bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Multicenter Cohort Study on Children Suffering from Acute Lymphoblastic Leukemia: Effects of Obesity on Mortality
Authors: Wang Xiangwen , Mu Dan , Geng Anyang , Zhao Anqi , Song Yiyuan 
Published: July 2022

Background. Overweight and obesity have been reported in specific patients and disease survivors compared to other types of childhood cancer. This study is aimed at determining the effect of children’s obesity on the mortality of acute lymphoblastic leukemia. Method. Children admitted to Inner Mongolia International Mongolian Hospital from 1 January 2017 to 31 December 2020 participated in this study. 1070 children were analyzed. A multi-middle-class poll was conducted. All children under the age of 15 were followed up within 24 months of diagnosis. Overweight and obesity are identified according to the World Health Organization and the Centers for Disease Control and Prevention. Premature death and reoccurrence of emergencies are the main consequences. Results. The initial ethical rate for the first 24 months of testing was 19.9% (NS 213). The lowest cancer survival rate (DFS) was childhood obesity (73%) (24 months), compared with average weight (81%). Diagnosis of overweight/obesity is a predictor of early death (WHO:

HR
=
1.4

, 95% CI: 1.0-2.0; CDC:

HR
=
1.6

, 95% CI: 1.1-2.3). However, there was no association between overweight and obesity (WHO:

HR
=
1.5

, 95% effective interval: 0.9-2.5; CDC:

human

resources
=
1.0

, 95% effective interval: 0.6-1.6) and obesity (WHO:

HR
=
1.5

, 95% effective interval: 0.7-3.2; CDC:

HR
=
1.4

, 95% effective interval: 0.9-2.3). Early recurrence was observed. Conclusion. Overweight and obese people belong to the subclass with a high risk of death in the treatment of leukemia.
Shining a FLASHlight on Ultrahigh Dose-Rate Radiation and Possible Late Toxicity
Authors: Maity Amit , Koumenis Constantinos 
Published: July 2022

Summary
A recent study reported results from a clinical trial in cats and from experiments in mini-pigs in which a single dose of radiotherapy was delivered at ultrahigh dose rates (FLASH). There was acceptable acute toxicity; however, some animals suffered severe late toxicity, raising caution in the design of future trials.
See related article by Rohrer Bley et al., p. 3814
Agonizing over the Stimulatory Immune Checkpoint ICOS
Authors: Lee Jerry C. , Fong Lawrence 
Published: July 2022

Summary
Vopratelimab, an anti-ICOS (inducible costimulator of T cells) agonist, alone and in combination with nivolumab, possesses limited toxicity and modest clinical activity in a large phase I/II trial. This treatment induced ICOS expression of CD4+ T cells, which may enable biomarkers for patient selection. Nevertheless, T-cell agonists as cancer immunotherapies continue to be challenging.
See related article by Yap et al., p. 3695
Inhibition of Integrin αVβ3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma
Authors: Cayrol Florencia , Revuelta Maria V. , Debernardi Mercedes , Paulazo Alejandra , Phillip Jude M. , Zamponi Nahuel , Sterle Helena , Díaz Flaqué María C. , Magro Cynthia , Marullo Rossella , Mulvey Erin , Ruan Jia , Cremaschi Graciela A. , Cerchietti Leandro 
Published: July 2022

Abstract

Bexarotene is a specific retinoid X receptor agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Because bexarotene causes hypothyroidism, it requires the administration of levothyroxine. However, levothyroxine, in addition to its ubiquitous nuclear receptors, can activate the αVβ3 integrin that is overexpressed in CTCL, potentially interfering the antineoplastic effect of bexarotene. We thus investigated the biological effect of levothyroxine in relation to bexarotene treatment. Although in isolated CTCL cells levothyroxine decreased, in an αVβ3-dependent manner, the antineoplastic effect of bexarotene, levothyroxine supplementation in preclinical models was necessary to avoid suppression of lymphoma immunity. Accordingly, selective genetic and pharmacologic inhibition of integrin αVβ3 improved the antineoplastic effect of bexarotene plus levothyroxine replacement while maintaining lymphoma immunity. Our results provide a mechanistic rationale for clinical testing of integrin αVβ3 inhibitors as part of CTCL regimens based on bexarotene administration.

Teaser:
Inhibiting αVβ3 integrin improves the antineoplastic effect of bexarotene while maintaining lymphoma immunity.
Efficacy, Tolerability, and Pharmacokinetic Studies of Antibody–Drug Conjugates Containing a Low-Potency Pyrrolobenzodiazepine Dimer
Authors: Gregson Stephen J. , Pugh Kathryn , Patel Neki , Afif-Rider Shameen , Vijayakrishnan Balakumar , Santos Kathleen , Riedl Jitka , Hutchinson Ian , Kang Gyoung-Dong , Chooi K. Phin , Beard Rhiannon , Adams Lauren , Barry Conor S. , Ball Kathryn , Masterson Luke A. , McFarlane Mary , Hartley John A. , Howard Philip W. 
Published: July 2022

Abstract
Antibody–drug conjugate (ADC) research has typically focused on the release of highly potent cytotoxic agents to achieve antitumor efficacy. However, recently approved ADCs trastuzumab deruxtecan and sacituzumab govitecan release lower-potency topoisomerase inhibitors. This has prompted interest in ADCs that release lower-potency cytotoxic drugs to potentially enhance therapeutic index and reduce unwanted toxicity. Pyrrolobenzodiazepine (PBD) dimer ADCs have been widely investigated in human clinical trials, which have focused on high-potency PBDs. In this study, we evaluated five ADCs that release the low-potency PBD dimer SG3650. The relatively low clogD for this agent facilitated higher drug-to-antibody ratio (DAR) conjugation without the need for antibody engineering or functionalization of the drug. The rank order of potency for DAR 2 site-specific ADCs (conjugated at the C239i position) matched the order for the corresponding free drugs in vitro. Despite free drug SG3650 being inactive in vivo, the DAR 2 ADCs derived from the corresponding drug-linker SG3584 showed antitumor efficacy in solid (anti-HER2) and hematologic (anti-CD22) xenograft models. Antitumor activity could be enhanced by conjugating SG3584 to trastuzumab at higher DARs of 4 and 8 and by adjusting dosing and schedule. Higher-DAR conjugates were stable and displayed good rat pharmacokinetic profiles as measured by ELISA and LC/MS-MS. A single intravenous dose of isotype control SG3584 DAR 2 ADC resulted in no mortality in rats or monkeys at doses of up to 25 and 30 mg/kg, respectively. These findings suggest that further investigations of low-potency PBD dimers in ADCs that target hematologic and solid tumors are warranted.
An Enzymatically Cleavable Tripeptide Linker for Maximizing the Therapeutic Index of Antibody–Drug Conjugates
Authors: Ha Summer Y.Y. , Anami Yasuaki , Yamazaki Chisato M. , Xiong Wei , Haase Candice M. , Olson Scott D. , Lee Jangsoon , Ueno Naoto T. , Zhang Ningyan , An Zhiqiang , Tsuchikama Kyoji 
Published: July 2022

Abstract
Valine–citrulline is a protease-cleavable linker commonly used in many drug delivery systems, including antibody–drug conjugates (ADC) for cancer therapy. However, its suboptimal in vivo stability can cause various adverse effects such as neutropenia and hepatotoxicity, leading to dose delays or treatment discontinuation. Here, we report that glutamic acid–glycine–citrulline (EGCit) linkers have the potential to solve this clinical issue without compromising the ability of traceless drug release and ADC therapeutic efficacy. We demonstrate that our EGCit ADC resists neutrophil protease–mediated degradation and spares differentiating human neutrophils. Notably, our anti-HER2 ADC shows almost no sign of blood and liver toxicity in healthy mice at 80 mg kg−1. In contrast, at the same dose level, the FDA-approved anti-HER2 ADCs Kadcyla and Enhertu show increased levels of serum alanine aminotransferase and aspartate aminotransferase and morphologic changes in liver tissues. Our EGCit conjugates also exert greater antitumor efficacy in multiple xenograft tumor models compared with Kadcyla and Enhertu. This linker technology could substantially broaden the therapeutic windows of ADCs and other drug delivery agents, providing clinical options with improved efficacy and safety.
Walking the Tightrope: Balancing Delicate Inflammation Response to Eradicate Acute Myeloid Leukemia
Authors: Puissant Alexandre , Medyouf Hind 
Published: July 2022

Summary:
Ellegast and colleagues show that monocytic acute myeloid leukemias (AML), enriched in inflammatory and immune gene sets, exploit a transcriptional repressor—namely, IRF2BP2—to mitigate their cell-intrinsic inflammatory output and ensure their maintenance. IRF2BP2 ablation results in heightened inflammatory signals that reach a set point that triggers apoptotic AML cell death in an NF-κB–IL1β–dependent manner. The study identifies IRF2BP2 as a cell-intrinsic vulnerability with potential therapeutic significance in monocytic AML.
See related article by Ellegast et al., p. 1760 (6).
Inducing Hypermutability to Promote Anti–PD-1 Therapy Response
Authors: Willis Jason A. , Overman Michael J. 
Published: July 2022

Summary:
The lack of clinical activity from various immune-checkpoint blockade approaches in mismatch repair– proficient (MMRp) colorectal cancer has demonstrated a critical need for novel approaches. In this issue, Crisafulli and colleagues provide proof of concept for the induction of hypermutability through the use of temozolomide as a potential pathway for enabling a productive anti–PD-1 immune response in MMRp colorectal cancer.
See related article by Crisafulli et al., p. 1656 (1) .
Influence of Entrainment on Centimeter-Scale Cloud Microphysics in Marine Stratocumulus Clouds Observed during CSET
Authors: La Inyeob , Yum Seong Soo , Yeom Jae Min , Shaw Raymond A. 
Published: July 2022

Abstract
Cloud microphysical relationships observed during the Cloud System Evolution in the Trades (CSET) campaign held between Northern California and Hawaii were analyzed to study the effects of entrainment and subsequent mixing of free-tropospheric and cloudy air on cloud microphysical properties of marine stratocumulus clouds. The data measured by Holographic Detector for Clouds (HOLODEC) were extensively used because they could provide the 3D positions and sizes of droplets within sample volume on the centimeter scale, making it possible to explore the 3D spatial distribution of droplets, which has not been possible for conventional cloud probes. This study focused on analyzing the 3D spatial distribution of droplets and visual traits of inhomogeneous mixing and on quantifying the relationship between 3D spatial distributions and traits of inhomogeneous mixing. Two types of spatial distributions are compared. The first is measured droplet spatial distribution and the second type is generated randomly distributed droplets using the Monte Carlo approach, that is, to analyze whether or not clustering is strong enough to classify as a clustered distribution for a hologram. The difference between the two types of spatial distributions depends on whether they are affected by entrainment and mixing. The holograms observed near the cloud top, where the effects of entrainment and mixing would be immediate, showed relatively high confidence in the significance test for spatially clustered populations of droplets. Moreover, spatially clustered holograms appeared to exhibit stronger visual traits of inhomogeneous mixing than perfectly randomly distributed holograms only when observed near the cloud top. On the other hand, these characteristics did not appear for holograms observed deeper into the cloud where the effects of entrainment and mixing would be reduced. Such 3D structural characteristics of droplet distributions seem to be consistent with vertical circulation mixing.
Diversity of MJO Initiation Regions and Processes
Authors: Wang Tianyi , Li Tim 
Published: July 2022

Abstract
The diversity of the Madden–Julian oscillation (MJO) initiation (i.e., initial onset of active convection before moving eastward) regions was explored using a clustering method. Regions favorable for MJO initiations are grouped into four longitude zones: the Atlantic and Africa (AA), the Indian Ocean (IO), the Maritime Continent (MC), and the western Pacific (WP). The region-dependent dominant initiation mechanisms are explored using a composite procedure. The AA initiation is attributed to a circumnavigating process associated with a preceding MJO. As upper-tropospheric westerly anomalies move into the AA region, the associated descending motion leads to suppressed convection over the IO, which further triggers convection onset to its west through anomalous westward moisture advection. The IO initiation arises from the downstream forcing of a preceding suppressed phase of MJO. A delayed air–sea interaction process also plays a role. The MC initiation is triggered by a westward-propagating dry equatorial Rossby wave in the Pacific. The low-level poleward flows associated with the anticyclonic Rossby wave gyres advect high mean moisture, promoting the convection onset over the MC. The WP initiation is triggered by a preceding suppressed phase of MJO that moves eastward, in a way similar to the downstream scenario in the IO. The AA initiation is usually associated with a La Niña–like background sea surface temperature pattern, which favors the decoupling of upper-tropospheric westerly anomalies from the preceding MJO. The MC and WP initiations are more frequent during El Niño, as the relevant meridional moisture gradient is sharper and the eastern Pacific is moister.
Trends in Post-Secondary Student Stress: A Pan-Canadian Study
Authors: Linden Brooke , Stuart Heather , Ecclestone Amy 
Published: July 2022

Objective Previous research has evaluated the sources of post-secondary student stress, but has failed to explore whether stressors fluctuate over time. The purpose of this research was to use the Post-Secondary Student Stressors Index to examine whether stressors changed significantly and meaningfully over the course of an academic year. Due to the timing of data collection, results also provide context around students’ experiences of stress during the COVID-19 pandemic. Method Cross-sectional data was collected at 3 time points via online surveys over the course of the 2020–2021 academic year from >10,000 students. Participants attended 15 post-secondary institutions across Canada, representing 9 provinces and 1 territory. Validated instruments were used to assess levels of stress, distress and the severity of student-specific stressors. Kruskal–Wallis ranked tests and multiple pairwise comparison analyses were conducted to assess whether the mean severity of stressors changed over time. Standard effect sizes were calculated using Cohen's d. Results Mean levels of stress and psychological distress were high at the start of the study and remained high across time points. A similarly high level of stress was observed on average for student-specific stressors. While significant differences in mean severity were observed over time for some stressors, standardized effect sizes were negligible, suggesting little meaningful change and consistent levels of chronic stress over the course of the academic year. Conclusions This is the first paper to examine trends in student-specific stress using a nationwide sample of Canadian post-secondary students during the first year of the COVID-19 pandemic. Patterns observed in student-specific stressors reflected changes likely to be indicative of the pandemic, including the most severe stress associated with academics, finances and concerns for the future. Implications for future research are discussed, in particular, the importance of examining stressors related to COVID-19 and their impact on student mental health.
E-Cigarette and Cannabis Use Patterns, Depression, and Suicide Behaviors Among US Youth: Analysis of 2019 Youth Risk Behavior Survey Data
Authors: Jacobs Wura , Orozco Georgina , Villanueva Guadalupe , Merianos Ashley L 
Published: July 2022

Purpose To examine the associations of current electronic cigarette and cannabis use patterns with depression symptoms and suicidal ideation and behavior overall and stratified by sex among U.S. high school students. Design Quantitative, cross-sectional study. Setting The 2019 National Youth Risk Behavior Survey. Subjects 12,401 high school students in 9th−12th grade. Measures Dependent variables were depression symptoms, suicidal ideation, suicide plan, suicide attempt, and suicide attempt-related injury. Independent variables were past 30 day e-cigarette and cannabis use patterns. Covariates included demographics, grade level, and other tobacco product use. Analysis Multivariable logistic regression models. Results Approximately 15.7% of students were exclusive e-cigarette users, 4.5% were exclusive cannabis users, and 16.4% were concurrent e-cigarette and cannabis users. Exclusive e-cigarette and cannabis users, and concurrent users were at increased odds ( P < .05) of having depression symptoms, seriously considered attempting suicide, planning suicide, suicide attempt, and having suicide attempt-related injury compared to non-users. Female users, especially concurrent users, had higher odds of reporting depression symptoms ( P < .01) and all suicidal ideation and behavior outcomes ( P < .01) than female non-users, but results varied for male students. Conclusion E-cigarette and cannabis use patterns significantly predicted depression symptomatology and suicidal ideation and behavior, with female students having higher odds. Results suggest the need for tailored interventions to address mental health and suicidality among U.S. adolescents, and especially female students.
Review of novel and supplemental approvals of the targeted cancer drugs by the Food and Drug Administration in 2021
Authors: Kandemir Esin Aysel 
Published: July 2022

Objective This review aims to present the most recent results from clinical trials of targeted cancer drugs that led to the Food and Drug Administration approval in 2021 and reflect the changing treatment landscape of solid malignancies. Data Sources Novel approvals and supplemental approvals in 2021 were retrieved from the official web page of the Food and Drug Administration (Drugs@FDA). This review did not include approvals for generics, biosimilars, imaging, and diagnostics agents. Data Summary This review included 10 novel drugs approved for 11 indications and 10 already-approved drugs approved for 21 indications by the Food and Drug Administration in 2021. Novel approvals mainly were related to treating an orphan disease. In addition, one-third of the supplemental approvals were given for neoadjuvant or adjuvant treatment, while the number of indications for each tumor site was as follows: gastrointestinal (7), genitourinary (5), skin (3), lung (2), breast (2), thyroid (1), and cervix (1). Conclusions Targeted cancer treatments are gaining more importance than ever in treating malignant diseases. As the approval of targeted cancer drugs provides a possibility for patients and this trend is expected to continue in the future, it remains vital for healthcare providers to stay up-to-date with newer therapeutic options.
Pulsed-wave Doppler for ultrasound-based tip location using bubble test: A pilot study
Authors: Gidaro Antonio , Casella Francesco , Cogliati Chiara , La Greca Antonio , Lugli Francesca , Trione Chiara , Calloni Maria , Melchionda Chiara , Samartin Federica , Salvi Emanuele , Ceriani Elisa 
Published: July 2022

Background: MicroBubbles Time test (MBT), consisting in the rapid infusion of saline with addition of air microbubbles, visualized by B-mode echocardiography, represents a potential alternative to Intracavitary ECG (IC-ECG) and chest X-ray for central venous catheters (CVCs) tip location. Even if promising, this technique lacks of standardization: a clear time cut-off between bubble infusion and their detection in heart’s right chambers hasn’t been yet established. At these regard, microbubbles could be also detected as microembolic signals (MES) with an alternative ultrasound technique: the pulse wave Doppler (PW). Objective and methods: The first aim of this pilot study is to establish agreement of MBT with PW test (MBT-PW) compared with reference standard IC-ECG and normal MBT for tip location on CVCs. Corrected tip’s position was established through reference standard IC-ECG, afterward MBT-PW was performed, with the sample volume placed at tricuspid valve to detect MES simultaneously with micro-bubbles injection in CVCs. The second aim was to evaluate inter-observer variability for MES detection and grading. Results: Eight patients were enrolled; we obtained three records for each patients (24 with MBT and 24 with MBT-PW, the two techniques were acquired simultaneously). Inter-methods agreement through reference standard IC-ECG versus MBT-PW and MBT versus MBT-PW methodic was satisfying (Cohen’s kappa value = 1). MBT-PW and MBT signals were recorded within the first heart beat after microbubble infusion in all patients. Mean time delay thorough MBT-PW and MBT was 0.76 ±0.07 and 0.78 ± 0.07 s respectively; Intraclass correlation coefficient was 0.992 (95% CI: 0.981–0.996) suggesting excellent correlation. Inter-observer variability for positive MBT-PW evaluation was optimal (Cohen’s kappa value was 1), while indicated substantial agreement for MES grade evaluation (Fleiss’ Kappa value was 0.704; 95% CI: 0.328–1.000). Conclusions: Our study supports agreement between MBT-PW and reference standard IC-ECG for tip location. Satisfactory agreement was observed also for MBT-PW and MBT.
Immune complications and their management in inherited and acquired bleeding disorders
Authors: Arruda Valder R. , Lillicrap David , Herzog Roland W. 
Published: July 2022

Abstract
Disorders of coagulation, resulting in serious risks for bleeding, may be caused by autoantibody formation or by mutations in genes encoding coagulation factors. In the latter case, antidrug antibodies (ADAs) may form against the clotting factor protein drugs used in replacement therapy, as is well documented in the treatment of the X-linked disease hemophilia. Such neutralizing antibodies against factors VIII or IX substantially complicate treatment. Autoantibody formation against factor VIII leads to acquired hemophilia. Although rare, antibody formation may occur in the treatment of other clotting factor deficiencies (eg, against von Willebrand factor [VWF]). The main strategies that have emerged to address these immune responses include (1) clinical immune tolerance induction (ITI) protocols; (2) immune suppression therapies (ISTs); and (3) the development of drugs that can improve hemostasis while bypassing the antibodies against coagulation factors altogether (some of these nonfactor therapies/NFTs are antibody-based, but they are distinct from traditional immunotherapy as they do not target the immune system). Choice of immune or alternative therapy and criteria for selection of a specific regimen for inherited and autoimmune bleeding disorders are explained. ITI serves as an important proof of principle that antigen-specific immune tolerance can be achieved in humans through repeated antigen administration, even in the absence of immune suppression. Finally, novel immunotherapy approaches that are still in the preclinical phase, such as cellular (for instance, regulatory T cell [Treg]) immunotherapies, gene therapy, and oral antigen administration, are discussed.