma stem cells (GSC) drive immunosuppression in GBM. Integrated analyses of the data from transcriptome profiling, single-cell RNA sequencing, and TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target of the CLOCK–BMAL1 complex in GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN in GSCs via hypoxia-inducible factor 1-alpha (HIF1α) signaling. Consequently, LGMN promotes microglial infiltration into the GBM TME via upregulating CD162 and polarizes infiltrating microglia toward an immune-suppressive phenotype. In GBM mouse models, inhibition of the CLOCK–OLFML3–HIF1α–LGMN–CD162 axis reduces intratumoral immune-suppressive microglia, increases CD8+ T-cell infiltration, activation, and cytotoxicity, and synergizes with anti–programmed cell death protein 1 (anti–PD-1 therapy). In human GBM, the CLOCK-regulated LGMN signaling correlates positively with microglial abundance and poor prognosis. Together, these findings uncover the CLOCK–OLFML3–HIF1α–LGMN axis as a molecular switch that controls microglial biology and immunosuppression, thus revealing potential new therapeutic targets for patients with GBM.
Visualizing Spatial and Stoichiometric Barriers to Bispecific T-Cell Engager Efficacy
Authors: You Ran , Artichoker Jordan , Ray Arja , Gonzalez Velozo Hugo , Rock Dan A. , Conner Kip P. , Krummel Matthew F. 
Published: April 2022

AbstractBispecific T-cell engager (BiTE) molecules are biologic T cell–directing immunotherapies. Blinatumomab is approved for treatment of B-cell malignancies, but BiTE molecule development in solid tumors has been more challenging. Here, we employed intravital imaging to characterize exposure and pharmacodynamic response of an anti-muCD3/anti-huEGFRvIII mouse surrogate BiTE molecule in EGFR variant III (EGFRvIII)-positive breast tumors implanted within immunocompetent mice. Our study revealed heterogeneous temporal and spatial dynamics of BiTE molecule extravasation into solid tumors, highlighting physical barriers to BiTE molecule function. We also discovered that high, homogeneous EGFRvIII expression on cancer cells was necessary for a BiTE molecule to efficiently clear tumors. In addition, we found that resident tumor-infiltrating lymphocytes (TIL) were sufficient for optimal tumor killing only at high BiTE molecule dosage, whereas inclusion of peripheral T-cell recruitment was synergistic at moderate to low dosages. We report that deletion of stimulatory conventional type I DCs (cDC1) diminished BiTE molecule–induced T-cell activation and tumor clearance, suggesting that in situ antigen-presenting cell (APC) engagements modulate the extent of BiTE molecule efficacy. In summary, our work identified multiple requirements for optimal BiTE molecule efficacy in solid tumors, providing insights that could be harnessed for solid cancer immunotherapy development.
Cost‐Effectiveness of Monitoring Patients Post‐Stroke With Mobile ECG During the Hospital Stay
Authors: Gao Lan , Moodie Marj , Freedman Ben , Lam Christina , Tu Hans , Swift Corey , Ma Sze‐Ho , Mok Vincent C. T. , Sui Yi , Sharpe David , Ghia Darshan , Jannes Jim , Davis Stephen , Liu Xinfeng , Yan Bernard 
Published: April 2022

Background
The effectiveness of a nurse‐led in‐hospital monitoring protocol with mobile ECG (iECG) was investigated for detecting atrial fibrillation in patients post‐ischemic stroke or post‐transient ischemic attack. The study aimed to assess the cost‐effectiveness of using iECG during the initial hospital stay compared with standard 24‐hour Holter monitoring.

Methods and Results
A Markov microsimulation model was constructed to simulate the lifetime health outcomes and costs. The rate of atrial fibrillation detection in iECG and Holter monitoring during the in‐hospital phase and characteristics of modeled population (ie, age, sex, CHA2DS2‐VASc) were informed by patient‐level data. Costs related to recurrent stroke, stroke management, medications (new oral anticoagulants), and rehabilitation were included. The cost‐effectiveness analysis outcome was calculated as an incremental cost per quality‐adjusted life‐year gained. As results, monitoring patients with iECG post‐stroke during the index hospitalization was associated with marginally higher costs (A$31 196) and greater benefits (6.70 quality‐adjusted life‐years) compared with 24‐hour Holter surveillance (A$31 095 and 6.66 quality‐adjusted life‐years) over a 20‐year time horizon, with an incremental cost‐effectiveness ratio of $3013/ quality‐adjusted life‐years. Monitoring patients with iECG also contributed to lower recurrence of stroke and stroke‐related deaths (140 recurrent strokes and 20 deaths avoided per 10 000 patients). The probabilistic sensitivity analyses suggested iECG is highly likely to be a cost‐effective intervention (100% probability).

Conclusions
A nurse‐led iECG monitoring protocol during the acute hospital stay was found to improve the rate of atrial fibrillation detection and contributed to slightly increased costs and improved health outcomes. Using iECG to monitor patients post‐stroke during initial hospitalization is recommended to complement routine care.
Towards a moralization of bibliometrics? A response to Kyle Siler
Authors: Gingras Yves 
Published: April 2022

Abstract
In a recent letter to QSS, Kyle Siler (2021), made harsh comments against the decision of the editors to publish a controversial paper signed by Alessandro Strumia (2021) about gender differences in high-energy physics. My aim here is to point to the elements in Siler’s letter that are typical of a new tendency to replace rational and technical arguments with a series of moral statements and ex cathedra affirmations that are not supported by cogent arguments. Such an approach can only be detrimental to rational debates within the bibliometric research community.
Treatment with low-dose prednisone in refractory obstetric antiphospholipid syndrome: A retrospective cohort study and meta-analysis
Authors: Riancho-Zarrabeitia Leyre , Lopez-Marin Laura , Cacho Pedro Muñoz , López-Hoyos Marcos , Barrio Rafael del , Haya Ana , Martínez-Taboada Víctor M 
Published: April 2022

Background Glucocorticoids have been suggested as a potential therapy in refractory obstetric antiphospholipid syndrome (oAPS). Our aims were to describe a cohort of patients with oAPS treated with low-dose glucocorticoids and to perform a systematic review and meta-analysis evaluating the effects of additional glucocorticoids on the pregnancy outcomes in oAPS patients. Methods Retrospective study that included 11 women diagnosed with primary antiphospholipid syndrome. The meta-analysis was conducted by fitting random effects models and was checked for heterogeneity. Results All women had suffered from early pregnancy losses and two also had a history of fetal deaths. We studied 47 pregnancies that resulted in 32 abortions (68.1%) and 3 fetal deaths (6.4%). Twenty-six pregnancies were under treatment, mainly LDA and LMWH. Low-dose glucocorticoids were indicated in 13 pregnancies (always in association with LDA and LMWH). There was a decrease in pregnancy loss in those patients treated with LDA and LMWH. Treatment with glucocorticoids significantly increased the rate of successful pregnancy (38.5% abortions in treated vs 85.3% abortions in non-treated pregnancies; p=0.003). After multivariate GEE analysis, only glucocorticoids remained inversely associated with pregnancy loss (OR=0.157, (CI 0.025–0.968, p=0.046)). The meta-analysis showed that glucocorticoids tended to improve the frequency of successful pregnancy (OR= 0.509 (0.252–1.028), p=0.06). Three cases of gestational diabetes and one of preeclampsia were observed in our cohort. The meta-analysis, which mostly included studies using high-dose steroids, showed that glucocorticoids increased not only the frequency of preeclampsia and gestational diabetes, but also the rate of pre-term birth. Conclusions The efficacy of low-dose glucocorticoids in addition to the standard therapy in patients with refractory oAPS should be confirmed in well-designed clinical trials. However, high doses of steroids significantly increase the frequency of maternal and fetal morbidities, making their use strongly inadvisable.
2019 ACR/EULAR classification criteria and therapy in predicting organ damage accrual in patients with childhood-onset systemic lupus erythematosus: A retrospective study over the last 29 years
Authors: Kifer Nastasia , Sestan Mario , Frkovic Marijan , Kifer Domagoj , Kozmar Ana , Padjen Ivan , Potocki Kristina , Anic Branimir , Batinic Drago , Malcic Ivan , Jelusic Marija 
Published: April 2022

Objective We explored damage occurrence in patients with childhood-onset SLE (cSLE) and aimed to predict the risk of organ damage occurrence in time. Methods The retrospective study included patients treated for cSLE at the Centre of Reference for Pediatric and Adolescent Rheumatology of the Republic Croatia over a 29-year period. Results The disease development of 97 patients (77 females) with cSLE was examined. The median (Q1, Q3) follow-up time was 6.5 (2.3, 12.0) years. SDI was determined at 5 time points (6, 12, 24, 36 months, and last follow-up). Thirty-eight patients (48%) had organ damage at the last follow-up. Prepubertal group of patients showed higher SLEDAI scores at the disease onset, while post-pubertal group had significantly lower proportion of patients with relapses. We estimated the time from the first symptom to the moment of damage and our findings suggest that it is unlikely that organ damage will occur in 50% of patients in the first 6 years since the diagnosis. The number of 2019 ACR/EULAR classification criteria at the time of diagnosis associated with SDI determined after 1 year of the follow-up period. The patients who received higher doses of glucocorticoids accumulated damage faster and mycophenolate mofetil was found to be a more frequent therapy in patients with SDI ≥3. Conclusion Knowing that damage will most likely happen after the first 6 years after diagnosis in 50% of patients enables physicians to better predict damage occurrence. High number of 2019 ACR/EULAR criteria and treatment with glucocorticoids in childhood-onset SLE are associated with damage accrual and these findings could enable us to detect patients which should be closely monitored for higher risk of damage development.
The role of language control in cross-language phoneme processing: Evidence from Chinese–English bilinguals
Authors: Zuo Mingyue , Schwieter John W. , Cao Ningning , Liu Huanhuan 
Published: April 2022

Aims: Cross-language interference studies of language control mainly focus on the lexical level, whereas language control may occur at the smallest unit phonemic level of language. In the present study, we examined the role of language control during cross-language phoneme processing. Design: Participants used one language to name pinyin or alphabet in the single-language blocks, and they used two languages for naming in the mixed-language blocks. Data and analysis: Using a linear mixed-effects model, we built models for mixing costs and switching costs based on reaction times (RTs) and accuracy. Findings: Switching between Chinese (L1) and English (L2) phonetic symbols revealed both mixing and switching costs. Originality: The findings suggest that switching of cross-language phonemes requires not only global control of the non-target phonemes, but also local control of the non-target phonemes. Significance: Just as cross-language interference control occurs at the lexical level, this study demonstrates that control also occurs at the phonemic level.
The emerging role of cross-resistance between taxanes and AR-targeting therapy in metastatic prostate cancer
Authors: Yao Kang , Li Shun , Liu Qingyong , Wu Fei 
Published: April 2022

Background: To date, the number of prostate cancer ranked first among newly diagnosed malignant tumors in men from multiple countries. Localized prostate cancer could be controlled by curative therapy. However, for patients with metastatic prostate cancer (mPC), the prognosis is poor. As among first-line treatments of systemic therapies for mPC, docetaxel and androgen receptor (AR)-targeted therapies have been widely used. However, mPC patients inevitably developed resistance to the current therapy. More importantly, there is a cross-resistance between docetaxel-based chemotherapy and AR-targeting therapy during the treatment process, which could impair the overall survival benefits without proper administration. Objective: Therefore, it is urgent to elucidate the mechanism of cross-resistance and explore the optimal sequential strategy. Methods: Here, in this review, we systematically reviewed and summarised the updated literature on clinical evidence and mechanistic research of treatment resistance in mPC. Results: Emerging evidence indicated that AR splice variants, AR overexpression or mutations, AR nuclear translocation, as well as AR signaling reactivation collectively contributed to the cross-resistance. With the current understanding of cross-resistance, multiple solutions are promising for improving the benefits, including refining the sequencing of available therapies for mPC, in combination with potential targeted inhibitors or immune checkpoint inhibitors. Further studies are needed to explore the combination of emerging strategies and eventually control the progression of prostate cancer. Conclusions: This review defined the mutual and unique resistant mechanism of these treatments, which might help to focus and accelerate therapeutic research that may ultimately improve clinical outcomes for patients with prostate cancer. Level of evidence: Not applicable
A complex proinflammatory cascade mediates the activation of HSCs upon LPS exposure in vivo
Authors: Demel Uta Margareta , Lutz Raphael , Sujer Stefanie , Demerdash Yasmin , Sood Shubhankar , Grünschläger Florian , Kuck Andrea , Werner Paula , Blaszkiewicz Sandra , Uckelmann Hannah Julia , Haas Simon , Essers Marieke Alida Gertruda 
Published: April 2022

AbstractInfections are a key source of stress to the hematopoietic system. While infections consume short-lived innate immune cells, their recovery depends on quiescent hematopoietic stem cells (HSCs) with long-term self-renewal capacity. Both chronic inflammatory stress and bacterial infections compromise competitive HSC capacity and cause bone marrow (BM) failure. However, our understanding of how HSCs act during acute and contained infections remains incomplete. Here, we used advanced chimeric and genetic mouse models in combination with pharmacological interventions to dissect the complex nature of the acute systemic response of HSCs to lipopolysaccharide (LPS), a well-established model for inducing inflammatory stress. Acute LPS challenge transiently induced proliferation of quiescent HSCs in vivo. This response was not only mediated via direct LPS-TLR4 conjugation on HSCs but also involved indirect TLR4 signaling in CD115+ monocytic cells, inducing a complex proinflammatory cytokine cascade in BM. Downstream of LPS-TLR4 signaling, the combined action of proinflammatory cytokines such as interferon (IFN)α, IFNγ, tumor necrosis factor-α, interleukin (IL)-1α, IL-1β, and many others is required to mediate full HSC activation in vivo. Together, our study reveals detailed mechanistic insights into the interplay of proinflammatory cytokine-induced molecular pathways and cell types that jointly orchestrate the complex process of emergency hematopoiesis and HSC activation upon LPS exposure in vivo.