bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma
Authors: Riscal Romain , Bull Caroline J. , Mesaros Clementina , Finan Jennifer M. , Carens Madeleine , Ho Elaine S. , Xu Jimmy P. , Godfrey Jason , Brennan Paul , Johansson Mattias , Purdue Mark P. , Chanock Stephen J. , Mariosa Daniela , Timpson Nicholas J. , Vincent Emma E. , Keith Brian , Blair Ian A. , Skuli Nicolas , Simon M. Celeste 
Published: July 2021

AbstractClear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses based on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell-cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels, and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer.Significance:We demonstrate that ccRCC cells are auxotrophic for exogenous cholesterol to maintain PI3K/AKT signaling pathway and ROS homeostasis. Blocking cholesterol import through the HDL transporter SCARB1 compromises ccRCC cell survival and tumor growth, suggesting a novel pharmacologic target for this disease.This article is highlighted in the In This Issue feature, p. 2945
Rationally Designed Transgene-Encoded Cell-Surface Polypeptide Tag for Multiplexed Programming of CAR T-cell Synthetic Outputs
Authors: Johnson Adam J. , Wei Jia , Rosser James M. , Künkele Annette , Chang Cindy A. , Reid Aquene N. , Jensen Michael C. 
Published: July 2021

Abstract

Synthetic immunology, as exemplified by chimeric antigen receptor (CAR) T-cell immunotherapy, has transformed the treatment of relapsed/refractory B cell–lineage malignancies. However, there are substantial barriers—including limited tumor homing, lack of retention of function within a suppressive tumor microenvironment, and antigen heterogeneity/escape—to using this technology to effectively treat solid tumors. A multiplexed engineering approach is needed to equip effector T cells with synthetic countermeasures to overcome these barriers. This, in turn, necessitates combinatorial use of lentiviruses because of the limited payload size of current lentiviral vectors. Accordingly, there is a need for cell-surface human molecular constructs that mark multi-vector cotransduced T cells, to enable their purification ex vivo and their tracking in vivo. To this end, we engineered a cell surface–localizing polypeptide tag based on human HER2, designated HER2t, that was truncated in its extracellular and intracellular domains to eliminate ligand binding and signaling, respectively, and retained the membrane-proximal binding epitope of the HER2-specific mAb trastuzumab. We linked HER2t to CAR coexpression in lentivirally transduced T cells and showed that co-transduction with a second lentivirus expressing our previously described EGFRt tag linked to a second CAR efficiently generated bispecific dual-CAR T cells. Using the same approach, we generated T cells expressing a CAR and a second module, a chimeric cytokine receptor. The HER2txEGFRt multiplexing strategy is now being deployed for the manufacture of CD19xCD22 bispecific CAR T-cell products for the treatment of acute lymphoblastic leukemia (NCT03330691).
TIGIT-Fc Promotes Antitumor Immunity
Authors: Shen Xian , Fu Wenyan , Wei Yongpeng , Zhu Junle , Yu Yue , Lei Changhai , Zhao Jian , Hu Shi 
Published: July 2021

Abstract

T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a checkpoint receptor that mediates both T-cell and natural killer (NK)–cell exhaustion in tumors. An Fc-TIGIT fusion protein was shown to induce an immune-tolerance effect in a previous report, but the relevance of the TIGIT-Fc protein to tumor immunity is unknown. Here, we found that TIGIT-Fc promotes, rather than suppresses, tumor immunity. TIGIT-Fc treatment promoted the effector function of CD8+ T and NK cells in several tumor-bearing mouse models. TIGIT-Fc treatment resulted in potent T cell– and NK cell–mediated tumor reactivity, sustained memory-induced immunity in tumor rechallenge models, enhanced therapeutic effects via an antibody against PD-L1, and induction of Th1 development in CD4+ T cells. TIGIT-Fc showed a potent antibody-dependent cell-mediated cytotoxicity effect but had no intrinsic effect on tumor cell development. Our findings elucidate the role of TIGIT-Fc in tumor immune reprogramming, suggesting that TIGIT-Fc treatment alone or in combination with other checkpoint receptor blockers is a promising anticancer therapeutic strategy.
Loss of Hepatic Angiotensinogen Attenuates Sepsis-Induced Myocardial Dysfunction
Authors: Rong Jiabing , Tao Xinran , Lin Yao , Zheng Haiqiong , Ning Le , Lu Hong S. , Daugherty Alan , Shi Peng , Mullick Adam E. , Chen Sicong , Zhang Zhaocai , Xu Yinchuan , Wang Jian’an 
Published: July 2021

Rationale:
The renin-angiotensin system is a complex regulatory network that maintains normal physiological functions. The role of the renin-angiotensin system in sepsis-induced myocardial dysfunction (SIMD) is poorly defined. AGT (Angiotensinogen) is the unique precursor of the renin-angiotensin system and gives rise to all angiotensin peptides. The effects and mechanisms of AGT in the development of SIMD have not been defined.

Objective:
To determine a role of AGT in SIMD and investigate the underlying mechanisms.

Methods and Results:
Either intraperitoneal injection of lipopolysaccharide or cecal ligation and puncture significantly enhanced AGT abundances in liver, heart, and plasma. Deficiency of hepatocyte-derived AGT, rather than cardiomyocyte-derived AGT, alleviated septic cardiac dysfunction in mice and prolonged survival time. Further investigations revealed that the effects of hepatocyte-derived AGT on SIMD were partially associated with augmented Ang II (angiotensin II) production in circulation. In addition, hepatocyte-derived AGT was internalized by LRP1 (LDL [low-density lipoprotein] receptor-related protein 1) in cardiac fibroblasts and subsequently activated NLRP3 (NLR family pyrin domain-containing 3) inflammasome via an Ang II–independent pathway, ultimately promoting SIMD by suppressing SERCA2a (sarco[endo]plasmic reticulum Ca[2+]-ATPase 2a) abundances in cardiomyocytes.

Conclusions:
Hepatocyte-derived AGT promoted SIMD via both Ang II–dependent and Ang II–independent pathways. We identified a liver-heart axis by which AGT regulated development of SIMD. Our study may provide a potential novel therapeutic target for SIMD.
Treatment Inertia in Patients With Familial Hypercholesterolemia
Authors: Langer Anatoly , Mancini G. B. John , Tan Mary , Goodman Shaun G. , Ahooja Vineeta , Grégoire Jean , Lin Peter J. , Stone James A. , Leiter Lawrence A. 
Published: July 2021

Background
We studied care gap in patients with familial hypercholesterolemia (FH) with respect to lipid‐lowering therapy.

Methods and Results

We enrolled patients with cardiovascular disease (CVD) or FH and low‐density lipoprotein‐cholesterol >2.0 mmol/L despite maximally tolerated statin therapy. During follow‐up physicians received online reminders of treatment recommendations of 2009 patients (median age, 63 years, 42% women), 52.4% had CVD only, 31.7% FH only, and 15.9% both CVD and FH. Patients with FH were younger and more likely to be women and non‐White with significantly higher baseline low‐density lipoprotein‐cholesterol level (mmol/L) as compared with patients with CVD (FH 3.92±1.48 versus CVD 2.96±0.94,
P
<0.0001). Patients with FH received less statin (70.6% versus 79.2%,
P
=0.0001) at baseline but not ezetimibe (28.1% versus 20.4%,
P
=0.0003). Among patients with FH only, 45.3% were at low‐density lipoprotein target (≥ 50% reduction from pre‐treatment level or low‐density lipoprotein <2.5 mmol/L) at baseline and increasing to 65.8% and 73.6% by visit 2 and 3, respectively. Among patients with CVD only, none were at recommended level (≤2.0 mmol/L) at baseline and 44.3% and 53.3% were at recommended level on second and third visit, respectively. When primary end point was analyzed as a difference between baseline and last available follow‐up observation, only 22.0% of patients with FH only achieved it as compared with 45.8% with CVD only (
P
<0.0001) and 55.2% with both FH+CVD (
P
<0.0001).

Conclusions
There is significant treatment inertia in patients with FH including those with CVD. Education focused on patients with FH should continue to be undertaken.
Amy Sara Carroll's ReMex: Toward an Art History of the NAFTA Era
Authors: Emmelhainz Irmgard 
Published: July 2021

Abstract
Amy Sara Carroll's ReMex: Toward an Art History of the NAFTA Era interprets Mexico City-based, feminist, and border, or Chicano, art in and around the 1990s. Its premise is that aesthetics and politics “form a loop” in order to express what the author calls “Greater Mexico.” With this term, Carroll proposes that “Mexico” is no longer a territory but rather an imaginary that transcends its geographic borders. In her view, the denationalization brought about by the liberalization of markets led to a multicultural utopia best expressed in border art and art concerned with race and gender issues. In her account, aesthetic practice must serve as a direct weapon against “NAFTAfication” and colonial heteropatriarchy. Carroll draws an analogy between the selling out of the nation through the NAFTA treaty and the selling out of “post-Mexican” art to the global culture industry through the ambition of curators, cultural managers and artists who placed Mexico and Mexican contemporary art as key global art destinations by taking advantage of generous State sponsorship brought about by market liberalization. Any hint of cosmopolitism is suspicious and thus Carroll insists on “ReMexing” Mexico.
The Reassertion of National Sovereignty
Authors: Hirschmann Gisela 
Published: July 2021

Abstract
International organizations (io s) have repeatedly been challenged in their existence. In this essay, I review arguments about the causes of their decline and survival in existing research. While the majority of research has focused on structural pressures such as geopolitical crises, I argue that io s can also be threatened by member-states reasserting their sovereignty, for example through budget cuts, non-compliance with core norms, obstruction of staff appointments and membership withdrawal. More systematic research is required to investigate when these challenges are more likely to lead to the demise of io s and which factors make io s survive these challenges.
Morphological and thermal characterization of an immiscible catalyzed polymer blends (PC/PET)
Authors: Meziane O , Bensedira AR , Guessoum M 
Published: July 2021

The aim is to study the reactive compatibilization of two immiscible thermoplastic polyesters, namely polycarbonate (PC) and poly (ethylene terephthalate) (PET), by transesterification reactions through melt compounding. For this, a catalyst, which is hydrated samarium acetylacetonate (Sm(acac)3), is incorporated with concentrations of 0.10, 0.15 and 0.20 phr into the 70PC/30PET mixture. The characterization of the PC/PET blends by differential scanning calorimetry (DSC) revealed that, the transesterification reactions in the absence of catalyst are undetectable or practically impossible; however, by increasing the catalyst concentration, significant variations are noticed on the thermal properties. These modifications, due to the interfacial reactions between the two phases of the system, were also evidenced by variations in morphological properties observed after the study of atomic force microscopy (AFM).
Clinical Outcomes of Patients With Metastatic Urothelial Carcinoma After Progression to Immune Checkpoint Inhibitors: A Retrospective Analysis by the Meet-Uro Group (Meet-URO 1 Study)
Authors: Bersanelli Melissa , Buti Sebastiano , Cortellini Alessio , Bandini Marco , Banna Giuseppe Luigi , Pederzoli Filippo , Farè Elena , Raggi Daniele , Giannatempo Patrizia , De Giorgi Ugo , Basso Umberto , Losanno Tania , Santini Daniele , Mucciarini Claudia , Tucci Marcello , Tambaro Rosa , Farnesi Azzurra , Caffo Orazio , Veccia Antonello , Naglieri Emanuele , Briganti Alberto , Procopio Giuseppe , Pignata Sandro , Necchi Andrea 
Published: July 2021

Background: Immune checkpoint inhibitors (ICIs) are currently the standard of care for metastatic urothelial cancer (mUC) after the failure of previous platinum-based chemotherapy. The choice of further therapy after ICI progression is a new challenge, and scarce data support it. We aimed to examine the outcomes of mUC patients after progression to ICI, especially when receiving chemotherapy. Methods: Data were retrospectively collected from clinical records of mUC patients whose disease progressed to anti-programmed death 1 (PD-1)or programmed death ligand 1 (PD-L1) therapy at 14 Italian centers. Patients were grouped according to ICI therapy setting into SALVAGE (ie, ICI delivered ⩾ second-line therapy after platinum-based chemotherapy) and NAÏVE (ie, first-line therapy) groups. Progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared among subgroups. Cox regression assessed the effect of treatments after progression to ICI on OS. Objective response rate (ORR) was calculated as the sum of partial and complete radiologic responses. Results: The study population consisted of 201 mUC patients who progressed after ICI: 59 in the NAÏVE cohort and 142 in the SALVAGE cohort. Overall, 52 patients received chemotherapy after ICI progression (25.9%), 20 (9.9%) received ICI beyond progression, 115 (57.2%) received best supportive care only, and 14 (7.0%) received investigational drugs. Objective response rate to chemotherapy in the post-ICI setting was 23.1% (28.0% in the NAÏVE group and 18.5% in the SALVAGE group). Median PFS and OS to chemotherapy after ICI-PD was 5 months (95% confidence interval [CI]: 3-11) and 13 months (95% CI: 7-NA) for the NAÏVE group; 3 months (95% CI: 2-NA) and 9 months (95% CI: 6-NA) for the SALVAGE group, respectively. Overall survival from ICI initiation was 17 months for patients receiving chemotherapy (hazard ratio [HR] = 0.09, p < 0.001), versus 8 months for patients receiving ICI beyond progression (HR = 0.13, p < 0.001), and 2 months for patients who did not receive further active treatment ( p < 0.001). Conclusions: Chemotherapy administered after ICI progression for mUC patients is advisable irrespective of the treatment line.
Disentangling the Associations Between Attention Deficit Hyperactivity Disorder and Child Sexual Abuse: A Systematic Review
Authors: Langevin Rachel , Marshall Carley , Wallace Aimée , Gagné Marie-Emma , Kingsland Emily , Temcheff Caroline 
Published: July 2021

Background: An association between child sexual abuse (CSA) and attention deficit hyperactivity disorder (ADHD) has been documented. However, the temporal relationship between these problems and the roles of trauma-related symptoms or other forms of maltreatment remain unclear. This review aims to synthesize available research on CSA and ADHD, assess the methodological quality of the available research, and recommend future areas of inquiry. Methods: Studies were searched in five databases including Medline and PsycINFO. Following a title and abstract screening, 151 full texts were reviewed and 28 were included. Inclusion criteria were sexual abuse occurred before 18 years old, published quantitative studies documenting at least a bivariate association between CSA and ADHD, and published in the past 5 years for dissertations/theses, in French or English. The methodological quality of studies was systematically assessed. Results: Most studies identified a significant association between CSA and ADHD; most studies conceptualized CSA as a precursor of ADHD, but only one study had a longitudinal design. The quality of the studies varied greatly with main limitations being the lack of (i) longitudinal designs, (ii) rigorous multimethod/ multiinformant assessments of CSA and ADHD, and (iii) control for two major confounders: trauma-related symptoms and other forms of child maltreatment. Discussion: Given the lack of longitudinal studies, the directionality of the association remains unclear. The confounding role of other maltreatment forms and trauma-related symptoms also remains mostly unaddressed. Rigorous studies are needed to untangle the association between CSA and ADHD.
Primary angiosarcoma of aorta: A systematic review
Authors: Kordzadeh Ali , Askari Alan , Navi Ali , Patel Sandeep , Parsa Ali D , Charalabopoulos Alexandros 
Published: July 2021

Purpose: To elucidate the epidemiology, anatomical, presentation, classification, pathology, investigative modalities, management and prognosis of primary angiosarcoma of the aorta. Material and Methods: A systematic review of literature from the database inception to January 2021 in PubMed and Embase, CINAHL and Cochrane Library in accordance to PRISMA was conducted. Retrieval and extraction was performed by two independent reviewers. The hierarchy of the evidence was assessed through the National Institute for Health and Care Excellence Checklist. Data were subjected to pooled prevalence analysis, Kaplan–Meier survival and test of probability using log-rank analysis. This review is registered with International Prospective Register of Systematic Reviews: RD42021231314. Results: 82 studies with n = 123 cases met the inclusion criterion. Abdominal (45%) aorta was the commonest anatomical site with female predominance in ascending aorta (4:1) and aortic arch (2:1). The longest survival was in the ascending aorta and the shortest in the abdominal aorta [540 (interquartile range [IQR], 7–1560 days vs. 180 (IQR, 1–5730 days)], respectively. The overall median survival was 210 days (IQR, 1–5730 days) or 7 months. Lack of metastasis (47%) was a marker of longer survival ( p < 0.03) irrespective of other attributes. Conclusion: The pathophysiology appears to be a trend of increasing fatigue, fever and weight loss associated with segmental dysfunction of the aorta projecting occlusive or destructive phenotypes. Computed tomography angiography features of volume-occupying, bulky, polypoid (intraluminal), protrusive vegetation, hyper vascular without atherosclerotic lesions are extremely suggestive of PA of the aorta at 5th and 6th decades of life.
Practical advantage of SPECT/CT image co-registration for accurate bleeding Meckel’s diverticulum localization in pediatrics: A case report
Authors: Tagiling Nashrulhaq , Tee Vincent Wei Shen , Lee Yeong Yeh , Che Jalil Nur Asyilla , Mat Nawi Norazlina 
Published: July 2021

Planar scintigraphy with 99mTc-pertechnetate or Meckel scan is the gold standard in the diagnosis of a bleeding Meckel’s diverticulum (MD) for pediatrics. However, several setbacks may occur during the interpretation of a scintigram, especially in cases of an atypical MD presentation. In this report, we highlight the importance of functional and anatomical image co-registration using a hybrid SPECT/CT scanner to precisely localize a MD lesion. An 18-month-old boy presented with severe hematochezia over 4 days with declining hemoglobin levels. He underwent a conventional 60-min dynamic planar imaging of the Meckel scan. Upon review of the Meckel scan, a suspicious increase in the 99mTc-pertechnetate uptake was observed at the right upper quadrant of the abdomen. Due to its atypical location at the right kidney, we could not differentiate between a physiological uptake of the right kidney or an ectopic gastric mucosa. The patient was imaged again using single-photon emission computed tomography (SPECT) and low-dose CT protocol with a hybrid SPECT/CT scanner, and the co-registration of both SPECT and CT images was able to confirm the MD, which was located anterior to the right kidney at the right hepatic flexure region. An exploratory laparotomy was then ensued to remove the bleeding MD. The patient was discharged after 3 days with no complications. In summary, this case illustrates that hybrid imaging modality and co-registration allow for a more definitive diagnosis, as well as a more precise localization of MD.
Epidemiology of NCAA Bone Stress Injuries: A Comparison of Athletes in Divisions I, II, and III
Authors: Bratsman Andrew , Wassef Audrey , Wassef Christina R. , Jayaram Prathap , Mosely J. Bruce , Shybut Theodore B. 
Published: July 2021

Background: Bone stress injuries (BSIs) are a major source of functional impairment in athletes of all sports, with many risk factors, including athlete characteristics and type of sport. In National Collegiate Athletic Association (NCAA) athletics, the stratification of programs into divisions with different characteristics and makeup has been identified as increasing the risk for certain kinds of injuries, but there have been no studies on the difference of BSI rates and characteristics between athletes in Division I (DI) and those in Divisions II and III (DII and DIII). Purpose/Hypothesis: To characterize the BSI rates in each division and compare the incidence and characteristics of BSIs within divisions. Our hypothesis was that BSI rates would be higher in DII and DIII athletes as compared with DI athletes. Study Design: Descriptive epidemiology study. Methods: Five years of recorded BSI data in collegiate athletes via the NCAA Injury Surveillance Program were examined for the academic years 2009-2010 to 2013-2014. BSI rates per 100,000 athlete-exposures (AEs) were compared for DI versus DII and DIII athletes using risk ratios and 95% CIs. Time lost to injury, time of season of injury, and class composition of injured athletes were also compared between divisions. Results: Over the 5 years studied, DII and DIII programs reported 252 BSIs more than 1,793,777 AEs (14.05 per 100,000 AEs), and DI programs reported 235 BSIs over 2,022,592 AEs (11.62 per 100,000 AEs). The risk ratio was significant for D1 versus DII and DIII (1.21; 95% CI, 1.01-1.44). There was a significant difference in time lost to injury in DI versus DII and DIII, χ2(5, n = 449) = 16.54; P = .006. When data were stratified by individual sport, there were no significant divisional differences in high-risk sports. Conclusion: In the current study, NCAA DII and DIII athletes had higher rates of BSI than their DI counterparts. As compared with DII and DIII athletes, the DI athletes had a significantly greater proportion of BSIs that did not result in absence from participation in sport.