bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type I T cells sensitize treatment refractory tumors to chemotherapy through inhibition of oncogenic signaling pathways
Authors: Cecil Denise , Park Kyong Hwa , Curtis Benjamin , Corulli Lauren , Disis Mary (Nora) 
Published: March 2021

BackgroundThe most common clinical outcome observed after treatment with immune checkpoint inhibitor antibodies is disease stabilization. Using vaccines to generate high levels of tumor antigen-specific T-helper 1 (Th1), we show that tumors not eradicated by vaccination demonstrate prolonged disease stabilization. We evaluated the mechanism by which type I T cells inhibit disease progression and potentially influence the subsequent clinical response to standard therapy in treatment refractory cancers.MethodsWe employed a meta-analysis of studies with tumor growth from four different vaccines in two different mammary cancer models. The T-cell subtype and cytokine essential for vaccine-induced tumor inhibition was determined by in vivo neutralization studies and immunohistochemistry. The role of interferon gamma (IFN-γ) in receptor tyrosine kinase and downstream signaling was determined by immunoblotting. The role of suppressor of cytokine signaling 1 (SOCS1) on IFN-γ signaling was evaluated on SOCS1-silenced cells with immunoblotting and immunoprecipitation. The effect of vaccination on growth factor receptor signaling pathways, performed in both luminal (TgMMTVneu) and basal (C3(1)-Tag) mammary cancer models treated with paclitaxel or an anti-HER2-neu monoclonal antibody were assessed via immunoblotting.ResultsImmunization with an epitope-based vaccine targeting a representative tumor antigen resulted in elevated tumor trafficking Tbet+CD4 T cells, decreased tumor proliferation and increased apoptosis compared with control vaccinated mice. The resulting disease stabilization was dependent on IFN-γ-secreting CD4+ T cells. In the presence of excess IFN-γ, SOCS1 became upregulated in tumor cells, bound insulin receptor, insulin like growth factor receptor 1 and epidermal growth factor receptor resulting in profound oncogenic signaling inhibition. Silencing SOCS1 restored growth factor receptor signaling and proliferation and prevented cell death. Similar signaling perturbations were detected in vaccinated mice developing antigen-specific Th1 cells. Vaccination synergized with standard therapies and restored disease sensitivity to treatment with both a neu-specific antibody and paclitaxel in TgMMTVneu and to paclitaxel in C3(1)-Tag. Combination of vaccination and chemotherapy or biological therapy was more effective than monotherapy alone in either model and resulted in complete resolution of disease in some individuals.ConclusionsThese data suggest the clinical activity of type I T cells extends beyond direct tumor killing and immune therapies designed to increase type I T cells and could be integrated into standard chemotherapy regimens to enhance therapeutic efficacy.
Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC)
Authors: Bilusic Marijo , McMahon Sheri , Madan Ravi A , Karzai Fatima , Tsai Yo-Ting , Donahue Renee N , Palena Claudia , Jochems Caroline , Marté Jennifer L , Floudas Charalampos , Strauss Julius , Redman Jason , Abdul Sater Houssein , Rabizadeh Shahrooz , Soon-Shiong Patrick , Schlom Jeffrey , Gulley James L 
Published: March 2021

BackgroundAntitumor vaccines targeting tumor-associated antigens (TAAs) can generate antitumor immune response. A novel vaccine platform using adenovirus 5 (Ad5) vectors [E1–, E2b–] targeting three TAAs—prostate-specific antigen (PSA), brachyury, and MUC-1—has been developed. Both brachyury and the C-terminus of MUC-1 are overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and have been shown to play an important role in resistance to chemotherapy, epithelial–mesenchymal transition, and metastasis. The transgenes for PSA, brachyury, and MUC-1 all contain epitope modifications for the expression of CD8+ T-cell enhancer agonist epitopes. We report here the first-in-human trial of this vaccine platform.MethodsPatients with mCRPC were given concurrently three vaccines targeting PSA, brachyury, and MUC-1 at 5×1011 viral particles (VP) each, subcutaneously every 3 weeks for a maximum of three doses (dose de-escalation cohort), followed by a booster vaccine every 8 weeks for 1 year (dose-expansion cohort only). The primary objective was to determine the safety and the recommended phase II dose. Immune assays and clinical responses were evaluated.ResultsEighteen patients with mCRPC were enrolled between July 2018 and September 2019 and received at least one vaccination. Median PSA was 25.58 ng/mL (range, 0.65–1006 ng/mL). The vaccine was tolerable and safe, and no grade >3 treatment-related adverse events or dose-limiting toxicities (DLTs) were observed. One patient had a partial response, while five patients had confirmed PSA decline and five had stable disease for >6 months. Median progression-free survival was 22 weeks (95% CI: 19.1 to 34). Seventeen (100%) of 17 patients mounted T-cell responses to at least one TAA, whereras 8 (47%) of 17 patients mounted immune responses to all three TAAs. Multifunctional T-cell responses to PSA, MUC-1, and brachyury were also detected after vaccination in the majority of the patients.ConclusionsAd5 PSA/MUC-1/brachyury vaccine is well tolerated. The primary end points were met and there were no DLTs. The recommended phase II dose is 5×1011 VP. The vaccine demonstrated clinical activity, including one partial response and confirmed PSA responses in five patients. Three patients with prolonged PSA responses received palliative radiation therapy. Further research is needed to evaluate the clinical benefit and immunogenicity of this vaccine in combination with other immuno-oncology agents and/or palliative radiation therapy.Trial registration numberNCT03481816.
Brain proteomic changes by histone deacetylase inhibition after traumatic brain injury
Authors: Pumiglia Luke , Williams Aaron M , Kemp Michael T , Wakam Glenn K , Alam Hasan B , Biesterveld Ben E 
Published: March 2021

BackgroundTraumatic brain injury (TBI) is a leading cause of morbidity and mortality. There are currently no cytoprotective treatments for TBI. There is growing evidence that the histone deacetylase inhibitor valproic acid (VPA) may be beneficial in the treatment of TBI associated with hemorrhagic shock and in isolation. We sought to further evaluate the mechanistic underpinnings of this demonstrated efficacy via proteomic analysis of injured brain tissue.MethodsSwine were subjected to TBI via controlled cortical impact, randomized to treatment with VPA or control and observed for 6 hours. The brains of the pigs were then sectioned, and tissue was prepared and analyzed for proteomic data, including gene ontology (GO), gene-set enrichment analysis and enrichment mapping, and network mapping.ResultsProteomic analysis demonstrated differential expression of hundreds of proteins in injured brain tissue after treatment with VPA. GO analysis and network analyses revealed groups of proteins and processes that are known to modulate injury response after TBI and impact cell fate. Processes affected included protein targeting and transport, cation and G-protein signaling, metabolic response, neurotransmitter response and immune function.DiscussionThis proteomic analysis provides initial mechanistic insight into the observed rescue of injured brain tissue after VPA administration in isolated TBI.Level of evidenceNot applicable (animal study).
Alternative Splicing of the Inhibitory Immune Checkpoint Receptor SLAMF6 Generates a Dominant Positive Form, Boosting T-cell Effector Functions
Authors: Hajaj Emma , Zisman Elad , Tzaban Shay , Merims Sharon , Cohen Jonathan , Klein Shiri , Frankenburg Shoshana , Sade-Feldman Moshe , Tabach Yuval , Yizhak Keren , Navon Ami , Stepensky Polina , Hacohen Nir , Peretz Tamar , Veillette André , Karni Rotem , Eisenberg Galit , Lotem Michal 
Published: March 2021

Abstract
SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor-exhausted T cells. Here we show that in humans, SLAMF6 has three splice isoforms involving its V-domain. Although the canonical receptor inhibited T-cell activation through SAP recruitment, the short isoform SLAMF6Δ17–65 had a strong agonistic effect. The costimulatory action depended on protein phosphatase SHP1 and led to a cytotoxic molecular profile mediated by the expression of TBX21 and RUNX3. Patients treated with immune checkpoint blockade showed a shift toward SLAMF6Δ17–65 in peripheral blood T cells. We developed splice-switching antisense oligonucleotides (ASO) designed to target the relevant SLAMF6 splice junction. Our ASOs enhanced SLAMF6Δ17–65 expression in human tumor-infiltrating lymphocytes and improved their capacity to inhibit human melanoma in mice. The yin-yang relationship of SLAMF6 splice isoforms may represent a balancing mechanism that could be exploited to improve cancer immunotherapy.
Association of Blood Pressure and Heart Rate Responses to Submaximal Exercise With Incident Heart Failure: The Framingham Heart Study
Authors: Carneiro Herman A. , Song Rebecca J. , Lee Joowon , Schwartz Brian , Vasan Ramachandran S. , Xanthakis Vanessa 
Published: March 2021

Background
Exercise stress tests are conventionally performed to assess risk of coronary artery disease. Using the FHS (Framingham Heart Study) Offspring cohort, we related blood pressure (BP) and heart rate responses during and after submaximal exercise to the incidence of heart failure (HF).

Methods and Results
We evaluated Framingham Offspring Study participants (n=2066; mean age, 58 years; 53% women) who completed 2 stages of an exercise test (Bruce protocol) at their seventh examination (1998–2002). We measured pulse pressure, systolic BP, diastolic BP, and heart rate responses during stage 2 exercise (2.5 mph at 12% grade). We calculated the changes in systolic BP, diastolic BP, and heart rate from stage 2 to recovery 3 minutes after exercise. We used Cox proportional hazards regression to relate each standardized exercise variable (during stage 2, and at 3 minutes of recovery) individually to HF incidence, adjusting for standard risk factors. On follow‐up (median, 16.8 years), 85 participants developed new‐onset HF. Higher exercise diastolic BP was associated with higher HF with reduced ejection fraction (ejection fraction <50%) risk (hazard ratio [HR] per SD increment, 1.26; 95% CI, 1.01–1.59). Lower stage 2 pulse pressure and rapid postexercise recovery of heart rate and systolic BP were associated with higher HF with reduced ejection fraction risk (HR per SD increment, 0.73 [95% CI, 0.57–0.94]; 0.52 [95% CI, 0.35–0.76]; and 0.63 [95% CI, 0.47–0.84], respectively). BP and heart rate responses to submaximal exercise were not associated with risk of HF with preserved ejection fraction (ejection fraction ≥50%).

Conclusions
Accentuated diastolic BP during exercise with slower systolic BP and heart rate recovery after exercise are markers of HF with reduced ejection fraction risk.
The Microstructure of Attentional Control in the Dorsal Attention Network
Authors: Rajan Abhijit , Meyyappan Sreenivasan , Liu Yuelu , Samuel Immanuel Babu Henry , Nandi Bijurika , Mangun George R. , Ding Mingzhou 
Published: March 2021

Abstract
The top–down control of attention involves command signals arising chiefly in the dorsal attention network (DAN) in frontal and parietal cortex and propagating to sensory cortex to enable the selective processing of incoming stimuli based on their behavioral relevance. Consistent with this view, the DAN is active during preparatory (anticipatory) attention for relevant events and objects, which, in vision, may be defined by different stimulus attributes including their spatial location, color, motion, or form. How this network is organized to support different forms of preparatory attention to different stimulus attributes remains unclear. We propose that, within the DAN, there exist functional microstructures (patterns of activity) specific for controlling attention based on the specific information to be attended. To test this, we contrasted preparatory attention to stimulus location (spatial attention) and to stimulus color (feature attention), and used multivoxel pattern analysis to characterize the corresponding patterns of activity within the DAN. We observed different multivoxel patterns of BOLD activation within the DAN for the control of spatial attention (attending left vs. right) and feature attention (attending red vs. green). These patterns of activity for spatial and feature attentional control showed limited overlap with each other within the DAN. Our findings thus support a model in which the DAN has different functional microstructures for distinctive forms of top–down control of visual attention.
Visual Predictions Operate on Different Timescales
Authors: Darriba Álvaro , Van Ommen Sandrien , Hsu Yi-Fang , Waszak Florian 
Published: March 2021

AbstractHumans live in a volatile environment, subject to changes occurring at different timescales. The ability to adjust internal predictions accordingly is critical for perception and action. We studied this ability with two EEG experiments in which participants were presented with sequences of four Gabor patches, simulating a rotation, and instructed to respond to the last stimulus (target) to indicate whether or not it continued the direction of the first three stimuli. Each experiment included a short-term learning phase in which the probabilities of these two options were very different (p = .2 vs. p = .8, Rules A and B, respectively), followed by a neutral test phase in which both probabilities were equal. In addition, in one of the experiments, prior to the short-term phase, participants performed a much longer long-term learning phase where the relative probabilities of the rules predicting targets were opposite to those of the short-term phase. Analyses of the RTs and P3 amplitudes showed that, in the neutral test phase, participants initially predicted targets according to the probabilities learned in the short-term phase. However, whereas participants not pre-exposed to the long-term learning phase gradually adjusted their predictions to the neutral probabilities, for those who performed the long-term phase, the short-term associations were spontaneously replaced by those learned in that phase. This indicates that the long-term associations remained intact whereas the short-term associations were learned, transiently used, and abandoned when the context changed. The spontaneous recovery suggests independent storage and control of long-term and short-term associations.
Which Ethics for Essex? Elizabeth Gaskell, Salem Witchcraft,
and the Problem of Forgiveness
Authors: Everton Michael 
Published: March 2021

Abstract
Hawthorne notwithstanding, the nineteenth-century literary response to the Salem witch hunt was not unilaterally unforgiving. There was an equally dominant response of compassion and forgiveness. A moral rationalization of resentment, Elizabeth Gaskell’s Lois the Witch articulates this debate and anticipates contemporary questions about the efficacy of forgiving crimes against humanity.
Peacemaking in Africa and Nobel Peace Prize 2019: The Role of Ahmed Abiy Ali in resolving the Ethiopia–Eritrea Cross-Border Conflict
Authors: Oando Samwel Odhiambo , Achieng’ Shirley Gabriella 
Published: March 2021

Abstract
Conflicts globally have reportedly declined even though the number of African countries plagued by internal cross border strife has increased. Given this trend, the African peace and security architecture has evolved considerably over the past decade, culminating in the award of the Nobel Peace Prize – to one of the key actors in peace-making process, Ahmed Abiy Ali. Hence, this paper explores how the inter-state conflicts in Africa, such as the Ethiopia-Eritrea conflict, reflect some colonial continuities of violence. We, therefore, stipulate the justification for the Nobel Peace Prize to illustrate how norms evolve, and further, how identities are constituted in peace-making. This, we argue, is parallel to other situations in African countries as manifested through identity, legitimacy, and authority in shaping political decisions, within the mutually constitutive relationships between agents and political structures. The paper, therefore, situates the conflict between Ethiopia and Eritrea into the African context using a model of the decisive action by Abiy, with limited Western influence towards peace, hence providing rationale for subaltern voices and indigenous peace processes in Africa.
Between “Free Use” and Denial of Access: A Critical Analysis of the Copyright Licensing Scheme for Scholarly Materials in Higher Education in Tanzania
Authors: Makulilo Alex B. 
Published: March 2021

Abstract
Over the past ten years universities in Tanzania through the Committee of Vice Chancellors, Principals of Public and Private Universities in Tanzania (CVCPT), have been in dispute with the Copyright Society of Tanzania (COSOTA) over the exploitation of literary copyright protected works. This long-standing dispute has centered on a controversial copyright licensing of reproduction and rental rights scheme issued by COSOTA. On the one hand, universities claim reproduction and rental rights for educational purposes are exempted from the requirement of license under the doctrine of “free use” while the licensing body refutes such claim. This article is set to critically discuss this tension and suggest how the dispute may be resolved. The present analysis is governed by the international and national legal framework on copyright exemptions and limitations.
A Wrong Sound in the Quest for a Symphony? The WTO and the Impact of EU’s Common Agricultural Policy on Africa: Insight from Senegal
Authors: Ufomba Henry 
Published: March 2021

Abstract
This paper is situated within the growing debate on how the domestic economic policies of developed countries condition that of the developing countries through the mechanism of international trade relations under the auspices of the WTO. Using the framework of the dependency theory I shall examine the economic impact of the EU Common Agricultural Policy (CAP) on Africa with critical attention on the agricultural sector of the former, drawing empirical evidence from the present situation in Senegal. This answered the overarching question: How does the EU CAP affect the economies of Africa in general and Senegal in particular? The empirical evidence from Senegal’s experience presented in this paper revealed that CAP negatively affects the economic growth of Africa through the suffocation of its agricultural sector as a result of its distortion of the domestic price and the inability of local farmers to produce at a price that can compete equally with the heavily subsidized imported alternatives from the EU.
The effect of 4-h versus 6-h time restricted feeding on sleep quality, duration, insomnia severity and obstructive sleep apnea in adults with obesity
Authors: Cienfuegos Sofia , Gabel Kelsey , Kalam Faiza , Ezpeleta Mark , Pavlou Vicky , Lin Shuhao , Wiseman Eric , Varady Krista A 
Published: March 2021

Background: Time restricted feeding (TRF) involves deliberately restricting the times during which energy is ingested. Preliminary findings suggest that 8–10-h TRF improves sleep. However, the effects of shorter TRF windows (4–6 h) on sleep, remain unknown. Aims: This study compared the effects of 4-h versus 6-h TRF on sleep quality, duration, insomnia severity and the risk of obstructive sleep apnea. Methods: Adults with obesity ( n = 49) were randomized into one of three groups: 4-h TRF (eating only between 3 and 7 p.m.), 6-h TRF (eating only between 1 and 7 p.m.), or a control group (no meal timing restrictions) for 8 weeks. Results: After 8 weeks, body weight decreased ( p < 0.001) similarly by 4-h TRF (–3.9 ± 0.4 kg) and 6-h TRF (–3.4 ± 0.4 kg), versus controls. Sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), did not change by 4-h TRF (baseline: 5.9 ± 0.7; week 8: 4.8 ± 0.6) or 6-h TRF (baseline: 6.4 ± 0.8; week 8: 5.3 ± 0.9), versus controls. Wake time, bedtime, sleep duration and sleep onset latency also remained unchanged. Insomnia severity did not change by 4-h TRF (baseline: 4.4 ± 1.0; week 8: 4.7 ± 0.9) or 6-h TRF (baseline: 8.3 ± 1.2; week 8: 5.5 ± 1.1), versus controls. Percent of participants reporting obstructive sleep apnea symptoms did not change by 4-h TRF (baseline: 44%; week 8: 25%) or 6-h TRF (baseline: 47%; week 8: 20%), versus controls. Conclusion: These findings suggest that 4- and 6-h TRF have no effect on sleep quality, duration, insomnia severity, or the risk of obstructive sleep apnea.
Palliative care consultation in patients with Staphylococcus aureus bacteremia
Authors: Kobayashi Takaaki , Salinas Jorge L , Ten Eyck Patrick , Chen Benjamin , Ando Tomo , Inagaki Kengo , Alsuhaibani Mohammed , Auwaerter Paul G. , Molano Ilonka , Diekema Daniel J. 
Published: March 2021

Background: Palliative care consultation has shown benefits across a wide spectrum of diseases, but the utility in patients with Staphylococcus aureus bacteremia remains unclear despite its high mortality. Aim: To examine the frequency of palliative care consultation and factors associated with palliative care consult in Staphylococcus aureus bacteremia patients in the United States. Design: A population-based retrospective analysis using the Nationwide Inpatient Sample database in 2014, compiled by the Healthcare Costs and Utilization Project of the Agency for Healthcare Research and Quality. Setting/subjects: All inpatients with a discharge diagnosis of Staphylococcus aureus bacteremia (ICD-9-CM codes; 038.11 and 038.12). Measurements: Palliative care consultation was identified using ICD-9-CM code V66.7. Patients’ baseline characteristics and outcomes were compared between those with and without palliative care consult. Results: A total of 111,320 Staphylococcus aureus bacteremia admissions were identified in 2014. Palliative care consult was observed in 8140 admissions (7.3%). Palliative care consultation was associated with advanced age, white race, comorbidities, higher income, teaching/urban hospitals, Midwest region, Methicillin-resistant Staphylococcus aureus bacteremia and the lack of echocardiogram. Palliative care consult was also associated with shorter but more expensive hospitalizations. Crude mortality was 53% (4314/8140) among admissions with palliative care consult and 8% (8357/10,3180) among those without palliative care consult ( p < 0.001). Conclusions: Palliative care consultation was infrequent during the management of Staphylococcus aureus bacteremia, and a substantial number of patients died during their hospitalizations without palliative care consult. Given the reported benefit in other medical conditions, palliative care consultation may have a role in Staphylococcus aureus bacteremia. Selecting patients who may benefit the most should be explored.