bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regression of EGFR positive established solid tumors in mice with the conditionally active T cell engager TAK-186
Authors: Dettling Danielle E , Kwok Eilene , Quach Lucy , Datt Aakash , Degenhardt Jeremiah D , Panchal Anand , Seto Pui , Krakow Jessica L , Wall Russell , Hillier Brian J , Zhu Ying , Vinogradova Maia , DuBridge Robert B , May Chad 
Published: June 2022

BackgroundDespite clinical success with T cell engagers (TCEs) targeting hematological malignancies, achieving a safe and efficacious dose in patients with solid tumors remains challenging. Due to potency, low levels of target antigen expression on normal tissues may not be tolerated. To overcome this, we engineered a novel conditionally active TCE design called COBRA (ConditionalBispecificRedirectedActivation). Administered as prodrugs, COBRAs bind to cell surface antigens on both normal and tumor tissues but are preferentially activated within the tumor microenvironment.MethodsA COBRA was engineered to target EGFR, TAK-186. The potency of precleaved TAK-186 relative to a non-cleavable control was assessed in vitro. Mice bearing established solid tumors expressing a range of EGFR levels were administered a single bolus of human T cells, and concurrently treated with TAK-186 and associated controls intravenously. We assessed the plasma and tumor exposure of intact and cleaved TAK-186.ResultsTAK-186 shows potent redirected T cell killing of antigen expressing tumor cells. In vivo efficacy studies demonstrate regressions of established solid tumors, dependent on intratumoral COBRA cleavage. Pharmacokinetic studies reveal TAK-186 is stable in circulation, but once activated is rapidly cleared due to loss of its albumin-binding half-life extension domain.ConclusionsThe studies shown support the advancement of TAK-186, and the pursuit of additional COBRA TCEs for the treatment of solid tumors.
Impact of elevated left ventricular filling pressure on long-term outcomes after transcatheter aortic valve replacement
Authors: Nair Raunak M , Chawla Sanchit , Verma Beni , Kumar Sachin , Abou Hassan Ossama , Ghimire Bindesh , Lak Hassan Mehmood , Chahine Johnny , Yun James , Puri Rishi , Reed Grant W , Krishnaswamy Amar , Harb Serge C , Kapadia Samir 
Published: June 2022

BackgroundIncrease in left ventricular filling pressure (FP) and diastolic dysfunction are established consequences of progressive aortic stenosis (AS). However, the impact of elevated FP as detected by pretranscatheter aortic valve replacement (TAVR) echocardiogram on long-term outcomes after TAVR remains unclear.ObjectiveTo understand the impact of elevated FP in patients with severe AS who undergo TAVR.MethodsThis was a retrospective study of all patients who underwent TAVR between 1 January 2014 and 31 December 2017. The presence of elevated FP was determined in accordance with the latest guidelines using the last available comprehensive echocardiogram prior to TAVR.ResultsOf 983 patients who were included in our study, 422 patients (43%) were found to have elevated FP and 561 patients (57%) had normal FP prior to TAVR. Patients with elevated FP had a mean age of 81.2±8.6 years and were more likely to be males (62%), diabetic (41% vs 35%, p=0.046), and have a higher prevalence of atrial fibrillation (Afib) (53% vs 39%, p<0.001). The 5-year all-cause mortality after TAVR was significantly higher in patients with elevated FP when compared with patients with normal FP (32% vs 24%, p=0.006). The presence of elevated FP, history of Afib and prior PCI emerged as independent predictors of long-term mortality after TAVR.ConclusionElevated FP is associated with increased mortality in patients with severe AS undergoing TAVR. Assessment of FP should be incorporated into the risk assessment of AS patients to identify those who may benefit from early intervention.
Classical solutions of $$\lambda $$-deformed coset models
Authors: Katsinis Dimitrios , Panopoulos Pantelis 
Published: June 2022

AbstractWe obtain classical solutions of $$\lambda $$
λ
-deformed $$\sigma $$
σ
-models based on $$SL(2,{\mathbb {R}})/U(1)$$

S
L
(
2
,
R
)
/
U
(
1
)

and SU(2)/U(1) coset manifolds. Using two different sets of coordinates, we derive two distinct classes of solutions. The first class is expressed in terms of hyperbolic and trigonometric functions, whereas the second one in terms of elliptic functions. We analyze their properties along with the boundary conditions and discuss string systems that they describe. It turns out that there is an apparent similarity between the solutions of the second class and the motion of a pendulum.
Experimental evaluation of heat transfer effect on turbocompressor performance operating with helium-neon gas mixtures
Authors: Podeur Maxime , Vogt Damian M. 
Published: June 2022

AbstractWithin the framework of the Future Circular Collider (FCC) currently being investigated at CERN, the entire cryogenic cycle had to be revised with respect to the existing Large Hadron Collider (LHC). In particular, a novel pre-cooling cycle had to be developed for this purpose. This led to a closed-loop cryogenic cycle operating with a mixture of helium and neon, also called Nelium. To better understand the challenges and opportunities associated with the design and operation of radial compressors with such light gases, a closed loop test facility has been designed, built and commissioned at the ITSM (University of Stuttgart). The test facility has been developed to operate with air as well as with helium-neon gas mixtures of varying mixing ratios ranging from pure neon to pure helium. In this paper, the test facility architecture and operation procedure are briefly introduced together with a description of the newly installed compressor stage. Experimental performance measurements are then compared to adiabatic and diabatic numerical simulation validating respectively the pressure rise and diabatic stage efficiency for various gases. The heat transfer effect on compressor stage performance is then described and the respective contribution of the influencing factors are quantified.
k-Means Clustering with Optimal Centroid: An Optimization Insisted Model for Removing Outliers
Authors: Rahul Kumar , Banyal Rohitash Kumar 
Published: June 2022

In data cleaning, the process of detecting and correcting corrupt, inaccurate or irrelevant records from the record set is a tedious task. Particularly, the process of “outlier detection” occupies a significant role in data cleaning that removes or eliminates the outlier’s that exist in data. Traditionally, more efforts have been taken to remove the outliers, and one of the promising ways is customizing clustering models. In this manner, this paper intends to propose a new outlier detection model via enhanced k-means with outlier removal (E-KMOR), which assigns all outliers into a group naturally during the clustering process. For assigning the point to be outliers, a new intra-cluster based distance evaluation is employed. The main contribution of this paper is to select cluster centroid optimally through a newly proposed hybrid optimization algorithm termed particle updated lion algorithm (PU-LA), which hybrids the concepts of LA and particle swarm optimization (PSO), respectively. Thereby, the proposed work is named as E-KMOR-PU-LA. Finally, the efficacy of the proposed E-KMOR-PU-LA model is proved through a comparative analysis over conventional models by concerning runtime and accuracy.
Assessment and Treatment of Postmenopausal Osteoporosis: An Appraisal of International Guidelines
Authors: Chaiamnuay Sumapa 
Published: June 2022

Recently, several updates in the assessment and treatment of postmenopausal osteoporosis guidelines were published. This review discusses international guidelines, including the algorithm for management of patients at risk of osteoporotic fracture from the International Osteoporosis Foundation (IOF) and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) 2020, The Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline (2019)/Guideline Update (2020), and the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update. Due to the recent COVID-19 pandemics, the joint guidance on osteoporosis management in the era of COVID-19 pandemic will also be included. The criterion for diagnosis of osteoporosis has been published by AACE/ACE. All postmenopausal women of age ≥50 years old should be evaluated for osteoporosis risk. Those at very high risk for fracture are recommended to start treatment with anabolic agents and those at high risk for fracture are recommended to start treatment with antiresorptive agent such as bisphosphonates or denosumab. Intervention thresholds and treatment options vary from country to country. Physicians should individualize the treatment according to risks, benefits, patient preferences, as well as treatment accessibility.
Handling Adverse Effects of Digital Screen Time on Preschool Children: Looking beyond Limiting Screen Time
Authors: Goyal Ruchi 
Published: June 2022

Author analyses excessive screen time issues with preschool children, and how counsellors can take a better counselling approach with parents while keeping in perspective Erik Erikson’s Theory of psychosocial development impacting the child by the age of 5 years. Preschool children spend more than 2.5 hours per day on digital screens; this is against recommended guidelines of less than 1 hour per day by * WHO and ** AAP. A literature review of research papers from online *** libraries by the author found that only a small percentage of children met the recommended guidelines resulting in the risk of language disorders, delayed development of physical, motor skills and cognitive abilities, obesity, sleep problems, depression and anxiety due to screen exposure. The loneliness of children is found to be the primary reason for the excessive screen time. The author suggests that counsellors help parents look beyond limiting a child’s screen time alone and improve the parental attitude toward the child’s behaviour which is the biggest barrier in managing a child’s screen time. The author’s contribution is the ‘SALT’ counselling approach emphasising listening Support, finding Alternatives, Loneliness and Time in this digital era to cater to all types of child learners - visual, auditory, and kinesthetic. Why is your paper of interest to readers? Exposure of preschool children to digital devices is more than double the recommended screen time, hampering a child’s critical personality development required as per Erik Erikson’s Theory. Counsellors need to look at other associated factors beyond screen time which affect children adversely and which are more important than just the screen time limitation prescribed as per government guidelines. Focus: SE Asia and Outside SE Asia (No IRB approval is sought as the paper is based on secondary research.)
Comparison of Different Invasive Devices for the Treatment of Urinary Incontinence after Radical Prostatectomy
Authors: Salciccia Stefano , Viscuso Pietro , Bevilacqua Giulio , Tufano Antonio , Casale Paolo , De Berardinis Ettore , Di Pierro Giovanni Battista , Cattarino Susanna , Gentilucci Alessandro , Lourdes Lia Francesca , Ivan Di Giulio , Rosati Davide , Del Giudice Francesco , Sciarra Alessandro , Mariotti Gianna 
Published: June 2022

Purpose. To compare different forms of invasive treatments for postradical prostatectomy (RP) urinary incontinence (UI) in terms of quantitative and qualitative parameters and continence recovery rate. Methods. We distinguished five categories of treatment: A = bulking agents, B = fixed slings, C = adjustable slings, D = circumferential compressor devices (artificial sphincter), and E = noncircumferential compressor devices (ProACT). A literature search was performed following the PRISMA guidelines. We performed a cumulative meta-analysis to explore the trend in the effect sizes across groups at postoperative follow-up. We compared the available treatment arms using standardized mean difference (SMD) and event rate (ER) for questionnaire results, number of pads/day, and percentage of pad-free patients. Evidence synthesis. 36 clinical trials were selected. At baseline, in the different populations, mean number of pad-day varied from 1.1 to 8.8, 24-hour pad weight varied extremely from 17.3

g

to 747.0

g

, and mean ICIQ-UI-SF questionnaire score varied from 4.8 to 18.6. Considering a random effect model among eligible studies, ER of continence recovery was 0.33 (95% CI −0.12–0.78), 0.63 (95% CI 0.55–0.71), 0.65 (95% CI 0.58–0.72), 0.50 (95% CI 0.34–0.66), and 0.53 (95%CI 0.36–0.70), respectively, in groups A, B, C, D, and E (I2 85.87%; Q 249.82—

P
>
0.01

) (test of group differences

P
=
0.22

). Conclusion. In our analysis, the use of adjustable and fixed slings is associated with the highest whereas the use of bulking agents is associated with the lowest recovery rate of continence after treatment. Results are conditioned by an elevated rate of heterogeneity in part explained with a high variability of consistence in urinary leakage at baseline among populations.
CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease
Authors: Zhao Ning , Chopra Shalini , Trepka Kai , Wang Yung-Hua , Sakhamuri Sasank , Hooshdaran Nima , Kim Hyunjung , Zhou Jie , Lim Shion A. , Leung Kevin K. , Egusa Emily A. , Zhu Jun , Zhang Li , Foye Adam , Sriram Renuka , Chan Emily , Seo Youngho , Feng Felix Y. , Small Eric J. , Chou Jonathan , Wells James A. , Aggarwal Rahul , Evans Michael J. 
Published: June 2022

Abstract

Purpose:
With the improvement in overall survival with 177Lu-PSMA 617, radioligand therapy (RLT) is now a viable option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, responses are variable, in part due to low PSMA expression in 30% of patients. Herein, we evaluated whether the cell surface protein CUB domain-containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, including in PSMA-low subsets.

Experimental Design:
CDCP1 levels were evaluated using RNA sequencing from 119 mCRPC biopsies. CDCP1 levels were assessed in 17 post–enzalutamide- or abiraterone-treated mCRPC biopsies, 12 patient-derived xenografts (PDX), and prostate cancer cell lines. 4A06, a recombinant human antibody that targets the CDCP1 ectodomain, was labeled with Zr-89 or Lu-177 and tested in tumor-bearing mice.

Results:
CDCP1 expression was observed in 90% of mCRPC biopsies, including small-cell neuroendocrine (SCNC) and adenocarcinomas with low FOLH1 (PSMA) levels. Fifteen of 17 evaluable mCRPC biopsies (85%) demonstrated membranous CDCP1 expression, and 4 of 17 (23%) had higher CDCP1 H-scores compared with PSMA. CDCP1 was expressed in 10 of 12 PDX samples. Bmax values of approximately 22,000, 6,200, and 2,800 fmol/mg were calculated for PC3, DU145, and C4–2B human prostate cancer cells, respectively. 89Zr-4A06 PET detected six human prostate cancer xenografts, including PSMA-low tumors. 177Lu-4A06 significantly suppressed growth of DU145 and C4–2B xenografts.

Conclusions:
The data provide the first evidence supporting CDCP1-directed RLT to treat mCRPC. Expanded studies are warranted to determine whether CDCP1 is a viable drug target for patients with mCPRC.
Novel Radiomic Measurements of Tumor-Associated Vasculature Morphology on Clinical Imaging as a Biomarker of Treatment Response in Multiple Cancers
Authors: Braman Nathaniel , Prasanna Prateek , Bera Kaustav , Alilou Mehdi , Khorrami Mohammadhadi , Leo Patrick , Etesami Maryam , Vulchi Manasa , Turk Paulette , Gupta Amit , Jain Prantesh , Fu Pingfu , Pennell Nathan , Velcheti Vamsidhar , Abraham Jame , Plecha Donna , Madabhushi Anant 
Published: June 2022

Abstract

Purpose:
The tumor-associated vasculature (TAV) differs from healthy blood vessels by its convolutedness, leakiness, and chaotic architecture, and these attributes facilitate the creation of a treatment-resistant tumor microenvironment. Measurable differences in these attributes might also help stratify patients by likely benefit of systemic therapy (e.g., chemotherapy). In this work, we present a new category of computational image-based biomarkers called quantitative tumor-associated vasculature (QuanTAV) features, and demonstrate their ability to predict response and survival across multiple cancer types, imaging modalities, and treatment regimens involving chemotherapy.

Experimental Design:
We isolated tumor vasculature and extracted mathematical measurements of twistedness and organization from routine pretreatment radiology (CT or contrast-enhanced MRI) of a total of 558 patients, who received one of four first-line chemotherapy-based therapeutic intervention strategies for breast (n = 371) or non–small cell lung cancer (NSCLC, n = 187).

Results:
Across four chemotherapy-based treatment strategies, classifiers of QuanTAV measurements significantly (P &lt; 0.05) predicted response in held out testing cohorts alone (AUC = 0.63–0.71) and increased AUC by 0.06–0.12 when added to models of significant clinical variables alone. Similarly, we derived QuanTAV risk scores that were prognostic of recurrence-free survival in treatment cohorts who received surgery following chemotherapy for breast cancer [P = 0.0022; HR = 1.25; 95% confidence interval (CI), 1.08–1.44; concordance index (C-index) = 0.66] and chemoradiation for NSCLC (P = 0.039; HR = 1.28; 95% CI, 1.01–1.62; C-index = 0.66). From vessel-based risk scores, we further derived categorical QuanTAV high/low risk groups that were independently prognostic among all treatment groups, including patients with NSCLC who received chemotherapy only (P = 0.034; HR = 2.29; 95% CI, 1.07–4.94; C-index = 0.62). QuanTAV response and risk scores were independent of clinicopathologic risk factors and matched or exceeded models of clinical variables including posttreatment response.

Conclusions:
Across these domains, we observed an association of vascular morphology on CT and MRI—as captured by metrics of vessel curvature, torsion, and organizational heterogeneity—and treatment outcome. Our findings suggest the potential of shape and structure of the TAV in developing prognostic and predictive biomarkers for multiple cancers and different treatment strategies.
EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma
Authors: Apfelbaum April A. , Wu Feinan , Hawkins Allegra G. , Magnuson Brian , Jiménez Jennifer A. , Taylor Sean D. , Wrenn Emma D. , Waltner Olivia , Pfaltzgraff Elise R. , Song Jane Y. , Hall Cody , Wellik Deneen M. , Ljungman Mats , Furlan Scott N. , Ryan Russell J.H. , Sarthy Jay F. , Lawlor Elizabeth R. 
Published: June 2022

Abstract

Purpose:
Propagation of Ewing sarcoma requires precise regulation of EWS::FLI1 transcriptional activity. Determining the mechanisms of fusion regulation will advance our understanding of tumor progression. Here we investigated whether HOXD13, a developmental transcription factor that promotes Ewing sarcoma metastatic phenotypes, influences EWS::FLI1 transcriptional activity.

Experimental Design:
Existing tumor and cell line datasets were used to define EWS::FLI1 binding sites and transcriptional targets. Chromatin immunoprecipitation and CRISPR interference were employed to identify enhancers. CUT&RUN and RNA sequencing defined binding sites and transcriptional targets of HOXD13. Transcriptional states were investigated using bulk and single-cell transcriptomic data from cell lines, patient-derived xenografts, and patient tumors. Mesenchymal phenotypes were assessed by gene set enrichment, flow cytometry, and migration assays.

Results:
We found that EWS::FLI1 creates a de novo GGAA microsatellite enhancer in a developmentally conserved regulatory region of the HOXD locus. Knockdown of HOXD13 led to widespread changes in expression of developmental gene programs and EWS::FLI1 targets. HOXD13 binding was enriched at established EWS::FLI1 binding sites where it influenced expression of EWS::FLI1-activated genes. More strikingly, HOXD13 bound and activated EWS::FLI1-repressed genes, leading to adoption of mesenchymal and migratory cell states that are normally suppressed by the fusion. Single-cell analysis confirmed that direct transcriptional antagonism between HOXD13-mediated gene activation and EWS::FLI1-dependent gene repression defines the state of Ewing sarcoma cells along a mesenchymal axis.

Conclusions:
Ewing sarcoma tumors are comprised of tumor cells that exist along a mesenchymal transcriptional continuum. The identity of cells along this continuum is, in large part, determined by the competing activities of EWS::FLI1 and HOXD13.
See related commentary by Weiss and Bailey, p. 4360
Mechanistic Modeling of Central Nervous System Pharmacokinetics and Target Engagement of HER2 Tyrosine Kinase Inhibitors to Inform Treatment of Breast Cancer Brain Metastases
Authors: Li Jing , Jiang Jun , Bao Xun , Kumar Vineet , Alley Stephen C. , Peterson Scott , Lee Anthony J. 
Published: June 2022

Abstract

Purpose:
This study evaluated the central nervous system (CNS) pharmacokinetics and target engagement of lapatinib, neratinib, and tucatinib in patients with cancer, using a physiologically based pharmacokinetic (PBPK) modeling approach.

Experimental Design:
Drug-specific parameters for in vitro metabolism, binding to plasma proteins and brain tissues, transcellular passive permeability, and interactions with efflux transporters were determined. Whole-body PBPK models integrated with a 4-compartment permeability-limited brain model was developed and verified for predicting plasma and CNS pharmacokinetics. Target engagement ratio (TER), defined as the ratio of the average steady-state unbound drug brain concentration (Css,ave,br) to in vitro IC50 for HER2 inhibition, was used as a predictor of intracranial efficacy.

Results:
PBPK models predicted that following 1 cycle of standard dosing, tucatinib and lapatinib achieved similar Css,ave,br (14.5 vs. 16.8 nmol/L), while neratinib Css,ave,br (0.68 nmol/L) was 20-fold lower. Tucatinib and neratinib were equally potent for HER2 inhibition (IC50, 6.9 vs. 5.6 nmol/L), while lapatinib was less potent (IC50, 109 nmol/L). The model-predicted population mean TER in the human normal brain was 2.1 for tucatinib, but &lt; 0.20 for lapatinib and neratinib.

Conclusions:
The PBPK modeling suggests that tucatinib induces sufficient HER2 inhibition (TER &gt; 2.0) in not only brain metastases with a disrupted blood–brain barrier (BBB), but also micrometastases where the BBB largely remains intact. These findings, in line with available clinical pharmacokinetics and efficacy data, support the therapeutic value of tucatinib for treatment of brain metastases and warrant further clinical investigation for the prevention of brain metastases in patients with HER2-positive breast cancer.