bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic Targeting of Mesothelin with Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia
Authors: Le Quy , Castro Sommer , Tang Thao , Loeb Anisha M. , Hylkema Tiffany , McKay Cyd Nourigat , Perkins LaKeisha , Srivastava Shivani , Call Lindsey , Smith Jenny , Leonti Amanda , Ries Rhonda , Pardo Laura , Loken Michael R. , Correnti Colin , Fiorenza Salvatore , Turtle Cameron J. , Riddell Stanley , Tarlock Katherine , Meshinchi Soheil 
Published: August 2021

Abstract

Purpose:
We previously identified mesothelin (MSLN) as highly expressed in a significant fraction of acute myeloid leukemia (AML) but entirely silent in normal hematopoiesis, providing a promising antigen for immunotherapeutic targeting that avoids hematopoietic toxicity. Given that T cells genetically modified to express chimeric antigen receptors (CAR) are effective at eradicating relapsed/refractory acute lymphocytic leukemia, we developed MSLN-directed CAR T cells for preclinical evaluation in AML.

Experimental Design:
The variable light (VL) and heavy (VH) sequences from the MSLN-targeting SS1P immunotoxin were used to construct the single-chain variable fragment of the standard CAR containing 41-BB costimulatory and CD3Zeta stimulatory domains. The preclinical efficacy of MSLN CAR T cells was evaluated against AML cell lines and patient samples expressing various levels of MSLN in vitro and in vivo.

Results:
We demonstrate that MSLN is expressed on the cell surface of AML blasts and leukemic stem cell–enriched CD34+CD38− subset, but not on normal hematopoietic stem and progenitor cells (HSPC). We further establish that MSLN CAR T cells are highly effective in eliminating MSLN-positive AML cells in cell line– and patient-derived xenograft models. Importantly, MSLN CAR T cells can target and eradicate CD34+CD38− cells without impacting the viability of normal HSPCs. Finally, we show that CAR T-cell functionality can be improved by inhibition of the ADAM17 metalloprotease that promotes shedding of MSLN.

Conclusions:
These findings demonstrate that MSLN is a viable target for CAR T-cell therapy in AML and that inhibiting MSLN shedding is a promising approach to improve CAR T-cell efficacy.
Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway
Authors: Zhang Wei , Bhagwath Ankur S. , Ramzan Zeeshan , Williams Taylor A. , Subramaniyan Indhumathy , Edpuganti Vindhya , Kallem Raja Reddy , Dunbar Kerry B. , Ding Peiguo , Gong Ke , Geurkink Samuel A. , Beg Muhammad S. , Kim James , Zhang Qiuyang , Habib Amyn A. , Choi Sung-Hee , Lapsiwala Ritu , Bhagwath Gayathri , Dowell Jonathan E. , Melton Shelby D. , Jie Chunfa , Putnam William C. , Pham Thai H. , Wang David H. 
Published: August 2021

Abstract
Itraconazole, an FDA-approved antifungal, has antitumor activity against a variety of cancers. We sought to determine the effects of itraconazole on esophageal cancer and elucidate its mechanism of action. Itraconazole inhibited cell proliferation and induced G1-phase cell-cycle arrest in esophageal squamous cell carcinoma and adenocarcinoma cell lines. Using an unbiased kinase array, we found that itraconazole downregulated protein kinase AKT phosphorylation in OE33 esophageal adenocarcinoma cells. Itraconazole also decreased phosphorylation of downstream ribosomal protein S6, transcriptional expression of the upstream receptor tyrosine kinase HER2, and phosphorylation of upstream PI3K in esophageal cancer cells. Lapatinib, a tyrosine kinase inhibitor that targets HER2, and siRNA-mediated knockdown of HER2 similarly suppressed cancer cell growth in vitro. Itraconazole significantly inhibited growth of OE33-derived flank xenografts in mice with detectable levels of itraconazole and its primary metabolite, hydroxyitraconazole, in esophagi and tumors. HER2 total protein and phosphorylation of AKT and S6 proteins were decreased in xenografts from itraconazole-treated mice compared to xenografts from placebo-treated mice. In an early phase I clinical trial (NCT02749513) in patients with esophageal cancer, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling.
Evaluation of Preclinical Activity of Isatuximab in Patients with Acute Lymphoblastic Leukemia
Authors: Wang Anlai , Song Zhili , Zheng Gang , Nicolazzi Celine , Fromm Jonathan R. , Shehu Elvis , Srinivasan Srimathi , Chen Xueyan , Zhu Chen , Blondel Marielle Chiron , Adrian Francisco J. 
Published: August 2021

Abstract
This study reports the pharmacologic effects of isatuximab, a CD38 mAb, on T- and B-cell acute lymphoblastic leukemia (ALL). We analyzed CD38 expression in 50-T-ALL and 50 B-ALL clinical samples, and 16 T-ALL and 11 B-ALL cell lines. We primarily focused on in vitro assessments of isatuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In vivo assessment of isatuximab activity was performed in several ALL xenograft models, including disseminated and subcutaneous tumor models in female C.B-17 severe combined immunodeficiency mice. Our study reveals that most patients (90%–100%) carried CD38+ blasts independent of disease burden. The median CD38 receptor density on abnormal lymphoblasts is 41,026 copies/cell on T-ALL and 28,137 copies/cell on B-ALL, respectively. In patients with T-ALL, there is a significant increase of CD38 expression in abnormal blasts compared with normal T cells. High-level CD38 receptor density (RD) is critical to trigger effective isatuximab-mediated ADCC against target ALL cells. In addition, a correlation between CD38 RD and isatuximab-mediated ADCP is demonstrated. In the disseminated CD38+, T-ALL, and B-ALL xenograft models, isatuximab is able to induce robust antitumor activity, even at low doses. This study shows that isatuximab has significant in vitro and in vivo activity against ALL cells with robust ADCC and ADCP effects that are associated with CD38 expression levels in both T-ALL and B-ALL.
Prognostication of Asymptomatic Penetrating Aortic Ulcers: A Modern Approach
Authors: DeCarlo Charles , Latz Christopher A. , Boitano Laura T. , Kim Young , Tanious Adam , Schwartz Samuel I. , Patell Rushad , Mohebali Jahan , Dua Anahita 
Published: August 2021

Background:
Literature detailing the natural history of asymptomatic penetrating aortic ulcers (PAUs) is sparse and lacks long-term follow-up. This study sought to determine the rate of asymptomatic PAU growth over time and adverse events from asymptomatic PAU.

Methods:
A cohort of patients with asymptomatic PAU from 2005 to 2020 was followed. One ulcer was followed per patient. Primary end points were change in size over time and the composite of symptoms, radiographic progression, rupture, and intervention; cumulative incidence function estimated the incidence of the composite outcome. Ulcer size and rate of change were modeled using a linear mixed-effects model. Patient and anatomic factors were evaluated as potential predictors of the outcomes.

Results:
There were 273 patients identified. The mean age was 75.5±9.6 years; 66.4% were male. The majority of ulcers were in the descending thoracic aorta (53.9%), followed by abdominal aorta (41.4%) and aortic arch (4.8%). Fusiform aneurysmal disease was present in 21.6% of patients at a separate location; 2.6% had an associated intramural hematoma; 23.6% had at least 1 other PAU. Symptoms developed in 1 patient who ruptured; 8 patients (2.9%) underwent an intervention for PAU (1 for rupture, 2 for radiographic progression, 5 for size/growth) at a median of 3.1 years (interquartile range, 1.0–6.5) after diagnosis. Five- and 10-year cumulative incidence of the primary outcome, adjusted for competing risk of death, was 3.6% (95% CI, 1.6%–6.9%) and 6.5% (95% CI, 3.1%–11.4%), respectively. For 191 patients with multiple computed tomography scans (760 total computed tomographies) with a median radiographic follow-up of 3.50 years (interquartile range, 1.20–6.63 years), mean initial ulcer width, ulcer depth, and total diameter were 13.6 mm, 8.5 mm, and 31.4 mm, respectively. A small but statistically significant change over time was observed for ulcer width (0.23 mm/y) and total diameter (0.24 mm/y); ulcer depth did not significantly change over time. Hypertension, hyperlipidemia, diabetes, initial ulcer width >20 mm, thrombosed PAU, and associated saccular aneurysm were associated with larger changes in ulcer size over time; however, the magnitude of difference was small, ranging from 0.4 to 1.9 mm/y.

Conclusions:
Asymptomatic PAU displayed minimal growth and infrequent complications including rupture. Asymptomatic PAU may be conservatively managed with serial imaging and risk factor modification.
Incidence, Predictors, and Outcomes of In‐Hospital Cardiac Arrest in COVID‐19 Patients Admitted to Intensive and Non‐Intensive Care Units: Insights From the AHA COVID‐19 CVD Registry
Authors: Acharya Prakash , Ranka Sagar , Sethi Prince , Bharati Rajani , Hu Jinxiang , Noheria Amit , Nallamothu Brahmajee K. , Hayek Salim S. , Gupta Kamal 
Published: August 2021

Background
Limited information is available regarding in‐hospital cardiac arrest (IHCA) in patients with COVID‐19.

Methods and Results

We leveraged the American Heart Association COVID‐19 Cardiovascular Disease (AHA COVID‐19 CVD) Registry to conduct a cohort study of adults hospitalized for COVID‐19. IHCA was defined as those with documentation of cardiac arrest requiring medication or electrical shock for resuscitation. Mixed effects models with random intercepts were used to identify independent predictors of IHCA and mortality while accounting for clustering at the hospital level. The study cohort included 8518 patients (6080 not in the intensive care unit [ICU]) with mean age of 61.5 years (SD 17.5). IHCA occurred in 509 (5.9%) patients overall with 375 (73.7%) in the ICU and 134 (26.3%) patients not in the ICU. The majority of patients at the time of ICHA were not in a shockable rhythm (76.5%). Independent predictors of IHCA included older age, Hispanic ethnicity (odds ratio [OR], 1.9; CI, 1.4–2.4;
P
<0.001), and non‐Hispanic Black race (OR, 1.5; CI, 1.1–1.9;
P
=0.004). Other predictors included oxygen use on admission, quick Sequential Organ Failure Assessment score on admission, and hypertension. Overall, 35 (6.9%) patients with IHCA survived to discharge, with 9.1% for ICU and 0.7% for non‐ICU patients.

Conclusions
Older age, Black race, and Hispanic ethnicity are independent predictors of IHCA in patients with COVID‐19. Although the incidence is much lower than in ICU patients, approximately one‐quarter of IHCA events in patients with COVID‐19 occur in non‐ICU settings, with the latter having a substantially lower survival to discharge rate.
(Ad)Dressing Foreign Women: Ancient Exegesis of Numbers 25 and Roman Prostitution
Authors: Livneh Atar 
Published: August 2021

Abstract
Does the infinitive לזנות in Num 25:1 suggest that the foreign women were prostitutes? Analyzing four Roman-period Jewish sources—Biblical Antiquities 18:13–14; Philo, Moses 1.294–304 and Virtues 34–50; and Sifre Numbers 131—this article demonstrates that the public exposure of naked bodies in LAB reflects Roman norms relating to prostitutes. Philo even more explicitly depicts the women as brothel prostitutes, projecting the Roman repugnance towards upper-class men openly entering such establishments onto the Israelites and presenting them as immoral by dressing them in the elaborate costume typically worn by courtesans in Greek sources. Sifre Numbers 131 is a satirical variation on the theme, the Israelites being tricked into entering the prostitute’s cubicle due to their ignorance of the (male elite Roman) stereotyping of female vendor markets as prostitutes and old women as bawds.
Depictions of God in the Drawings of German-Muslim Children
Authors: Güleç Yasemin 
Published: August 2021

Abstract
This empirical inquiry aimed to examine the qualitative differences of the ‘God’ concept of Turkish-German Sunni Muslim children living in Germany. In this study, non-anthropomorphic drawings did not increase gradually with age. Anthromoporphic God depictions seem to be ontologically moving away from people with age. In the present study, indirect God depictions occurred six times more than the direct God depictions. ‘Religious-cultural drawings’ were the most common in the sample. The girls drew more aesthetic drawings that expressed an emotional bond with God. Boys depicted God more rationally and pragmatically in regard to human life and the world.
Richard Rorty’s Critique of the Self in Term of Interaction Between the Self and Others
Authors: Do Trung Kien 
Published: August 2021

Abstract
The experiential self in interaction with an object is not, as Richard Rorty emphasizes, an inherent attribute that exists before real interactions, nor is it an entity with fixed characteristics. What Rorty constantly highlights is that the interaction in forming the self must achieve self-awareness as an entity impacted, acknowledged, and evaluated by others. This line of interpretation leads to two important concepts regarding the self’s formation that need to be clarified: First, when an individual expands his/her ability to manage space outside the reach of his/her physical person and visual perception, it is imperative that the individual is aware that he/she is controlling his/her own body. Second, the reciprocal effect from others cannot make the individual self-aware of his/her own existence as an independent entity if there is a lack of the other’s skepticism and questioning of the subject himself/herself. In this step of the self-experience process, the self’s attributes and its existence in relation to its surroundings are questioned. This article will focus on the explanation of the feasibility of perceiving the self as a form made up of biological premises and the awareness of the self as a living entity with contingent and flexible characteristics.
A Machine Learning Approach in Predicting Mortality Following Emergency General Surgery
Authors: Gao Jeff , Merchant Aziz M. 
Published: August 2021

Background There is a significant mortality burden associated with emergency general surgery (EGS) procedures. The objective of this study was to develop and validate the use of a machine learning approach to predict mortality following EGS. Methods The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent EGS between 2012 and 2017. We developed a machine learning algorithm to predict mortality following EGS and compared its performance with existing risk-prediction models of American Society of Anesthesiologists (ASA) classification, American College of Surgeon Surgical Risk Calculator (ACS-SRC), and the modified frailty index (mFI) using the area under receiver operative curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results The machine learning algorithm had a very high performance for predicting mortality following EGS, and it had superior performance compared to the ASA classification, ACS-SRC, and the mFI, as measured by the AUC, sensitivity, specificity, PPV, and NPV. Discussion Machine learning approaches may be a promising tool to predict outcomes for EGS, aiding clinicians in surgical decision-making and counseling of patients and family, improving clinical outcomes by identifying modifiable risk factors than can be optimized, and decreasing treatment costs through resource allocation.
The Effect of the Mobile Subtalar Joint on Calcaneal and Supramalleolar Osteotomies
Authors: Krause Fabian , Zderic Ivan , Gueorguiev Boyko , Vellasamy Anandakumar , Schmid Timo 
Published: August 2021

Background: The mobile subtalar joint (STJ) may compensate for supra- and inframalleolar deformities and counteract the effect of realigning calcaneal or distal tibial osteotomies. The purpose of this study was to evaluate the compensatory effect of the mobile STJ after supramalleolar osteotomy (SMOT) and calcaneus osteotomy (COT) and whether the extent of the compensation correlates with STJ shape and orientation. Methods: In 10 human lower leg cadavers without evidence of deformity or prior trauma 700 Newton load were applied as a simulated standing pose. The center of force (COF) migration, maximum pressure (Pmax), and the area loaded were measured with high-resolution sensors in the ankle before and after 10-mm varus/valgus sliding COT and 10-degree varus / valgus SMOT. A computed tomographic evaluation of subtalar anatomy was conducted to correlate posterior facet curvature, its varus/valgus orientation in the coronal plane, and the effect on COF, Pmax, and area loaded. Results: The COF migration was significant for both varus and valgus SMOTs (varus SMOT: 1.78 mm, P = .0029; valgus SMOT: 1.85 mm, P = .0018) but not for COT (varus COT: 0.45 mm, P = .85; valgus COT: 1.15 mm, P = .11). Pmax and area loaded changed but not significantly. The radius of the posterior STJ surface showed a moderate correlation (varus SMOT: r = 0.61, P = .063; valgus SMOT: r = 0.28, P = .43, varus COT: r = −0.61, P = .063; valgus COT: r = 0.13, P = .38) and the axis a weak inverse correlation (varus SMOT: r = −0.51, P = .013; valgus SMOT: r = 0.58, P = .079; varus COT: r = −0.51, P = .14; valgus COT: r = 0.38, P = .28) with the COF migration after the osteotomies. Conclusion: The compensatory capacity of a mobile STJ is relatively small but appears to limit the effect of COT more than SMOT. The COT is less effective in influencing ankle joint pressure for realignment purposes than SMOT in mobile STJ and clinically more consistent in stiff STJ. Correlations are moderate to weak, whereas the curvature more than orientation of posterior facet inversely correlates with osteotomy’s effects. Level of Evidence: Level IV, biomechanical cadaver study.
Orthodontic clinicians’ attitudes and knowledge of dentogingival aesthetics: A cross-sectional survey of BOS members
Authors: Ajrash Eman , DiBiase Andrew T , Pandis Nikolaos , Cobourne Martyn T , Seehra Jadbinder 
Published: August 2021

Objective: To assess orthodontic clinicians’ knowledge and attitudes towards dentogingival aesthetics and to explore characteristics that predict the knowledge of dentogingival aesthetics. Design: Cross-sectional questionnaire Setting: On-line survey of members of the British Orthdontic Society. Materials and Methods: An 11-item online questionnaire was sent to orthodontic practitioners for completion. The questionnaire covered respondent demographics and questions relating to both knowledge and attitudes towards dentogingival aesthetics (six parameters). Descriptive statistics were calculated for study characteristics and summary values for the survey items. Responses to the eight knowledge-based questions were converted to a binary outcome (correct and incorrect answer). The maximum score that could be achieved was eight. Multivariable modelling was used in order to examine associations between the study characteristics and the aggregate score. Results: A total of 252 responses were obtained resulting in a response rate of 17%. Within this cohort, the respondents were primarily women (52.8%) and aged 30–40 years (35.7%). The mean score for the eight knowledge-based questions was 3.8 ± 1.8 (range = 0−8). Knowledge of the ideal gingival margin position of the anterior teeth was high (92.4%). Knowledge of the other five dentogingival aesthetic parameters was variable. In the multivariable analysis, lower knowledge scores were predicated by respondents who did not have a special interest in dental aesthetics (−0.54; 95% confidence interval [CI] = −1.01 to −0.07; P = 0.02), who could not recall attending courses, lectures or seminars on dental aesthetics in the past five years (−0.80; 95% CI = −1.43 to −0.17; P = 0.01) and with increasing age (−0.43; 95% CI = −0.62 to −0.23; P < 0.001). Conclusion: Knowledge of ideal dentogingival parameters is generally suboptimal among orthodontists in the UK. The reported lack of knowledge of the ideal dentogingival parameters may also influence respondents’ attitudes towards the importance of dentogingival aesthetics. Further teaching or courses related to dentogingival aesthetics is desired by orthodontic clinicians.
Do Orthopedic Surgery Residency Program Web Sites Address Diversity and Inclusion?
Authors: Mortman Ryan J. , Gu Alex , Berger Peter , Choudhury Samrat , Bernstein Simone A. , Stake Seth , Fassihi Safa C. , Thakkar Savyasachi C. , Campbell Joshua C. 
Published: August 2021

Background: Orthopedic surgery is one of the least diverse medical specialties. Other medical specialties have employed diversity-related initiatives to increase the number of students underrepresented in medicine (URM). Furthermore, with the suspension of visiting student rotations during the COVID-19 pandemic, medical students used residency program Web sites as a main source of program-specific information. Aims/Purpose: The purpose of this study was to measure the extent to which orthopedic surgery residency program Web sites describe diversity and inclusion initiatives. Methods: The Electronic Residency Application Service (ERAS) was used to identify U.S. orthopedic surgery residency programs. The programs’ Web sites were reviewed, and data on commitments to diversity and inclusion were collected. Descriptive statistics of these data were generated. Results: There were 192 residency programs identified and 3 were excluded from the analysis due to lack of Web sites. Of the remaining 189 residency program Web sites, only 55 (29.10%) contained information on diversity and inclusion. Information on a commitment to improving diversity and inclusion was the most prevalent data point found among program Web sites, although it was found on only 15% of program Web sites. Conclusion: Orthopedic surgery residency programs rarely address topics related to diversity and inclusion on their program Web sites. An emphasis on opportunities for URM students and initiatives related to diversity and inclusion on program Web sites may improve URM outreach and serve as one method for increasing URM matriculation into orthopedic surgery.
Hybrid Closed-loop to Manage Gastroparesis in People With Type 1 Diabetes: a Case Series
Authors: Daly Aideen , Hartnell Sara , Boughton Charlotte K. , Evans Mark 
Published: August 2021

Background: Gastroparesis is associated with unpredictable gastric emptying and can lead to erratic glucose profiles and negative impacts on quality-of-life. Many people with gastroparesis are unable to meet glycemic targets and there is a need for new approaches for this population. Hybrid closed-loop systems improve glucose control and quality-of-life but evidence for their use in people with diabetic gastroparesis is limited. Methods: We present a narrative review of the challenges associated with type 1 diabetes management for people with gastroparesis and present a case series of 7 people with type 1 diabetes and gastroparesis. We compare glycemic control before and during the first 12 months of hybrid closed-loop therapy. Data were analyzed using electronic patient records and glucose management platforms. We also discuss future advancements for closed-loop systems that may benefit this population. Results: Five of 7 patients had data available for time in range before and during hybrid closed-loop therapy, and all had an improvement in percentage time in target glucose range, with the overall mean time in range increasing from 26.0% ± 15.7% to 58.4% ± 8.6% during HCL use, ( P = .004). There were significant reductions in HbA1c (83 ± 9 mmol/mol to 71 ± 14 mmol/mol) and mean glucose from 13.0 ± 1.7 mmol/L (234 ± 31 mg/dL) to 10.0 ± 0.7 mmol/L (180 ± 13 mg/dL) with use of a hybrid closed-loop system. Importantly, this was achieved without an increase in time in hypoglycemia ( P = .50). Conclusion: Hybrid closed-loop systems may represent a valuable approach to improve glycemic control for people with type 1 diabetes and gastroparesis. Prospective studies are required to confirm these findings.