bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumour-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc–xCT
Authors: Tian Shaobo , Chu Yanan , Hu Jia , Ding Xueliang , Liu Zhibo , Fu Daan , Yuan Ye , Deng Yan , Wang Guobin , Wang Lin , Wang Zheng 
Published: January 2022

ObjectiveReciprocal cellular crosstalk within the tumour microenvironment (TME) actively participates in tumour progression. The anterior gradient-2 (AGR2) can be secreted to extracellular compartments and contribute to colorectal cancer (CRC) metastasis. We investigated the cellular source for secreted AGR2 in the TME and underlying mechanisms mediating secreted AGR2’s effects.DesignTissue microarray, tumour tissues, blood samples and tumour-associated neutrophils (TANs) from patients with CRC were isolated for phenotypical and functional analyses. The role of TAN-secreted AGR2 was determined in neutrophil-specific Agr2 knockout (Agr2f/f;Mrp-Cre) mice. The biological roles and mechanisms of secreted AGR2 in CRC metastasis were determined in vitro and in vivo.ResultsTANs were a predominant cell type for secreting AGR2 in the TME of CRC. TANs-secreted AGR2 promoted CRC cells’ migration. Neutrophils-specific ablation of Agr2 in mice ameliorated CRC liver metastases. The heavy chain of CD98 (CD98hc) served as the functional receptor for secreted AGR2. Mechanistically, secreted AGR2 increased xCT activity in a CD98hc-dependent manner, subsequently activating Ras homologue family member A/Rho-associated protein kinase 2 cascade. CRC cells actively recruited TANs through the C-X-C motif chemokine 2. Moreover, CRC-derived transforming growth factor beta 1 (TGF-β1) educated peripheral blood neutrophils to become AGR2+TANs that secrete AGR2. Abundant infiltration of AGR2+TANs and high expression of TGF-β1 and CD98hc–xCT were correlated with poor prognosis of patients with CRC.ConclusionsOur study unveils a novel crosstalk between TANs and CRC cells involving the secreted AGR2–CD98hc–xCT axis that promotes metastasis and impacts the outcomes of patients with CRC.
Overcoming tumor heterogeneity by ex vivo arming of T cells using multiple bispecific antibodies
Authors: Park Jeong A , Cheung Nai-Kong V 
Published: January 2022

BackgroundTumorous heterogeneity is a hallmark of tumor evolution and cancer progression, being a longstanding challenge to targeted immunotherapy. Ex vivo armed T cells (EATs) using IgG-(L)-scFv bispecific antibodies (BsAbs) are potent tumor-specific cytotoxic effectors. To improve the anti-tumor efficacy of EATs against heterogeneous solid tumors, we explored multi-antigen targeting approaches.MethodsEx vivo expanded T cells were armed with BsAbs built on the IgG-(L)-scFv platform, where an anti-CD3 (huOKT3) scFv was attached to the carboxyl end of both light chains of a tumor specific IgG. Multispecificity was created by combining monospecific EATs, combining BsAbs on the same T cell, or combining specificities on the same antibody. Three multi-antigens targeting EAT strategies were tested: (1) pooled-EATs (EATs each with unique specificity administered simultaneously) or alternate-EATs (EATs each with unique specificity administered in an alternating schedule), (2) dual-EATs or multi-EATs (T cells simultaneously armed with ≥2 BsAbs), and (3) TriAb-EATs (T cells armed with BsAb specific for two targets besides CD3 (TriAb)). The properties and efficiencies of these three strategies were evaluated by flow cytometry, in vitro cytotoxicity, cytokine release assays, and in vivo studies performed in BALB-Rag2-/-IL-2R-γc-KO (BRG) mice xenografted with cancer cell line (CDX) or patient-derived tumor (PDX).ResultsMulti-EATs retained target antigen specificity and anti-tumor potency. Cytokine release with multi-EATs in the presence of tumor cells was substantially less than when multiple BsAbs were mixed with unarmed T cells. When tested against CDXs or PDXs, dual-EATs or multi-EATs effectively suppressed tumor growth without clinical toxicities. Most importantly, dual-EATs or multi-EATs were highly efficient in preventing clonal escape while mono-EATs or TriAb- EATs were not as effective.ConclusionsMulti-EATs have the potential to increase potency, reduce toxicity, and overcome tumor heterogeneity without excessive cytokine release. Arming T cells with multiple BsAbs deserves further exploration to prevent or to treat cancer resistance.
Mortality in patients with psychogenic non-epileptic seizures a population-based cohort study
Authors: Zhang Le , Beghi Ettore , Tomson Torbjörn , Beghi Massimiliano , Erba Giuseppe , Chang Zheng 
Published: January 2022

ObjectivesTo compare mortality, comorbidities and causes of death in people with psychogenic non-epileptic seizures (PNES), epilepsy and the general population.MethodsUsing linkage of multiple Swedish national registers, we identified individuals with incident diagnosis of PNES, epilepsy and conversion disorder with motor symptoms or deficits, and 10 controls for each. Main outcome was all-cause mortality. Causes of death were categorised into non-natural (eg, suicide, injuries) and natural. Conditional Cox regression models were used to estimate HRs and 95% CIs for mortality. HRs were adjusted for socioeconomic factors and psychiatric comorbidities.ResultsIncluded were 885 individuals with PNES, 50 663 with epilepsy and 1057 with conversion disorder and motor symptoms or deficits. We found 32 (3.6%) deaths among individuals with PNES, compared with 46 (0.5%) deaths in controls, giving an adjusted HR of 5.5 (95% CI 2.8 to 10.8). Patients with epilepsy had a 6.7 times higher risk of death (95% CI 6.4 to 7.0) compared with individuals without epilepsy. The association between conversion disorder with motor symptoms or deficits was non-significant after adjusting for psychiatric comorbidities. PNES carried a higher risk of natural (HR 8.1, 95% CI 4.0 to 16.4) and non-natural causes of death (HR 15.3, 95% CI 3.0 to 78.6). Suicide ranked high in patients with PNES (18.8%) and conversion disorder with motor symptoms and deficits. The association between PNES diagnosis and all-cause mortality varied with age and time since diagnosis.ConclusionLike epilepsy, PNES carries a higher than expected risk of both natural and non-natural causes of death. The high proportion of suicides requires further investigation.
Influence of torsion charge on shadow and observation signature of black hole surrounded by various profiles of accretions
Authors: He Ke-Jian , Tan Shuang-Cheng , Li Guo-Ping 
Published: January 2022

AbstractIn this paper, we carefully study the shadow and observational signature of the black hole with torsion charge for a distant observer, and further compare the results with that gotten in Schwarzschild spacetime. For thin disk accretion cases, the result shows that there are not only dark areas in the observed image of black hole, but also photon rings and lensing rings, which are closely associated with the torsion charge. The change of torsion charge will directly affect the range of photon ring and lens ring, and the contribution proportion of these rings to the observed intensity. In addition, the total flux of observed intensity is mainly provided by direct emission, and the lensing ring and photon ring contribute only a small part. By further considering the static and infalling cases of spherically symmetric accretion, one can find that the observed image is much darker for the falling accretion matters, but the shadow radius does not change. However, both the observed intensity and shadow size are significantly different when the torsion charge changes. That is, the size of the observed shadow is related to the spacetime geometry. In addition, based on the shadow of M87, we also constraint the torsion charge of black hole by using the diameter of shadow approximately. Finally, by comparing our results and that in Schwarzschild spacetime, it shows that black hole shadow can provide a feasible method for distinguishing those two spacetime.
Shadows and precession of orbits in rotating Janis–Newman–Winicour spacetime
Authors: Solanki Divyesh N. , Bambhaniya Parth , Dey Dipanjan , Joshi Pankaj S. , Pathak Kamlesh N. 
Published: January 2022

AbstractIn this paper, we construct the rotating Janis–Newman–Winicour (JNW) naked singularity spacetime using Newman–Janis Algorithm (NJA). We analyse NJA with and without complexification methods and find that the energy conditions do satisfied when we skip the complexification step. We study the shadows cast by rotating JNW naked singularity and compare them with the shadows cast by the Kerr black hole. We find that the shadow of the rotating naked singularity can be distinguished from the shadow of the Kerr black hole. While we analyse the precession of timelike bound orbits in rotating JNW spacetime, we find that it can have a negative (or opposite) precession, which is not present in the Kerr black hole case. These novel signatures of the shadow and orbital precession in rotating JNW naked singularity spacetime could be important in the context of the recent observation of the shadow of the M87 galactic center and the stellar dynamics of ‘S-stars’ around Milkyway galactic center.
Aspirin, Statins, Non-aspirin NSAIDs, Metformin, and the Risk of Biliary Cancer: A Swedish Population-Based Cohort Study
Authors: Marcano-Bonilla Lorena , Schleck Cathy D. , Harmsen William S. , Sadr-Azodi Omid , Borad Mitesh J. , Patel Tushar , Petersen Gloria M. , Therneau Terry M. , Roberts Lewis R. , Brusselaers Nele 
Published: January 2022

AbstractBackground:Chemoprevention for biliary tract cancers (BTC), which comprise intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder cancer, is controversial. We examined associations between low-dose aspirin, statins, NSAIDs, and metformin with BTC risk.Methods:We used a population-based cohort of 5.7 million persons over age 18 without personal history of cancer (except nonmelanoma skin cancer), receiving at least one commonly prescribed drug between July 1, 2005, and December 31, 2012, from the Swedish Prescribed Drug Registry. Hazard ratios (HR) were calculated using age-scaled multivariable-adjusted Cox models.Results:2,160 individuals developed BTC. Low-dose aspirin was not associated with BTC risk [HR, 0.93; 95% confidence interval (CI), 0.81–1.07], iCCA (HR, 1.21; 95% CI, 0.93–1.57), eCCA (HR, 0.80; 95% CI, 0.60–1.07), or gallbladder cancer (HR, 0.87; 95% CI, 0.71–1.06). Statins were associated with lower risk of BTC (HR, 0.66; 95% CI, 0.56–0.78), iCCA (HR, 0.69; 95% CI, 0.50–0.95), eCCA (HR 0.54; 95% CI, 0.38–0.76), and gallbladder cancer (HR, 0.72; 95% CI, 0.57–0.91). For all BTC subtypes, combined low-dose aspirin and statins were not associated with lower risk than statins alone. NSAIDs were associated with higher risk of BTC and its subtypes. Metformin was not associated with BTC risk (HR, 0.98; 95% CI, 0.82–1.18), iCCA (HR, 1.06; 95% CI, 0.77–1.48), eCCA (HR, 1.15; 95% CI, 0.82–1.61), or gallbladder cancer (HR, 0.84; 95% CI, 0.63–1.11).Conclusions:Statins were associated with a decreased risk of BTC and its subtypes. Low-dose aspirin alone was not associated with a decreased risk, and use of both was not associated with further decrease in risk beyond statins alone.Impact:Statins were most consistently associated with a decreased risk of BTC and its subtypes.
Critical Role for Cap-Independent c-MYC Translation in Progression of Multiple Myeloma
Authors: Shi Yijiang , Sun Fumou , Cheng Yan , Holmes Brent , Dhakal Binod , Gera Joseph F. , Janz Siegfried , Lichtenstein Alan 
Published: January 2022

Abstract
Dysregulated c-myc is a determinant of multiple myeloma progression. Translation of c-myc can be achieved by an mTOR-mediated, cap-dependent mechanism or a cap-independent mechanism where a sequence in the 5′UTR of mRNA, termed the internal ribosome entry site (IRES), recruits the 40S ribosomal subunit. This mechanism requires the RNA-binding factor hnRNP A1 (A1) and becomes critical when cap-dependent translation is inhibited during endoplasmic reticulum (ER) stress. Thus, we studied the role of A1 and the myc IRES in myeloma biology. A1 expression correlated with enhanced c-myc expression in patient samples. Expression of A1 in multiple myeloma lines was mediated by c-myc itself, suggesting a positive feedback circuit where myc induces A1 and A1 enhances myc translation. We then deleted the A1 gene in a myc-driven murine myeloma model. A1-deleted multiple myeloma cells demonstrated downregulated myc expression and were inhibited in their growth in vivo. Decreased myc expression was due to reduced translational efficiency and depressed IRES activity. We also studied the J007 inhibitor, which prevents A1's interaction with the myc IRES. J007 inhibited myc translation and IRES activity and diminished myc expression in murine and human multiple myeloma lines as well as primary samples. J007 also inhibited tumor outgrowth in mice after subcutaneous or intravenous challenge and prevented osteolytic bone disease. When c-myc was ectopically reexpressed in A1-deleted multiple myeloma cells, tumor growth was reestablished. These results support the critical role of A1-dependent myc IRES translation in myeloma.
Microneedle-mediated Intratumoral Delivery of Anti-CTLA-4 Promotes cDC1-dependent Eradication of Oral Squamous Cell Carcinoma with Limited irAEs
Authors: Gilardi Mara , Saddawi-Konefka Robert , Wu Victoria H. , Lopez-Ramirez Miguel Angel , Wang Zhiyong , Soto Fernando , Ramms Dana J. , Proietto Marco , Mikulski Zbigniew , Miki Haruka , Sharabi Andrew , Kupor Daniel , Rueda Ricardo , Hollern Daniel P. , Wang Joseph , Gutkind J. Silvio 
Published: January 2022

Abstract
Head and neck squamous cell carcinoma (HNSCC) ranks sixth in cancer incidence worldwide and has a 5-year survival rate of only 63%. Immunotherapies—principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity—offer the greatest promise for HNSCC treatment. Anti-PD-1 has been recently approved for first-line treatment of recurrent and metastatic HNSCC; however, less than 20% of patients show clinical benefit and durable responses. In addition, the clinical application of ICI has been limited by immune-related adverse events (irAE) consequent to compromised peripheral immune tolerance. Although irAEs are often reversible, they can become severe, prompting premature therapy termination or becoming life threatening. To address the irAEs inherent to systemic ICI therapy, we developed a novel, local delivery strategy based upon an array of soluble microneedles (MN). Using our recently reported syngeneic, tobacco-signature murine HNSCC model, we found that both systemic and local-MN anti-CTLA-4 therapy lead to &gt;90% tumor response, which is dependent on CD8 T cells and conventional dendritic cell type 1 (cDC1). However, local-MN delivery limited the distribution of anti-CTLA-4 antibody from areas distal to draining lymphatic basins. Employing Foxp3-GFPDTR transgenic mice to interrogate irAEs in vivo, we found that local-MN delivery of anti-CTLA-4 protects animals from irAEs observed with systemic therapy. Taken together, our findings support the exploration of MN-intratumoral ICI delivery as a viable strategy for HNSCC treatment with reduced irAEs, and the opportunity to target cDC1s as part of multimodal treatment options to boost ICI therapy.
Parques temáticos e aquáticos no Brasil
Authors: Pereira Alexandre Queiroz , Dantas Eustogio Wanderley Correia 
Published: January 2022

Os parques temáticos e aquáticos são estruturas de lazer disseminadas por todos os continentes, configurando-se como importantes espaços turísticos. O Brasil também tem participação nesse sistema e apresenta exemplos caros à análise. Assim sendo, objetivamos apreender lógica espacial de instalação e funcionamento dos referidos no Brasil e a convergir como indutor e, concomitantemente, induzido pelo processo de urbanização e a metropolização do espaço, em tônica basilar de instituição dos lazeres como elemento central na reprodução das cidades e do urbano. Enquanto base de dados, serão utilizados os dados do relatório Global Attractions Attendance da Themed Entertainment Association (TEA). A lógica de localização dos parques foi analisada via cartografia multiescalar, mas, sobretudo, a regional e a metropolitana. A escolha analítica destaca a possível relação entre o urbano e o turístico ao refletir o papel desses parques na constituição de espacialidades semelhantes a complexos turísticos em zonas de expansão urbano-metropolitana.
Piera Paola Pasoliniego pętla faszystowska
Authors: Kozłowski Michał 
Published: January 2022

Pier Paolo Pasolini’s Pendulum Swing on FascismThe following work is a case study. Its purpose is to reconstruct a particular situation involving the recognition and understanding of fascism. This situation is determined by both history and the social dynamics of the present day. The time and place is Italy of the 1960s and 70s, the observer – Pier Paolo Pasolini. But not because he offers us an original, complex and versatile theory of fascism. On the contrary, Pasolini can be superficial and rash, while his polemic passion often devours the argument and the analysis. However, Pasolini’s method of intellectual and political involvement allows us to use it as a keystone of a makeshift synthesis of a certain version of leftist anti-fascism. Piera Paola Pasoliniego pętla faszystowskaPoniższy tekst jest studium przypadku. Jego celem jest odtworzenie pewnej sytuacji rozpoznawania i rozumienia faszyzmu. Sytuacja ta jest wyznaczona zarówno przez historię, jak i przez społeczną dynamikę współczesności. Czas i miejsce to Włochy lat sześćdziesiątych i siedemdziesiątych XX wieku. Podmiotem rozpoznającym jest Pier Paolo Pasolini. Nie dlatego, że oferuje nam oryginalną, złożoną i wszechstronną teorię faszyzmu. Przeciwnie, Pasolini bywa powierzchowny, gwałtowny, jego pasja polemiczna często pochłania argument i analizę. Jednak sposób intelektualnego i politycznego zaangażowania Pasoliniego pozwala nam posłużyć się nim jako zwornikiem w prowizorycznej syntezie pewnej wersji lewicowego antyfaszyzmu.
Low-velocity and ballistic impact resistances of particle reinforced metal–matrix composites: An experimental study
Authors: Kosedag Ertan , Ekici Recep 
Published: January 2022

This study investigates the low-velocity and ballistic impact responses of SiC-reinforced Al6061 metal–matrix composites in different reinforcement volume fractions. Low-velocity impact (LVI) tests were performed with samples having SiC particle volume fractions of 0, 5, 10, 15, 20, 30, and 40%, while ballistic tests were carried out with samples having volume fractions of 0, 10, 20, and 30%. The weight-drop test method was used for LVI by applying 50 J (4.45 m/s) energy to all samples. Ballistic tests were carried out under the same conditions on all samples with the projectile launched at an average velocity of 500 m/s. For the determination of the ballistic resistance of the samples, the projectile penetrations in the witness structures were taken into consideration. The damage and deformations caused by both the LVI and the ballistic test in composites were examined. By the LVI test results, composite samples have absorbed less impact energy by increasing the reinforcement volume fraction, as well as demonstrated superior performance compared to unreinforced samples. In addition, the crack formation was mainly observed in the samples containing 30% reinforcement, while the composite material with a 40% volume fraction was completely broken. With the increase in the reinforcement volume fraction, the ballistic resistance of the samples increased significantly.
Single Leg Balance Training: A Systematic Review
Authors: Marcori Alexandre J , Monteiro Pedro H M , Oliveira Júlia A , Doumas Michail , Teixeira Luis A 
Published: January 2022

Single leg balance training promotes significant increments in balance control, but previous reviews on balance control have not analyzed this form of balance training. Accordingly, we aimed to review the single leg balance training literature to better understand the effects of applying this training to healthy individuals. We searched five databases—PubMed, EMBASE, Scopus, Lilacs, and Scielo—with the following inclusion criteria: (a) peer-reviewed articles published in English; (b) analysis of adult participants who had no musculoskeletal injuries or diseases that might impair balance control; and (c) use of methods containing at least a pre-test, exclusive single leg balance training, and a post-test assessment. We included 13 articles meeting these criteria and found that single leg balance training protocols were effective in inducing balance control gains in either single- or multiple-session training and with or without progression of difficulty. Balance control gains were achieved with different amounts of training, ranging from a single short session of 10 minutes to multiple sessions totaling as much as 390 min of unipedal balance time. Generalization of balance gains to untrained tasks and cross-education between legs from single leg balance training were consistent across studies. We concluded that single leg balance training can be used in various contexts to improve balance performance in healthy individuals. These results extend knowledge of expected outcomes from this form of training and aid single leg balance exercise prescription regarding volume, frequency, and potential progressions.
Unique Barriers to Workplace Health Promotion Programs by Wage Category: A Qualitative Assessment of Secondary Data
Authors: Stiehl Emily , Bales Susan L. , Jenkins Kristi Rahrig , Sherman Bruce W. 
Published: January 2022

Purpose To understand barriers around accessing or using workplace health promotion (WHP) programs among workers in different wage categories. Approach We conducted qualitative analysis of responses to three open-ended questions about WHP program participation, collected as part of an existing WHP program evaluation. Setting: A large mid-western university. Participants Of the 20,000 employees emailed an online survey, 3,212 responded (16.1%). The sample was mostly female (75%), white (79%), and comprised of staff members (84%). The average age was 44 years and 67% had annual incomes <$75,001. Method We used NVivo-12 Plus and two coders to apply Grounded Theory on the open-ended questions and identify emergent themes. Results Although most respondents were happy with the program, differences across wage categories emerged around time, financial incentives, commute, workload, and organizational policies/support. Employees at all wage levels were enthusiastic about creating a culture of health but needed different cultural supports to do so. For instance, higher-wage workers needed to overcome self-made time constraints, while lower-wage workers needed supervisor support to overcome coverage constraints that prevented participation. Conclusion The unique participation challenges experienced by employees in different wage categories provide justification for WHP programs that can better accommodate the participation barriers of all employees. While some programs may simply require more flexible offerings, supervisors may need to be trained to support and foster healthy environments.