bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P156: Identification of previously unknown targets for approved small-molecule drugs using chemoproteomic platform IMTACTM
Authors: Zhang Vivian , Huang Cindy , Zhang Chao , Cao Ping 
Published: December 2021

Abstract
Small-molecule drugs exert their therapeutic effects through binding and modulating functions of their target proteins. While most approved drugs have defined target(s), a comprehensive target map is generally lacking for clinical and experimental drugs. This limits both understandings of a drug’s actions and hampers further optimization. Leveraging its proprietary chemoproteomic platform IMTACTM, BridGene Biosciences has developed an approach to generate more comprehensive target maps for approved small-molecule drugs. This approach can also be applied to drug candidates. The approach was successfully applied to a covalent drug ibrutinib and a non-covalent drug sunitinib, revealing previously unknown targets of these drugs. The drug, sunitinib or ibrutinib, was first chemically modified to generate probe compounds, which were then treated on live cells. Quantitative mass spec analysis of the resulting proteomes was performed to identify the binding targets and quantify their apparent binding affinity to the drug. The identified probe-binding proteins were then ranked based on their apparent binding affinity to determine the proteome-wide selectivity to the drug. BridGene’s IMTACTM profiling verified BTK to be the top target and two other kinases (BLK and TEC) to be prominent targets of ibrutinib in Ramos cells. Analogous IMTACTM profiling confirmed sunitinib’s binding to over a dozen of protein kinases with high to moderate affinity in Ramos cells. The kinase targets of sunitinib in Ramos cells include BLK, LYN, PTK2B, etc. Importantly, non-kinase targets included metabolic enzymes were also identified for ibrutinib and sunitinib in the IMTACTM profiling. The binding of the drugs to select new targets was verified using biochemical or binding assays. Our study demonstrates that IMTACTM profiling is a powerful approach for generating comprehensive target maps for clinical and experimental drugs, both covalent and non-covalent ones. Having target scope information will be invaluable at various stages of drug discovery and development, such as the repurposing of existing drugs, the optimization of drug candidates, as well as target identification and deconvolution for phenotypic screening hits.
Citation Format: Vivian Zhang, Cindy Huang, Chao Zhang, Ping Cao. Identification of previously unknown targets for approved small-molecule drugs using chemoproteomic platform IMTACTM [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P156.
Abstract P172: Rubber- and amoeba-like RNA nanoparticles facilitate drug delivery for lung cancer
Authors: Li Xin , Ellipilli Satheesh , Wang Hongzhi , Lee Wen-Jui , Ho Yuan Soon , Guo Peixuan 
Published: December 2021

Abstract
Lung cancer is the leading cause of cancer death in the United States. Here we report the utilization of the special rubber- and amoeba-like property of RNA nanoparticles to deliver two kinds of anticancer drugs for highly efficient regression of lung cancer. Conjugation of the chemical drugs to RNA nanoparticle enhance the solubility of the drug by 32,000-fold. 5% of the RNA/drug complexes reached the tumor within 30 minutes after systemic injection, and those that did not reach the tumor were excreted from the kidney and found in urine 30 minutes after IV injection. RNA nanoparticles loaded with drugs significantly inhibited the tumor growth in the A549 xenograft mouse model without the need for targeting ligand. This could be explained by several factors, such as the deformative property, the longer circulation time, the passive accumulation, and the quick renal excretion time of the RNA/drug complex.
Citation Format: Xin Li, Satheesh Ellipilli, Hongzhi Wang, Wen-Jui Lee, Yuan Soon Ho, Peixuan Guo. Rubber- and amoeba-like RNA nanoparticles facilitate drug delivery for lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P172.
Abstract P214: MTAPnull-selective PRMT5 inhibitors drive regressions in MTAP-deleted xenograft models across histologies
Authors: Briggs Kimberly J. , Cottrell Kevin M. , Tonini Matthew R. , Wilker Erik , Gu Lina , Davis Charles B. , Whittington Doug , Gotur Deepali , Jahic Haris , Goldstein Matthew J. , Huang Alan , Maxwell John P. 
Published: December 2021

Abstract
PRMT5 is a type II arginine methyltransferase that regulates essential cellular functions via symmetric dimethylation of target proteins involved in spliceosome regulation, cell cycle progression, apoptosis, the DNA-damage response, and other functions. PRMT5 dependence in cells with MTAP deletions is a strong and prevalent synthetic lethal interaction. Due to their mechanisms of action, existing clinical PRMT5 inhibitors do not recapitulate the selectivity for MTAPnull cells demonstrated by genetic perturbation. Given that MTAP deletion occurs in approximately 10-15% of all human cancer[i],[ii],[iii], a molecule that selectively kills MTAPnull cancer cells provides an important opportunity to deliver a targeted treatment to a significant patient population. We have discovered small molecules that exhibit MTA-cooperative PRMT5 binding and selectively kill MTAPnull cancer cells. Striking MTAP-dependent viability effects are demonstrated in MTAP-isogenic cell lines representing multiple lineages, and in a multi-lineage cell line panel comprised of 200 cancer cell lines. Furthermore, oral administration of an MTAPnull-selective PRMT5 inhibitor demonstrates dose-dependent antitumor activity and strong regressions across multiple histologies in both cancer cell line and patient-derived xenografts. These data suggest the therapeutic potential of MTAPnull-selective PRMT5 inhibitors in MTAP-deleted cancers. [i] Cerami et al., 2012 [ii] Gao et al., 2013 [iii] Lee et al., 2014
Citation Format: Kimberly J. Briggs, Kevin M. Cottrell, Matthew R. Tonini, Erik Wilker, Lina Gu, Charles B. Davis, Doug Whittington, Deepali Gotur, Haris Jahic, Matthew J. Goldstein, Alan Huang, John P. Maxwell. MTAPnull-selective PRMT5 inhibitors drive regressions in MTAP-deleted xenograft models across histologies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P214.
Abstract P229: Pre-clinical evaluation of next-generation inhibitor targeting a wide spectrum of oncogenic BRAF dimers
Authors: Han Yoon-Chi , Ng Pui Yee , Schulz Ryan , Yang Shao Ning , Lelo Alana , Shin Luisa , O'Connor Matthew , Jewett Ivan , Ishiyama Noboru , Romashko Darlene , Thakur Shalabh , Salomatov Andrei , Smith Sherri , Buck Elizabeth , Roberts Christopher , Lucas Matthew , Lin Tai-An 
Published: December 2021

Abstract
The canonical BRAF V600E (Class I) mutation is a potent oncogene uniquely active as a RAS-independent monomer, successfully targeted by several FDA-approved inhibitors. However, these first-generation BRAF inhibitors are not active against non-canonical BRAF oncogenic mutations, including BRAF-fusions, that drive RAS-independent (Class II) or RAS-dependent (Class III) dimers. As such, developing inhibitors directed against dimeric BRAF oncogenic mutations that avoid paradoxical activation is a major unmet clinical need. We applied proprietary Mutation-Allostery-Pharmacology (MAP) platform technology developed by Black Diamond Therapeutics to identify and validate a group of previously uncharacterized non-canonical oncogenic Class II and Class III BRAF mutation clusters. We further demonstrate that this ensemble of novel and previously validated non-canonical oncogenic BRAF mutants can form the basis of a differentiated drug discovery program aimed at identifying small molecules that potently and selectively target this family of dimeric BRAF mutations. Herein, we describe a small molecule inhibitor, BDTX BRAF-A, with potent anti-proliferative activity directed against tumor cells expressing a wide spectrum of non-canonical Class II/III mutations. This broad activity (“MasterKey” profile) of BDTX BRAF-A is further demonstrated in cell lines that harbor endogenous oncogenic dimer-inducing BRAF mutations and in various solid tumor patient-derived xenograft (PDX) models ex vivo. Importantly, BDTX BRAF-A did not induce paradoxical RAF activation characteristic of Class I BRAF inhibitors. Finally, BDTX BRAF-A achieves robust anti-tumor efficacy and target engagement of dimeric BRAF oncogenes in mouse models. These data support the continued development of rationally designed molecules targeting a broad range of non-canonical BRAF dimer-promoting mutations to extend the prospect of precision medicine in patients.
Citation Format: Yoon-Chi Han, Pui Yee Ng, Ryan Schulz, Shao Ning Yang, Alana Lelo, Luisa Shin, Matthew O'Connor, Ivan Jewett, Noboru Ishiyama, Darlene Romashko, Shalabh Thakur, Andrei Salomatov, Sherri Smith, Elizabeth Buck, Christopher Roberts, Matthew Lucas, Tai-An Lin. Pre-clinical evaluation of next-generation inhibitor targeting a wide spectrum of oncogenic BRAF dimers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P229.
Sustained Wind Forcing and Water Level Anomalies in Annapolis, Maryland
Authors: Davies Alexander R. , Smith Joseph P. , Mandell David S. , Davis George , Wan Forest Y. 
Published: December 2021

Abstract
Like many coastal communities throughout the mid-Atlantic region, relative sea level rise and accelerating instances of coastal nuisance flooding are having a tangible negative impact on economic activity and infrastructure in Annapolis, Maryland. The drivers of coastal nuisance flooding, in general, are a superposition of global, regional, and local influences that occur across spatial and temporal scales that determine water levels relative to a coastal datum. Most of the research to date related to coastal flooding has been focused on high-impact episodic events, decomposing the global and regional drivers of sea level rise, or assessing seasonal-to-interannual trends. In this study, we focus specifically on the role of short-duration (hours) meteorological wind forcing on water level anomalies in Annapolis. Annapolis is an ideal location to study these processes because of the orientation of the coast relative to the prevailing wind directions and the long record of reliable data observations. Our results suggest that 3-, 6-, 9-, and 12-h sustained wind forcing significantly influences water level anomalies in Annapolis. Sustained wind forcing out of the northeast, east, southeast, and south is associated with positive water level anomalies, and sustained wind forcing out of the northwest and north is associated with negative water level anomalies. While these observational results suggest a relationship between sustained wind forcing and water level anomalies, a more robust approach is needed to account for other meteorological variables and drivers that occur across a variety of spatial and temporal scales.

Significance Statement
Coastal nuisance flooding, often the result of positive water level anomalies, is having a negative economic impact in Annapolis, Maryland. Coastal flooding research has primarily focused on high-impact episodic events, trends in sea level rise, or seasonal to interannual variability in flooding. In this study we show that short-duration wind forcing (≤12 h) likely has a significant impact on both positive and negative water level anomalies in Annapolis. While this was empirically known by local stakeholders, in this study we attempt to quantify the relationship. These results could help local stakeholders to mitigate against economic and infrastructure losses resulting from coastal nuisance flooding.
Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant
Authors: Bednarski Jeffrey J. , Zimmerman Clare , Berrien-Elliott Melissa M. , Foltz Jennifer A. , Becker-Hapak Michelle , Neal Carly C. , Foster Mark , Schappe Timothy , McClain Ethan , Pence Patrick P. , Desai Sweta , Kersting-Schadek Samantha , Wong Pamela , Russler-Germain David A. , Fisk Bryan , Lie Wen-Rong , Eisele Jeremy , Hyde Stephanie , Bhatt Sima T. , Griffith Obi L. , Griffith Malachi , Petti Allegra A. , Cashen Amanda F. , Fehniger Todd A. 
Published: December 2021

Abstract
Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have an extremely poor prognosis. Standard salvage chemotherapy and donor lymphocyte infusions (DLIs) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), -15, and -18 to generate memory-like (ML) NK cells with enhanced antileukemia responses. We treated 9 pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells in a phase 1 trial. Patients received fludarabine, cytarabine, and filgrastim followed 2 weeks later by infusion of donor lymphocytes and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical and matched-related and -unrelated donors. After infusion, donor-derived ML NK cells expanded and maintained an ML multidimensional mass cytometry phenotype for &gt;3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered interferon-γ production. After DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for &gt;3 months, with 1 patient in remission for &gt;2 years. No significant toxicity was experienced. This study demonstrates that, in a compatible post-HCT immune environment, donor ML NK cells robustly expand and persist with potent antileukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://clinicaltrials.gov as #NCT03068819.
Plasma biomarkers of hemoglobin loss in Plasmodium falciparum–infected children identified by quantitative proteomics
Authors: Mahamar Almahamoudou , Gonzales Hurtado Patricia A. , Morrison Robert , Boone Rachel , Attaher Oumar , Diarra Bacary S. , Gaoussou Santara , Issiaka Djibrilla , Dicko Alassane , Duffy Patrick E. , Fried Michal 
Published: December 2021

Abstract
Anemia is common among young children infected with Plasmodium falciparum and severe malarial anemia (SMA) is a major cause of their mortality. Two major mechanisms cause malarial anemia: hemolysis of uninfected as well as infected erythrocytes and insufficient erythropoiesis. In a longitudinal birth cohort in Mali, we commonly observed marked hemoglobin reductions during P falciparum infections with a small proportion that progressed to SMA. We sought biomarkers of these processes using quantitative proteomic analysis on plasma samples from 9 P falciparum-infected children, comparing those with reduced hemoglobin (with or without SMA) vs those with stable hemoglobin. We identified higher plasma levels of circulating 20S proteasome and lower insulin-like growth factor-1 (IGF-1) levels in children with reduced hemoglobin. We confirmed these findings in independent enzyme-linked immunosorbent assay-based validation studies of subsets of children from the same cohort (20S proteasome, N = 71; IGF-1, N = 78). We speculate that circulating 20S proteasome plays a role in digesting erythrocyte membrane proteins modified by oxidative stress, resulting in hemolysis, whereas decreased IGF-1, a critical factor for erythroid maturation, might contribute to insufficient erythropoiesis. Quantitative plasma proteomics identified soluble mediators that may contribute to the major mechanisms underlying malarial anemia. This study was registered at www.clinicaltrials.gov as #NCT01168271.
Efficient anaerobic consumption of D-xylose by E. coli BL21(DE3) via xylR adaptive mutation
Authors: Heo Jung Min , Kim Hyun Ju , Lee Sang Jun 
Published: December 2021

Abstract
Background
Microorganisms can prioritize the uptake of different sugars depending on their metabolic needs and preferences. When both D-glucose and D-xylose are present in growth media, E. coli cells typically consume D-glucose first and then D-xylose. Similarly, when E. coli BL21(DE3) is provided with both D-glucose and D-xylose under anaerobic conditions, glucose is consumed first, whereas D-xylose is consumed very slowly.

Results
When BL21(DE3) was adaptively evolved via subculture, the consumption rate of D-xylose increased gradually. Strains JH001 and JH019, whose D-xylose consumption rate was faster, were isolated after subculture. Genome analysis of the JH001 and JH019 strains revealed that C91A (Q31K) and C740T (A247V) missense mutations in the xylR gene (which encodes the XylR transcriptional activator), respectively, controlled the expression of the xyl operon. RT-qPCR analyses demonstrated that the XylR mutation caused a 10.9-fold and 3.5-fold increase in the expression of the xylA (xylose isomerase) and xylF (xylose transporter) genes, respectively, in the adaptively evolved JH001 and JH019 strains. A C91A adaptive mutation was introduced into a new BL21(DE3) background via single-base genome editing, resulting in immediate and efficient D-xylose consumption.

Conclusions
Anaerobically-adapted BL21(DE3) cells were obtained through short-term adaptive evolution and xylR mutations responsible for faster D-xylose consumption were identified, which may aid in the improvement of microbial fermentation technology.
COVID-19 vaccine hesitancy in people with migratory backgrounds: a cross-sectional study among Turkish- and German-speaking citizens in Munich
Authors: Aktürk Zekeriya , Linde Klaus , Hapfelmeier Alexander , Kunisch Raphael , Schneider Antonius 
Published: December 2021

Abstract
Background
This study aimed to investigate the knowledge, attitudes, behaviors, and COVID-19 vaccine hesitancy of people with migratory backgrounds among Turkish- and German-speaking patients in Munich.

Methods
Primary outcomes were the intention to get vaccinated for COVID-19 and COVID-19 knowledge levels (25 true/false items). Other variables included demographics, attitudes to COVID-19 and vaccination (7 items), and behaviors regarding COVID-19 (7 items). The attitude and behavior questions had 5-point Likert scales. Of the 10 Turkish-speaking family physicians in Munich, six agreed to administer Turkish or German questionnaires to consecutive patients in February 2021. Furthermore, participants with either citizenship, country of origin, native language, or place of birth being non-German were categorized as “Having a migratory background.” Data from 420 respondents were analyzed.

Results
Women constituted 41.4% (n = 174), the mean age was 42.2 ± 15.5 years, 245 (58.3%) preferred the Turkish questionnaire, 348 (82.9%) had a migratory background, and 197 (47.9%) intended to be vaccinated. The mean knowledge, attitude, and behavioral scores were 21.5 ± 3.2 (max = 25), 3.7 ± 0.8 (max = 5), and 4.0 ± 0.5 (max = 5). While 42.3% (n = 145) of the participants with a migratory background considered getting vaccinated, this proportion was 76.5% (n = 52) for non-immigrant Germans (Chi-square = 26.818, p < 0.001). Non-migratory background (odds ratio (OR): 3.082), high attitude scores (OR: 2.877), male sex (OR: 2.185), years of schooling (OR: 1.064), and age (OR: 1.022) were positively associated with vaccination intention.

Conclusions
We suggest initiating or supporting projects run by persons or groups with immigrant backgrounds to attempt to elaborate and change their vaccination attitudes.
Meningitis, meningoencephalitis and encephalitis in Bern: an observational study of 258 patients
Authors: Ungureanu Anamaria , van der Meer Julia , Bicvic Antonela , Abbuehl Lena , Chiffi Gabriele , Jaques Léonore , Suter-Riniker Franziska , Leib Stephen L. , Bassetti Claudio L. A. , Dietmann Anelia 
Published: December 2021

Abstract
Background
Depending on geographic location, causes of encephalitis, meningoencephalitis and meningitis vary substantially. We aimed to identify the most frequent causes, clinical presentation and long-term outcome of encephalitis, meningoencephalitis and meningitis cases treated in the Inselspital University Hospital Bern, Switzerland.

Methods
In this monocentric, observational study, we performed a retrospective review of clinical patient records for all patients treated within a 3-year period. Patients were contacted for a telephone follow-up interview and to fill out questionnaires, especially related to disturbances of sleep and wakefulness.

Results
We included 258 patients with the following conditions: encephalitis (18%), nonbacterial meningoencephalitis (42%), nonbacterial meningitis (27%) and bacterial meningoencephalitis/meningitis (13%). Herpes simplex virus (HSV) was the most common cause of encephalitis (18%); tick-borne encephalitis virus (TBEV) was the most common cause of nonbacterial meningoencephalitis (46%), enterovirus was the most common cause of nonbacterial meningitis (21%) and Streptococcus pneumoniae was the most common cause of bacterial meningoencephalitis/meningitis (49%). Overall, 35% patients remained without a known cause. After a median time of 16 months, 162 patients participated in the follow-up interview; 56% reported suffering from neurological long-term sequelae such as fatigue and/or excessive daytime sleepiness (34%), cognitive impairment and memory deficits (22%), headache (14%) and epileptic seizures (11%).

Conclusions
In the Bern region, Switzerland, TBEV was the overall most frequently detected infectious cause, with a clinical manifestation of meningoencephalitis in the majority of cases. Long-term neurological sequelae, most importantly cognitive impairment, fatigue and headache, were frequently self-reported not only in encephalitis and meningoencephalitis survivors but also in viral meningitis survivors up to 40 months after acute infection.