bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting FLT3 with a new-generation antibody-drug conjugate in combination with kinase inhibitors for treatment of AML
Authors: Roas Maike , Vick Binje , Kasper Marc-André , Able Marina , Polzer Harald , Gerlach Marcus , Kremmer Elisabeth , Hecker Judith S. , Schmitt Saskia , Stengl Andreas , Waller Verena , Hohmann Natascha , Festini Moreno , Ludwig Alexander , Rohrbacher Lisa , Herold Tobias , Subklewe Marion , Götze Katharina S. , Hackenberger Christian P. R. , Schumacher Dominik , Helma-Smets Jonas , Jeremias Irmela , Leonhardt Heinrich , Spiekermann Karsten 
Published: August 2022

AbstractFms-like tyrosine kinase 3 (FLT3) is often overexpressed or constitutively activated by internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations in acute myeloid leukemia (AML). Despite the use of receptor tyrosine kinase inhibitors (TKI) in FLT3-ITD–positive AML, the prognosis of patients is still poor, and further improvement of therapy is required. Targeting FLT3 independent of mutations by antibody-drug conjugates (ADCs) is a promising strategy for AML therapy. Here, we report the development and preclinical characterization of a novel FLT3-targeting ADC, 20D9-ADC, which was generated by applying the innovative P5 conjugation technology. In vitro, 20D9-ADC mediated potent cytotoxicity to Ba/F3 cells expressing transgenic FLT3 or FLT3-ITD, to AML cell lines, and to FLT3-ITD–positive patient-derived xenograft AML cells. In vivo, 20D9-ADC treatment led to a significant tumor reduction and even durable complete remission in AML xenograft models. Furthermore, 20D9-ADC demonstrated no severe hematotoxicity in in vitro colony formation assays using concentrations that were cytotoxic in AML cell line treatment. The combination of 20D9-ADC with the TKI midostaurin showed strong synergy in vitro and in vivo, leading to reduction of aggressive AML cells below the detection limit. Our data indicate that targeting FLT3 with an advanced new-generation ADC is a promising and potent antileukemic strategy, especially when combined with FLT3-TKI in FLT3-ITD–positive AML.
Endothelial cell–leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities
Authors: Cappelli Luca Vincenzo , Fiore Danilo , Phillip Jude M. , Yoffe Liron , Di Giacomo Filomena , Chiu William , Hu Yang , Kayembe Clarisse , Ginsberg Michael , Consolino Lorena , Barcia Duran Jose Gabriel , Zamponi Nahuel , Melnick Ari M. , Boccalatte Francesco , Tam Wayne , Elemento Olivier , Chiaretti Sabina , Guarini Anna , Foà Robin , Cerchietti Leandro , Rafii Shahin , Inghirami Giorgio 
Published: August 2022

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient–derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an EC/T-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct “education signatures.” These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALL/EC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities.
Leukemia inhibitory factor protects against graft-versus-host disease while preserving graft-versus-leukemia activity
Authors: Wang Jianming , Chang Chun-Yuan , Yang Xue , Zhou Fan , Liu Juan , Zhu Sining , Yu Xue-Zhong , Liu Chen , O’Sullivan Timothy E. , Xie Ping , Feng Zhaohui , Hu Wenwei 
Published: August 2022

Abstract
Graft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation, a widely used therapy for hematologic malignancies and blood disorders. Here, we report an unexpected role of cytokine leukemia inhibitory factor (LIF) in protecting against GVHD development. Administrating recombinant LIF protein (rLIF) protects mice from GVHD-induced tissue damage and lethality without compromising the graft-versus-leukemia activity, which is crucial to prevent tumor relapse. We found that rLIF decreases the infiltration and activation of donor immune cells and protects intestinal stem cells to ameliorate GVHD. Mechanistically, rLIF downregulates IL-12–p40 expression in recipient dendritic cells after irradiation through activating STAT1 signaling, which results in decreased major histocompatibility complex II levels on intestinal epithelial cells and decreased donor T-cell activation and infiltration. This study reveals a previously unidentified protective role of LIF for GVHD-induced tissue pathology and provides a potential effective therapeutic strategy to limit tissue pathology without compromising antileukemic efficacy.
RNA secondary structure factorization in prime tangles
Authors: Marchei Daniele , Merelli Emanuela 
Published: August 2022

AbstractBackgroundDue to its key role in various biological processes, RNA secondary structures have always been the focus of in-depth analyses, with great efforts from mathematicians and biologists, to find a suitable abstract representation for modelling its functional and structural properties. One contribution is due to Kauffman and Magarshak, who modelled RNA secondary structures as mathematical objectsconstructedin link theory:tangles of the Brauer Monoid. In this paper, we extend the tangle-based model with its minimal prime factorization, useful to analyze patterns that characterize the RNA secondary structure.ResultsBy leveraging the mapping between RNA and tangles, we prove that the prime factorizations of tangle-based models share some patterns with RNA folding’s features. We analyze theE. colitRNA and provide some visual examples of interesting patterns.ConclusionsWe formulate an open question on the nature of the class of equivalent factorizations and discuss some research directions in this regard. We also propose some practical applications of the tangle-based method to RNA classification and folding prediction as a useful tool for learning algorithms, even though the full factorization is not known.
Modeled microgravity alters apoptotic gene expression and caspase activity in the squid-vibrio symbiosis
Authors: Vroom Madeline M. , Troncoso-Garcia Angel , Duscher Alexandrea A. , Foster Jamie S. 
Published: August 2022

Abstract
Background
Spaceflight is a novel and profoundly stressful environment for life. One aspect of spaceflight, microgravity, has been shown to perturb animal physiology thereby posing numerous health risks, including dysregulation of normal developmental pathways. Microgravity can also negatively impact the interactions between animals and their microbiomes. However, the effects of microgravity on developmental processes influenced by beneficial microbes, such as apoptosis, remains poorly understood. Here, the binary mutualism between the bobtail squid, Euprymna scolopes, and the gram-negative bacterium, Vibrio fischeri, was studied under modeled microgravity conditions to elucidate how this unique stressor alters apoptotic cell death induced by beneficial microbes.

Results
Analysis of the host genome and transcriptome revealed a complex network of apoptosis genes affiliated with extrinsic/receptor-mediated and intrinsic/stress-induced apoptosis. Expression of apoptosis genes under modeled microgravity conditions occurred earlier and at high levels compared to gravity controls, in particular the expression of genes encoding initiator and executioner caspases. Functional assays of these apoptotic proteases revealed heightened activity under modeled microgravity; however, these increases could be mitigated using caspase inhibitors.

Conclusions
The outcomes of this study indicated that modeled microgravity alters the expression of both extrinsic and intrinsic apoptosis gene expression and that this process is mediated in part by caspases. Modeled microgravity-associated increases of caspase activity can be pharmacologically inhibited suggesting that perturbations to the normal apoptosis signaling cascade can be mitigated, which may have broader implications for maintaining animal-microbial homeostasis in spaceflight.
Associations among drinking water quality, dyslipidemia, and cognitive function for older adults in China: evidence from CHARLS
Authors: Pan Xi , Luo Ye , Zhao Dandan , Zhang Lingling 
Published: August 2022

Abstract
Background
The current study aimed to examine the association between drinking water quality and cognitive function and to identify the direct and indirect effects of drinking water quality and dyslipidemia on cognitive function among older adults in China.

Methods
Primary data for the study were selected from China Health and Retirement Longitudinal Study (CHARLS, 2015) and 4,951 respondents aged 60 and above were included. Data on drinking water quality were selected from the 2015 prefectural water quality data from the Institute of Public and Environment Affairs in China and measured by the Blue City Water Quality Index. Dyslipidemia was measured by self-reported dyslipidemia diagnosis and lipid panel. Three composite measures of cognitive function included mental status, episodic memory, and global cognition. Mixed effects models were conducted to assess the associations between drinking water quality or dyslipidemia and cognitive function. The mediation effects of dyslipidemia were examined by path analyses.

Results
Exposure to high quality drinking water was significantly associated with higher scores in mental status, episodic memory, and global cognition (β = 0.34, p < 0.001 for mental status; β = 0.24, p < 0.05 for episodic memory; β = 0.58, p < 0.01 for global cognition). Respondents who reported dyslipidemia diagnosis had higher scores in the three composite measures of cognitive function (β = 0.39, p < 0.001 for mental status; β = 0.27 p < 0.05 for episodic memory; β = 0.66, p < 0.001 for global cognition). An elevated blood triglycerides was only associated with higher scores in mental status (β = 0.21, p < 0.05). Self-reported dyslipidemia diagnosis was a suppressor, which increased the magnitude of the direct effect of drinking water quality on mental status, episodic memory, and global cognition.

Conclusion
Drinking water quality was associated with cognitive function in older Chinese and the relationship was independent of natural or socioeconomic variations in neighborhood environments. Improving drinking water quality could be a potential public health effort to delay the onset of cognitive impairment and prevent the dementia pandemic in older people.
Using CUSUM in real time to signal clinically relevant decreases in estimated glomerular filtration rate
Authors: Zafarnejad Reyhaneh , Dumbauld Steven , Dumbauld Diane , Adibuzzaman Mohammad , Griffin Paul , Rutsky Edwin 
Published: August 2022

Abstract
Background
The electronic health record (EHR), utilized to apply statistical methodology, assists provider decision-making, including during the care of chronic kidney disease (CKD) patients. When estimated glomerular filtration (eGFR) decreases, the rate of that change adds meaning to a patient’s single eGFR and may represent severity of renal injury. Since the cumulative sum chart technique (CUSUM), often used in quality control and surveillance, continuously checks for change in a series of measurements, we selected this statistical tool to detect clinically relevant eGFR decreases and developed CUSUMGFR.

Methods
In a retrospective analysis we applied an age adjusted CUSUMGFR, to signal identification of eventual ESKD patients prior to diagnosis date. When the patient signaled by reaching a specified threshold value, days from CUSUM signal date to ESKD diagnosis date (earliness days) were measured, along with the corresponding eGFR measurement at the signal.

Results
Signaling occurred by CUSUMGFR on average 791 days (se = 12 days) prior to ESKD diagnosis date with sensitivity = 0.897, specificity = 0.877, and accuracy = .878. Mean days prior to ESKD diagnosis were significantly greater in Black patients (905 days) and patients with hypertension (852 days), diabetes (940 days), cardiovascular disease (1027 days), and hypercholesterolemia (971 days). Sensitivity and specificity did not vary by sociodemographic and clinical risk factors.

Conclusions
CUSUMGFR correctly identified 30.6% of CKD patients destined for ESKD when eGFR was > 60 ml/min/1.73 m2 and signaled 12.3% of patients that did not go on to ESKD (though almost all went on to later-stage CKD). If utilized in an EHR, signaling patients could focus providers’ efforts to slow or prevent progression to later stage CKD and ESKD.
A predictive model of macrosomic birth based upon real-world clinical data from pregnant women
Authors: Jing Gao , Huwei Shi , Chao Chen , Lei Chen , Ping Wang , Zhongzhou Xiao , Sen Yang , Jiayuan Chen , Ruiyao Chen , Lu Lu , Shuqing Luo , Kaixiang Yang , Jie Xu , Weiwei Cheng 
Published: August 2022

Abstract
Background
Fetal macrosomia is associated with an increased risk of several maternal and newborn complications. Antenatal predication of fetal macrosomia remains challenging. We aimed to develop a nomogram model for the prediction of macrosomia using real-world clinical data to improve the sensitivity and specificity of macrosomia prediction.

Methods
In the present study, we performed a retrospective, observational study based on 13,403 medical records of pregnant women who delivered singleton infants at a tertiary hospital in Shanghai from 1 January 2018 through 31 December 2019. We split the original dataset into a training set (n = 9382) and a validation set (n = 4021) at a 7:3 ratio to generate and validate our model. The candidate variables, including maternal characteristics, laboratory tests, and sonographic parameters were compared between the two groups. A univariate and multivariate logistic regression was carried out to explore the independent risk factors for macrosomia in pregnant women. Thus, the regression model was adopted to establish a nomogram to predict the risk of macrosomia. Nomogram performance was determined by discrimination and calibration metrics. All the statistical analysis was analyzed using R software.

Results
We compared the differences between the macrosomic and non-macrosomic groups within the training set and found 16 independent risk factors for macrosomia (P < 0.05), including biparietal diameter (BPD), head circumference (HC), femur length (FL), amniotic fluid index (AFI) at the last prenatal examination, pre-pregnancy body mass index (BMI), and triglycerides (TG). Values for the areas under the curve (AUC) for the nomogram model were 0.917 (95% CI, 0.908–0.927) and 0.910 (95% CI, 0.894–0.927) in the training set and validation set, respectively. The internal and external validation of the nomogram demonstrated favorable calibration as well as discriminatory capability of the model.

Conclusions
Our model has precise discrimination and calibration capabilities, which can help clinical healthcare staff accurately predict macrosomia in pregnant women.
Real-world patient characteristics and treatment outcomes among nontransplanted multiple myeloma patients who received Bortezomib in combination with Lenalidomide and Dexamethasone as first line of therapy in the United States
Authors: Medhekar Rohan , Ran Tao , Fu Alex Z. , Patel Sharmila , Kaila Shuchita 
Published: August 2022

Abstract
Background
There is limited real-world evidence that describes patients with newly diagnosed multiple myeloma (NDMM) treated with the bortezomib, lenalidomide, and dexamethasone (VRd) triplet regimen. We evaluated patient characteristics and treatment outcomes among nontransplanted NDMM patients who received VRd as their first line of therapy (LOT) in US oncology practice settings.

Methods
This retrospective observational cohort study evaluated patients from the Flatiron MM Core Registry who received VRd as first LOT between November 1, 2015, and February 28, 2021. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. Associations between patient demographic and clinical characteristics and PFS were evaluated using a multivariable Cox proportional hazards model.

Results
A total of 2342 eligible patients with VRd as first LOT were identified (mean age, 67.0 years). Among all identified patients, 64.3% were ≥ 65 years of age, 25.5% were elderly (≥75 years), and 47.9% were frail. Among patients with available data, 21.2% had high-risk cytogenetics, and the majority had International Staging System (ISS) stage I/II disease (71.8%), and Eastern Cooperative Oncology Group performance status (ECOG PS) score 0/1 (81.2%). Median duration of therapy was 5.5 months. With median follow-up of 21.0 months, median PFS and time-to-next-treatment were 26.5 and 16.1 months, respectively. Higher risk of disease progression or death was seen in patients categorized as elderly (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.13-1.66 vs patients < 65 years), having high-risk cytogenetics (HR = 1.44; 95% CI: 1.19-1.75 vs standard risk), having ISS disease stages II and III (HR = 1.31; 95% CI: 1.06-1.63 and HR = 1.37; 95% CI: 1.10-1.70 versus stage I, respectively), and having worse ECOG PS score (≥2) (HR = 1.49; 95% CI: 1.22-1.81 versus functionally active patients).

Conclusions
The majority of patients treated with VRd in this study were ≥ 65 years of age, were ISS stage I/II, had an ECOG PS score of 0/1, and had standard cytogenetic risk. Median PFS observed in real-world practice was notably shorter than that observed in the SWOG S0777 clinical trial. In nontransplanted patients treated with VRd as first LOT, a higher risk of disease progression or death was associated with older age, having high-risk cytogenetics, worse disease stage, and worse ECOG PS score.
Colorectal cancer risk in association with colorectal cancer as a second malignancy in relatives: a nationwide cohort study
Authors: Zheng Guoqiao , Sundquist Jan , Sundquist Kristina , Ji Jianguang 
Published: August 2022

Abstract
Background
Increasing number of individuals will have first-degree relatives (FDRs) diagnosed with colorectal cancer (CRC), as a second primary malignancy (CRCa-2) after a non-CRC cancer. We aimed to estimate whether and to what extent a family history of CRCa-2 is associated with an increased CRC risk.

Methods
In this Swedish nationwide cohort study, rate ratio (RR) and cumulative incidence of CRC were estimated among 172,531 individuals with a family history of CRC as a first primary malignancy (CRCa-1) and 17,830 with a family history of CRCa-2, respectively, using individuals without cancer family history as the reference group.

Results
A cumulative incidence of CRC by age 80 was 6.3 and 5.6% for individuals with a parental and a sibling family history of CRCa-2, respectively. RRs of CRC for one FDR diagnosed with CRCa-1 and CRCa-2 were respectively 1.72 (95% CI, 1.65–1.79) and 1.50 (1.32–1.70); the latter RR was lower than the former (P = 0.0356), but no difference was observed after adjusting age of diagnosis of CRC in FDR and family relationship (P = 0.6898). Increased RRs were found to be associated with a CRCa-2 diagnosis in FDR that occured after cancers in upper aerodigestive tract, breast, prostate, kidney and nervous system.

Conclusions
Individuals who have relatives with CRCa-2 have an increased risk of CRC, but the magnitude is lower than those having relatives with CRCa-1, which is related to different ages of diagnosis of CRC in FDR and family relationships.
Tight adherent feature on optical coherence tomography predict postoperative visual outcome in epiretinal membrane eyes
Authors: Lai Tzu-Ting , Wu Li-Li , Hsieh Yi-Ting , Lee Chia-Chen , Peng Yi-Jie 
Published: August 2022

Abstract
Background
To identify the predictive parameter among preoperative measurements that best predicts postoperative visual outcome in the epiretinal membrane (ERM).

Methods
Thirty-three consecutive patients with idiopathic unilateral ERM patients between 2015 and 2018 were enrolled. Nineteen healthy normal eyes were selected as an independent age-matched group. Based on preoperative optical coherence tomography (OCT), we further divided the patients with ERM into two groups: type 1, loosely attached ERM, and type 2, tight adherent ERM. We documented the vision and thickness of various retinal layers: nerve fiber layer, ganglion cell layer, inner plexiform layer (GCL + IPL), inner nuclear layer (INL), outer retinal layer (ORL), and retinal pigment epithelium/Bruch complex layer before and after the surgery. The association between postoperative visual acuity and these variables was analyzed using multiple linear regression analysis.

Results
All retinal layers of ERM eyes were thicker than the normal eyes (P < 0.05). Among ERMs, we identified 11 eyes with type 1 adhesions and 22 eyes with type 2 adhesions. The preoperative GCL + IPL layers were significantly thicker in type 2 patients than in type 1 patients (93.67 ± 33.03 um vs 167.71 ± 13.77 um; P = 0.023). Greater GCL + IPL thickness was correlated with a worse postoperative visual acuity and multiple linear regression analysis showed that GCL + IPL thickness was an independent predictor of postoperative visual acuity (VA) (beta value = 0.689; P = 0.012). A greater thickness of GCL + IPL layers of type 2 patients had worse postoperative best-corrected visual acuity (BCVA) (P = 0.028). Ectopic inner foveal layers with disappearance of fovea pit were persistently presented in OCT profiles of both groups.

Conclusion
Idiopathic ERM demonstrated significantly thicker inner retinal layers (GCL + IPL and INL). However, the ORL thickness was similar between the normal eyes and ERM eyes. The preoperative GCL + IPL layers were significantly thicker in patients with type 2 ERM than that in patients with type 1 ERM. The increase in GCL + IPL thickness was significantly correlated with worse postoperative visual outcomes.