bluuebunny/crossref_metadata_2025_split huggingface dataset:
BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer
Authors: Lim Sun Min , Fujino Toshio , Kim Chulwon , Lee Gwanghee , Lee Yong-Hee , Kim Dong-Wan , Ahn Jin Seok , Mitsudomi Tetsuya , Jin Taiguang , Lee Sang-Yoon 
Published: May 2023

Abstract

Purpose:
Resistance to third-generation EGFR inhibitors including osimertinib arises in part from the C797S mutation in EGFR. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting the C797S mutation.

Patients and Methods:
Recombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells, and patient-derived xenografts expressing mutant EGFRs were used to test the inhibitory potency and the anticancer efficacy of BBT-176 both in vitro and in vivo. Patient case data are also available from an ongoing phase I clinical trial (NCT04820023).

Results:
The half maximal inhibitory concentration (IC50) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S proteins were measured at 4.36, 1.79, and 5.35 nmol/L, respectively (vs. 304.39, 124.82, and 573.72 nmol/L, for osimertinib). IC50 values of BBT–176 against Ba/F3 cells expressing EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, EGFR L858R/C797S, and EGFR L858R/T790M/C797S were 42, 49, 183, and 202 nmol/L, respectively (vs. 869, 1,134, 2,799, and 2,685 nmol/L for osimertinib). N-ethyl-N-nitrosourea mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the EGFR gene but increases EGFR expression levels. Combined with the EGFR antibody cetuximab, BBT-176 effectively suppressed the growth of BBT-176–resistant clones. BBT-176 strongly inhibited the tumor growth, and in some conditions induced tumor regression in mouse models. In the clinical trial, two patients harboring EGFR 19Del/T790M/C797S in blood showed tumor shrinkage and radiologic improvements.

Conclusions:
BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKI, with early clinical efficacy and safety.
Abstract 1470: ASCL1 dimerizes with TCF12 protein and activates BMP-SMAD1 pathway during subtype switching from mesenchymal towards adrenergic neuroblastoma
Authors: Wang Lu , Tan Tze King , Kim Hyoju , Kappei Dennis , Tan Shi Hao , Look A. Thomas , Sanda Takaomi 
Published: May 2023

Abstract
Recently, several studies have demonstrated two semi-stable and interchangeable subtypes of neuroblastoma, namely mesenchymal (MES) and adrenergic (ADRN) subtypes, which are associated with the early neural crest and committed adrenergic neural progenitor stages, respectively. Each of these subtypes is controlled by a different set of transcription factors forming the core regulatory circuit (CRC) and exhibits different enhancer and transcription profiles. However, transcription factors
that drives transition of the subtype switching and the corresponding regulated signaling pathways remain to be investigated. In this study, we demonstrate that ASCL1, a critical member of the ADRN CRC, can induce a subtype switching from MES to ADRN neuroblastoma. Our study shows that a forced expression of ASCL1 in MES neuroblastoma cells results in cell cycle arrest and cell differentiation towards the ADRN lineage with induction of ADRN gene expression, such as DLL3 and DBH. Furthermore, we have identified TCF12 as an important interaction partner of ASCL1 via SILAC analysis. ASCL1 forms a complex with TCF12 and regulates the expression of downstream target genes. On the other hand, overexpression of ASCL1 inhibits existing MES specific TGFβ-SMAD2/3 signaling pathway, while it activates BMP-SMAD1 signaling pathway. Interestingly, activation of BMP-SMAD1 signaling pathway results in the upregulation of the ID proteins, which can form dimer with TCF12 protein and sequester it away from ASCL1 protein. Thus, the BMP SMAD1-ID protein signaling cascade in turn serves as a negative feedback loop to prevent the cells from terminal differentiation via equilibration of the amount of ASCL1-TCF12 dimer. In summary, ASCL1 can induce the subtype switching and partially define the ADRN transcription program. ASCL1 serves as a lineage master initiator that characterizes ADRN neuroblastoma.
Citation Format: Lu Wang, Tze King Tan, Hyoju Kim, Dennis Kappei, Shi Hao Tan, A. Thomas Look, Takaomi Sanda. ASCL1 dimerizes with TCF12 protein and activates BMP-SMAD1 pathway during subtype switching from mesenchymal towards adrenergic neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1470.
Abstract ND07: Discovery of RMC-6291, a tri-complex KRASG12C(ON) inhibitor
Authors: Cregg Jim , Nichols R J. , Yang Y C. , Schulze C J. , Wang Z , Dua R , Jiang J , Nasholm N , Knox J E. , Seamon K , Longhi M , Tomlinson A , Chou K , Li S , Wildes D P. , Singh M , Koltun E S. , Gill A L. , Smith J A. 
Published: May 2023

Abstract
The KRASG12C mutation occurs in 11 - 14% of non-small cell lung cancers, ~4% of colorectal cancers, and ~2% of pancreatic cancers in the U.S., and drives these cancers by shifting the cellular equilibrium of KRAS towards the GTP-bound, active state, KRASG12C(ON). The resulting increased levels of KRASG12C(ON) in turn increase signaling output to initiate and support the oncogenic state. RMC-6291 is a potent, orally bioavailable inhibitor of KRASG12C(ON) that forms a tri-complex within tumor cells along with KRASG12C(ON) and cyclophilin A (CypA), driving a near-immediate disruption of RAS effector binding and extinction of KRASG12C(ON) signaling. RMC-6291 treatment produces deep and durable suppression of RAS pathway activity in KRASG12C tumor models and drives profound tumor regressions in vivo. In a mouse clinical trial with a representative panel of xenograft models of KRASG12C NSCLC, RMC-6291 outperformed adagrasib, displaying a potential ‘best-in-class’ profile with an increased number of responses, greater depth of tumor regressions and improved durability of responses. Thus, RMC-6291 is a clinical stage inhibitor of KRASG12C(ON) that potentially overcomes limitations of first-generation KRASG12C(OFF) inhibitors.
Citation Format: Jim Cregg, R J. Nichols, Y C. Yang, C J. Schulze, Z Wang, R Dua, J Jiang, N Nasholm, J E. Knox, K Seamon, M Longhi, A Tomlinson, K Chou, S Li, D P. Wildes, M Singh, E S. Koltun, A L. Gill, J A. Smith. Discovery of RMC-6291, a tri-complex KRASG12C(ON) inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND07.
Abstract ND09: M3913 induces the maladaptive unfolded protein response through a novel mechanism resulting in strong anti-tumor activity
Authors: Czauderna Frank , Schneider Richard , Ramaswamy Shivapriya , Brandstetter Susanne , Drouin Elise , Bogatyrova Olga , Mazur Johanna , Sun Qing , Jorand-Lebrun Catherine , Sherbetjian Eva , Nachtigall Jonny , Wing Carolyn , Hildebrand Christian , Ellinghaus Peter , Lemoine Isabelle , Johnson Mac , Hoover Russell , Clark Michael , Lindemann Ralph 
Published: May 2023

Abstract
Therapeutic strategies based on exacerbated stress signaling may represent novel and effective treatment paradigms in oncology. Here, we disclose for the first time the endoplasmic reticulum (ER) stress modulator (ERSM) M3913 that was discovered and developed following a phenotypic screening campaign. Mechanistically, M3913 engages an ER transmembrane protein not yet implicated in cancer biology to induce a Ca2+ shift from the ER towards the cytoplasm, resulting in an unfolded protein response and subsequent antitumor activity in sensitive preclinical models. We detected concurrent elevation of bona fide ER stress markers by several methods including qRT-PCR, Western Blotting analysis, and unbiased transcriptome analysis. Genetic removal of M3913’s putative ER transmembrane target abrogated the M3913-mediated, but not the Thapsigargin-mediated, ER stress response. PK/PD studies confirmed a dose- and time-dependent upregulation of ER stress markers in preclinical cancer models in vivo. As a monotherapy, M3913 induced full and partial tumor regression in preclinical models of multiple myeloma, non-small-cell lung cancer, triple-negative breast cancer, and other cancers. An in vitro combination screen indicated combination potential of M3913 with standard-of-care agents and novel candidate drugs. IND-enabling toxicology and additional mechanism-of-action studies in rat and minipig uncovered specific target organs for M3913 in line with expression of the target in human tissues. This presentation details mechanistic profiling data from M3913, reveals its putative ER-resident target and discusses forward translation studies that support M3913 as a novel therapeutic option for hard-to-treat subtypes of a variety of cancers.
Citation Format: Frank Czauderna, Richard Schneider, Shivapriya Ramaswamy, Susanne Brandstetter, Elise Drouin, Olga Bogatyrova, Johanna Mazur, Qing Sun, Catherine Jorand-Lebrun, Eva Sherbetjian, Jonny Nachtigall, Carolyn Wing, Christian Hildebrand, Peter Ellinghaus, Isabelle Lemoine, Mac Johnson, Russell Hoover, Michael Clark, Ralph Lindemann. M3913 induces the maladaptive unfolded protein response through a novel mechanism resulting in strong anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND09.
Abstract ND10: Discovery of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for MYC-driven cancers
Authors: Wallace Owen B. , Gavory Gerald , Ghandi Mahmoud , d’Alessandro Anne-Cecile , Bonenfant Debora , Cabanski Maciej , Cantagallo Lisa , Chicas Agustin , Chen Qian , Diesslin Anna , King Christopher , Massafra Vittoria , Narayan Rajiv , Osmont Arnaud , Peck Dave , Ortiz Carolina Perdomo , Schillo Martin , Singh Ambika , Tiedt Ralph , Tortoioli Simone , Buonamici Silvia , Warmuth Markus , Janku Filip , Fasching Bernhard 
Published: May 2023

Abstract
MYC transcription factors have been demonstrated to be drivers of many cancers, yet have remained recalcitrant to new drug development. We hypothesized that MYC-driven cancer cell lines are addicted to protein translation, and therefore are vulnerable to the loss of the translation termination factor, GSPT1. We have discovered MRT-2359, a selective GSPT1 molecular glue degrader, that demonstrates potent and preferential antiproliferative activity in MYC-driven cell lines, such as high N- and L-MYC mRNA expressing non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) lines. MRT-2359 has been optimized for differential toxicity between MYC- and non-MYC-driven cancer cell lines, kinetics and depth of degradation, oral bioavailability, and in vivo efficacy. The anti-tumor activity of MRT-2359 was assessed in more than 80 lung patient-derived xenografts (PDXs) that confirmed the preferential anti-tumor activity in N- and L-MYC high NSCLC and SCLC PDXs when dosed orally daily or intermittently. Similar levels of activity were also observed in neuroendocrine lung cancer PDXs and lymphoma models. Oral MRT-2359 is currently in a Phase 1/2 clinical trial in selected cancer patients with MYC-driven NSCLC, SCLC, high grade neuroendocrine cancers and diffuse large B-cell lymphoma (NCT05546268).
Citation Format: Owen B. Wallace, Gerald Gavory, Mahmoud Ghandi, Anne-Cecile d’Alessandro, Debora Bonenfant, Maciej Cabanski, Lisa Cantagallo, Agustin Chicas, Qian Chen, Anna Diesslin, Christopher King, Vittoria Massafra, Rajiv Narayan, Arnaud Osmont, Dave Peck, Carolina Perdomo Ortiz, Martin Schillo, Ambika Singh, Ralph Tiedt, Simone Tortoioli, Silvia Buonamici, Markus Warmuth, Filip Janku, Bernhard Fasching. Discovery of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for MYC-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND10.
Spatial Multiplexed Protein Profiling of Cardiac Ischemia-Reperfusion Injury
Authors: Yao Luyan , He Funan , Zhao Quanyi , Li Dandan , Fu Shufang , Zhang Mingzhi , Zhang Xingzhong , Zhou Bingying , Wang Li 
Published: May 2023

Background:
Reperfusion therapy is critical to myocardial salvage in the event of a myocardial infarction but is complicated by ischemia-reperfusion injury (IRI). Limited understanding of the spatial organization of cardiac cells, which governs cellular interaction and function, has hindered the search for targeted interventions minimizing the deleterious effects of IRI.

Methods:
We used imaging mass cytometry to characterize the spatial distribution and dynamics of cell phenotypes and communities in the mouse left ventricle following IRI. Heart sections were collected from 12 cardiac segments (basal, mid-cavity, apical, and apex of the anterior, lateral, and inferior wall) and 8 time points (before ischemia [I-0H], and postreperfusion [R-0H, R-2H, R-6H, R-12H, R-1D, R-3D, R-7D]), and stained with 29 metal-isotope-tagged antibodies. Cell community analysis was performed on reconstructed images, and the most disease-relevant cell type and target protein were selected for intervention of IRI.

Results:

We obtained a total of 251 multiplexed images, and identified 197 063 single cells, which were grouped into 23 distinct cell communities based on the structure of cellular neighborhoods. The cellular architecture was heterogeneous throughout the ventricular wall and exhibited swift changes following IRI. Analysis of proteins with posttranslational modifications in single cells unveiled 13 posttranslational modification intensity clusters and highlighted increased H3K9me3 (tri-methylated lysine 9 of histone H3) as a key regulatory response in endothelial cells during the middle stage of IRI. Erasing H3K9 methylation, by silencing its methyltransferase
Suv39h1
or overexpressing its demethylase
Kdm4d
in isolated endothelial cells, attenuated cardiac dysfunction and pathological remodeling following IRI. in vitro, H3K9me3 binding significantly increased at endothelial cell function-related genes upon hypoxia, suppressing tube formation, which was rescued by inhibiting H3K9me3.

Conclusions:
We mapped the spatiotemporal heterogeneity of cellular phenotypes in the adult heart upon IRI, and uncovered H3K9me3 in endothelial cells as a potential therapeutic target for alleviating pathological remodeling of the heart following myocardial IRI.
Can hubs of the human connectome be identified consistently with diffusion MRI?
Authors: Gajwani Mehul , Oldham Stuart , Pang James C. , Arnatkevičiūtė Aurina , Tiego Jeggan , Bellgrove Mark A. , Fornito Alex 
Published: May 2023

Abstract
Recent years have seen a surge in the use of diffusion MRI to map connectomes in humans, paralleled by a similar increase in processing and analysis choices. Yet these different steps and their effects are rarely compared systematically. Here, in a healthy young adult population (n = 294), we characterized the impact of a range of analysis pipelines on one widely studied property of the human connectome: its degree distribution. We evaluated the effects of 40 pipelines (comparing common choices of parcellation, streamline seeding, tractography algorithm, and streamline propagation constraint) and 44 group-representative connectome reconstruction schemes on highly connected hub regions. We found that hub location is highly variable between pipelines. The choice of parcellation has a major influence on hub architecture, and hub connectivity is highly correlated with regional surface area in most of the assessed pipelines (ρ &gt; 0.70 in 69% of the pipelines), particularly when using weighted networks. Overall, our results demonstrate the need for prudent decision-making when processing diffusion MRI data, and for carefully considering how different processing choices can influence connectome organization.
Erasure of Unaligned Attributes from Neural Representations
Authors: Shao Shun , Ziser Yftah , Cohen Shay B. 
Published: May 2023

AbstractWe present the Assignment-Maximization Spectral Attribute removaL (AMSAL) algorithm, which erases information from neural representations when the information to be erased is implicit rather than directly being aligned to each input example. Our algorithm works by alternating between two steps. In one, it finds an assignment of the input representations to the information to be erased, and in the other, it creates projections of both the input representations and the information to be erased into a joint latent space. We test our algorithm on an extensive array of datasets, including a Twitter dataset with multiple guarded attributes, the BiasBios dataset, and the BiasBench benchmark. The latter benchmark includes four datasets with various types of protected attributes. Our results demonstrate that bias can often be removed in our setup. We also discuss the limitations of our approach when there is a strong entanglement between the main task and the information to be erased.1
The evolution of informed consent in gastroenterology
Authors: O’Neill Fallon , O’Neill Parker , Schaffer Sierra , Poullis Andrew 
Published: May 2023

With medical litigation on the rise, physicians require a nuanced understanding of the legalities of consenting patients to reduce their liability while practising evidence-based medicine. This study aims to a) clarify the legal duties of gastroenterologists in the UK and USA when gaining informed consent and b) provide recommendations at the international and physician level to improve the consent process and reduce liability. A bibliometric analysis of the Web of Science database with the MeSH terms “gastroenterology” and “informed consent” yielded 383 articles, of which 228 were excluded due to not meeting the inclusion criteria. Of the top 50 articles, 48% were from American institutions and 16% were from the UK. Thematic analysis showed 72% of the articles discussed informed consent in relation to diagnostic procedures, 14% regarding treatment, and 14% regarding research participation. Both the USA and the UK have progressed from previously paternalistic Natanson case (1960) and Bolam test (1957), respectively, where physicians were held to the standard of a “reasonable and prudent medical doctor”. The American Canterbury case (1972) and the British Montgomery case (2015) radically shifted the standard of disclosure during the consent process by requiring physicians to explain all information pertinent to a “reasonable patient”. It is our recommendation that a two-pronged approach be taken; a) creation of international guidelines for consenting patients for invasive procedures in gastroenterology, and b) development of internationally standardised endoscopy consent forms containing all the details pertinent to a “reasonable patient”.
Neuropalliative care for progressive neurological diseases: A scoping review on models of care and priorities for future research
Authors: Grossman Christopher H , Hearn Rowan , McPhee Maryanne , Fisher Fiona , Wools Christine , Mathers Susan 
Published: May 2023

Background: Neuropalliative care is a newly-defined subspeciality bringing specific aspects of fields of neurology and palliative care together to better meet the complex care needs of people with progressive neurological diseases. Examining these needs would help provide guidance about developing relevant models of care and identify gaps in research knowledge. Aim: To identify current models and approaches to neuropalliative care for people with progressive neurological diseases and the priorities for future research work. Design: A scoping literature review following the methods described by the Joanna Briggs Institute. Data sources: An electronic search of the literature was undertaken from six sources including MEDLINE (Ovid), EMCARE, PsycINFO and CINAHL covering the years January 2011 to September 2021. Results: Twenty-eight studies were found examining neuropalliative care from the perspectives of 4795 PND patients, 774 informal carers and 138 health professionals. All studies held themes of integrative care, with most studies employing outpatient models of multidisciplinary care. Topics discussed included: overcoming local system-issues, providing education for professionals, patients and carers, early referral and capturing outcome measures for quality-assurance and future research work. Conclusions: Most models of neuropalliative care described in the international literature are predominantly outpatient, multidisciplinary and integrative. Clinicians typically utilise existing neurology and palliative care infrastructure to provide care. More high-quality research and outcome tools are needed to guide the design of evidence-based palliative care for people with progressive neurological diseases.
Return to Sport After Anatomic Lateral Ankle Stabilization Surgery for Chronic Ankle Instability: A Systematic Review and Meta-analysis
Authors: Li Yanzhang , Su Tong , Hu Yuelin , Jiao Chen , Guo Qinwei , Jiang Yanfang , Jiang Dong 
Published: May 2023

Background: Chronic lateral ankle instability that develops after ankle sprains has a severe, negative influence on the patient’s lower extremity function. Anatomic repair or reconstruction of the lateral ankle ligament is an effective treatment for people with chronic lateral ankle instability who want to regain their preinjury levels of work and sport. Purpose: To determine the rate of return to sport (RTS) and related factors after anatomic lateral ankle stabilization (ALAS) surgery. Study Design: Systematic review and meta-analysis; Level of evidence, 4. Methods: Electronic databases including Medline, Embase, the Cochrane Library, and EBSCO Rehabilitation & Sports Medicine Source were searched from the earliest feasible entrance until August 2021. Articles reporting the number of patients who returned to sport after ALAS surgery and analyzing the relevant factors were included. The results were combined using proportion meta-analyses. Results: A total of 25 publications were reviewed, with a total of 1384 participants. Results showed that 95% of patients (95% CI, 91%-99%) returned to any sport, 83% (95% CI, 73%-91%) returned to their preinjury level of sport, and 87% (95% CI, 71%-98%) returned to competitive sport after surgery. The mean time to RTS was 12.45 weeks (95% CI, 10.8-14.1 weeks). Each decade of age increased the likelihood of RTS failure by 6%, and increases in body mass index (BMI) of 5 kg/m2 raised the risk of RTS failure by 4%. The rate of RTS was higher in professional and competitive athletes (93%; 95% CI, 73%-100%) than in recreational athletes (83%; 95% CI, 76%-89%). Analysis showed no differences for arthroscopy versus open surgery, repair versus reconstruction, and early versus late weightbearing. Conclusion: In most cases, patients may return to some kind of sport after ALAS surgery, and some patients RTS at their preinjury level. The relative risk of RTS failure increases according to the magnitude of the increase in age and BMI. Elite athletes are more likely to return compared with nonelite athletes.