bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B005: RAS inhibitors to treat luminal B breast cancer
Authors: Clarke Geoff , Donninger Howard , Jigo Raphael , Arshad Tariq , von Baby Becca , Ferrill Rachel , Sabo Mike , Burlison Joe , Trent John 
Published: May 2023

Abstract
Since RAS mutations are rare in Breast Cancer, RAS has not traditionally been considered as an important driver of this disease. However, RAS signaling pathways are frequently hyper-activated in breast cancers and genetic/epigenetic inactivation of RAS negative regulators (GAPs) is common. This is particularly true for Luminal B breast cancer.   Luminal breast cancer makes up the majority of Breast Cancers, ~ 65% of cases.   The Luminal B form makes up around 1/3 of these. Although current therapeutic options for luminal A (surgery, endocrine therapy) can be reasonably effective, Luminal B tumors are much more dangerous. These tumors are less sensitive to therapy in the first place and have a high frequency of relapse.   Moreover, Luminal B tumors tend to occur more frequently in younger women and have a higher incidence of metastasis. One recent analysis has shown that Luminal B cancers have little better overall survival rates than the notorious triple negative breast cancers. Therefore, better therapies for Luminal B breast cancer are urgently required. One approach may be to target the hyper-active wild-type RAS oncoprotein that drives many of these tumors. We have in used in silico library screening followed by Medicinal Chemistry optimization to develop a series of novel small molecules that bind to all three main RAS proteins and block RAS function. We have validated the agents by using Microscale Thermophoresis binding procedures to quantify recombinant protein interaction. We used 3D growth inhibition and protein-based RAS signaling assays to quantify the biological action of the agents. Finally, we validated one of the more effective agents in vivo against a Luminal B cell line xenograft. This may be the first example of an effective anti-RAS therapy in breast cancer. It serves as proof of principal for the use of ant-RAS drugs in Luminal B disease. As basal breast cancers often exhibit loss of function of the RAS GAP called NF1, this strategy may have applications beyond Luminal B disease.
Citation Format: Geoff Clarke, Howard Donninger, Raphael Jigo, Tariq Arshad, Becca von Baby, Rachel Ferrill, Mike Sabo, Joe Burlison, John Trent. RAS inhibitors to treat luminal B breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B005.
Abstract IA06: Targeting the ERK-MYC signaling network for the treatment of KRAS-mutant cancers
Authors: Der Channing J. 
Published: May 2023

Abstract
KRAS is mutationally activated in 95% of pancreatic ductal adenocarcinomas (PDAC) and essential for maintenance of PDAC tumorigenic growth. The recent clinical evaluation of inhibitors of one KRAS mutant (KRASG12C) supports the therapeutic value of direct targeting of KRAS for PDAC treatment. However, this mutant comprises less than 2% of KRAS mutations in PDAC. Therefore, we have evaluated direct inhibitors of the predominant KRAS mutations (G12D, G12V and G12R) in PDAC. Additionally, both innate and treatment-associated resistance mechanisms will limit the effectiveness of direct KRAS inhibitors. Genomic sequencing analyses of patients who relapsed on KRASG12C inhibitors suggest that reactivation of KRAS effector signaling comprises one major mechanism of resistance. We determined that activation of MEK-ERK but not AKT activation alone is sufficient to drive resistance to KRASG12C/D inhibitors. However, our recent clinical evaluation of direct ERK inhibition in PDAC found that toxicity limited the effectiveness of this therapeutic approach. These observations prompted our studies to complete a system-wide determination of the molecular mechanisms by which ERK signaling supports KRAS-dependent PDAC growth. First, we determined the KRAS-ERK regulated transcriptome, kinome, total proteome and phosphoproteome in KRAS-mutant PDAC. We identified KRAS-dependent gene signature (677 KRAS-dependent and 1,051 KRAS-suppressed genes) that diverged significantly from the classical Hallmark KRAS gene signature. We identified 5,117 ERK-dependent phosphosites on 2,252 proteins, of which 88% and 67%, respectively, were not previously associated with ERK. Second, since a major consequence of ERK signaling involves activation of MYC-regulated gene transcription, we also determined the MYC-dependent transcriptome (2,086 MYC-dependent and 2,403 MYC-suppressed genes) that include 80 protein kinases. Together, these analyses define a highly complex and dynamic ERK-regulated signaling network that deregulates cell cycle progression, RHO GTPase function and metabolism to support KRAS-dependent PDAC growth.
Citation Format: Channing J. Der. Targeting the ERK-MYC signaling network for the treatment of KRAS-mutant cancers [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA06.
Abstract IA10: K-RAS hyperexchange mutants in colorectal cancer
Authors: Haigis Kevin 
Published: May 2023

Abstract
K-RAS can be functionally activated by reducing its ability to catalyze the hydrolysis of GTP and/or by increasing its nucleotide exchange activity. Cancer-associated mutations that increase exchange – termed hyperexchange mutants – are relatively rare and exhibit unique structural, biochemical, and biologic properties relative to hydrolysis mutants. The most common hyperexchange mutant is Ala146Thr, which exhibits a 10-fold increase in exchange activity relative to wild-type K-RAS while not significantly affecting GTP hydrolysis. This mutant is relatively common in colorectal cancer, but exceedingly rare in pancreatic cancer. The hyperexchange property of K-RASA146T leads to relatively low steady state levels of K-RAS-GTP, which underlies the tissue specific oncogenic activity of the mutant. Another hyperexchange mutant, K-RASA59T, is unique in that it uses the gamma-phosphate of GTP to phosphorylate Thr59 in the active site. This mutant also exhibits attenuated MAPK signaling, but through a distinct mechanism. K-RAS proteins with oncogenic substitutions at position 59 fail to properly engage RAF proteins and cannot induce B-RAF/C-RAF dimers. As a result, residue 59 mutants require cooperating mutations in other MAPK pathway genes in order to be fully oncogenic. This obligate cooperativity is borne out in the genetics of human cancers and in genetically engineered mouse models. In summary, hyperexchange mutants represent a class of oncogenic forms of K-RAS that exhibit distinct biochemically properties and attenuated MAPK. As such, this class of mutants may be sensitive to therapeutic approaches that are not effective in cancers expressing stronger forms of oncogenic K-RAS.
Citation Format: Kevin Haigis. K-RAS hyperexchange mutants in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA10.
Abstract IA17: Use of RAS isoforms in nerve tumors
Authors: Ratner Nancy , Hu Liang , Pundavela Jay , Epstein Jonathan A. 
Published: May 2023

Abstract
Neurofibromatosis Type I (NF1) is a common genetic disorder caused by mutations in the NF1 gene, which encodes a RAS-GAP. NF1 loss of function renders patients susceptible to tumors including NF1-/- benign neurofibromas, which can transform into atypical neurofibromas with NF1 and CDKN2A loss, and then lethal malignant peripheral nerve sheath tumors with NF1. CDKN2A, and PRC2 component loss. NF1 mutations are also common in many sporadic cancers. NF1 loss is known to increase or prolong wild type RAS activation, but the relative contribution of RAS paralogs (classical H-, N-, K-RAS and non-classical R-RAS, TC21, MRAS) to NF1 nerve tumorigenesis remains unknown. Our goal was to define the critical RAS paralog mediating the effect of NF1 protein deficiency due to NF1 mutations in neurofibromas and atypical neurofibromas, and to test whether targeting specific RAS paralogs might provide therapeutic strategies. Our data shows that KRAS is activated in RAS protein in NF1-deficient human and mouse Schwann cells (SCs), and in atypical Schwann cells. We find that a PKC agonist, prostratin, known to kill KRAS mutant cells, also selectively kills NF1 mutant Schwann cells in vitro and in mouse neurofibromas, and reduces tumor growth in a xenograft model of atypical neurofibroma. Prostratin acts through use of a subset of PKC isoforms. We anticipate that these findings can ultimately be used to develop an effective RAS targeting therapy for NF1 tumor prevention and treatment. Supported by: NIH R37 NS083580 and R01 NS12082 (N.R.), CancerFree KIDS (N.R.) and a Strauss Fellow Award (L.H.).
Citation Format: Nancy Ratner, Liang Hu, Jay Pundavela, Jonathan A. Epstein. Use of RAS isoforms in nerve tumors [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA17.
Abstract IA19: Oncogenic KRAS and the regulation of the pancreatic cancer microenvironment.
Authors: Magliano Marina Pasca di 
Published: May 2023

Abstract
Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, is characterized by almost universal presence of oncogenic KRAS. A key characteristic of pancreatic cancer is the abundant accumulation of tumor microenvironment, rich in infiltrating immune cells and an extensive fibroblast population. Pancreatic cancer is preceded by precursor lesions known as Pancreatic Intraepithelial Neoplasia (PanIN); PanIN formation is accompanied by the formation of a pre-TME. Analysis of donor pancreas from healthy individual revealed that PanIN is common in human samples, and accompanied by pre-TME accumulation in human samples. We sought to determine whether oncogenic KRAS drives accumulation and maintenance of the pre-TME. For this purpose, we utilized the iKRAS mouse model of pancreatic cancer, which allows tissue-specific, inducible and reversible activation of KRASG12D, the most common mutant form in human pancreatic cancer. Activation of oncogenic KRAS in iKRAS mice leads to PanIN formation. We observed that fibroblast activation occurs upon KRAS activation and precedes the formation of overt lesions. Further, epithelial oncogenic KRAS is required to maintain fibroblast reprogramming in PanIN. To comprehensively understand changes in fibroblasts, we used single cell RNA sequencing, and observed that the fibroblast transcriptional program is extrinsically regulated by epithelial oncogenic KRAS. The reprogramming process can be modeled in vivo using conditioned media from pancreatic cancer cells expressing oncogenic KRAS, and is mediated by JAK/STAT3 signaling in fibroblasts. We then sought to determine whether the extrinsic effects of oncogenic KRAS induced reprogramming of fibroblasts at distal sites. We chose to study the lung, which is a common site of metastasis for pancreatic cancer. Our data show that lung fibroblasts are activated following expression of oncogenic KRAS in the pancreas; fibroblast activation is accompanied by phospho-Stat3 signaling, a readout of the JAK/Stat3 pathway, and precedes metastasis outgrowth in the pancreas. Thus, oncogenic KRAS extrinsically reprograms the local and systemic environments, possibly facilitating metastatic spread of pancreatic cancer.
Citation Format: Marina Pasca di Magliano. Oncogenic KRAS and the regulation of the pancreatic cancer microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA19.
Abstract IA21: Immune rewiring of mutant Ras tumors: Mechanisms and translational implications
Authors: Bar-Sagi Dafna 
Published: May 2023

Abstract
Oncogenic mutations in KRas are found in more than 90% of pancreatic tumors. These mutations are acquired at an early stage of disease and, in experimental models, have been shown to be essential for tumor initiation, progression and maintenance. Studies from our lab have shown that the growth of oncogenic KRas harboring pancreatic tumors is associated with an immuo-suppressed state that is established via the dynamic interplay between the tumor cells and the immune milieu. Molecular dissection of the mechanisms that mediate this interplay reveals the engagement of a transcriptional program that drives the expression of a plethora of cytokines and chemokines. This presentation will focus on a subgroup of cytokines and the role they play in activating specific immunosuppressive pathways. The implication of our findings to disease progression and therapeutic intervention will be discussed.
Citation Format: Dafna Bar-Sagi. Immune rewiring of mutant Ras tumors: Mechanisms and translational implications [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA21.
Abstract PR09: KRAS-targeted PROTAC degraders are broadly efficacious against KRAS-dependent tumor models
Authors: Smith Kathryn , Lopez-Arroyo Andrea , Berk Jason , Hegan Peter , Nower Peter , Tice Samantha , Moutran Aurelie , Pizzano Jennifer , Dowtin Amanda , Bookbinder Mark , Bortolon Elizabeth , Cadelina Greg , Karim Fazlul , Digianantonio Katie , Bekes Miklos , Medina Jesus 
Published: May 2023

Abstract
KRAS is genomically altered in about one third of all human tumors. Due to its central role in oncogenesis, many attempts have been made in the last four decades to drug mutant KRAS, either directly or indirectly. Despite recent advances in targeting KRAS using small molecule inhibitors, the majority of KRAS alterations do not yet have an existing targeted therapy, and where inhibitors are available, resistance rapidly emerges. Thus, novel approaches to drugging KRAS are needed. Eliminating mutant KRAS using a targeted protein degradation approach may lead to superior efficacy relative to inhibiting the protein. KRAS PROTAC® degraders that selectively target the G12D mutant form of KRAS were identified and profiled in KRAS-dependent cancer models. In vitro, PROTAC degraders targeting the G12D mutant degrade KRAS with picomolar potency, robustly suppress MAPK and PI3K/AKT signaling, induce apoptosis, and have antiproliferative activity that is superior to known inhibitors. These molecules are selective for mutant KRAS G12D, neither degrading wild-type KRAS nor the related isoforms HRAS and NRAS. In vivo, these degraders can eliminate &gt;95% of mutant KRAS from relevant xenograft models, induce apoptosis, and lead to tumor regression. Consistent with the extended pharmacodynamics often observed with PROTAC degraders, a single dose of a G12D PROTAC results in prolonged KRAS degradation and significant pERK suppression up to one week after administration. Combined, these data show that degrading mutant KRAS G12D in tumors is highly efficacious and may have advantages over inhibition, making it an exciting potential new approach for the treatment of KRAS mutant cancers.
Citation Format: Kathryn Smith, Andrea Lopez-Arroyo, Jason Berk, Peter Hegan, Peter Nower, Samantha Tice, Aurelie Moutran, Jennifer Pizzano, Amanda Dowtin, Mark Bookbinder, Elizabeth Bortolon, Greg Cadelina, Fazlul Karim, Katie Digianantonio, Miklos Bekes, Jesus Medina. KRAS-targeted PROTAC degraders are broadly efficacious against KRAS-dependent tumor models [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr PR09.
LONG-COVID ТА АСОЦІЙОВАНІ УРАЖЕННЯ СЕРЦЕВО-СУДИННОЇ ТА НЕРВОВОЇ СИСТЕМ
Authors: Світайло В. С. , Чемич М. Д. , Саєнко О. С. 
Published: May 2023

З метою вивчення особливостей клінічного перебігу Long-COVID здійснили огляд наукових публікацій, які містять дані про Long-COVID як окремий патологічний стан, актуальну інформацію про його прояви, та деякі патофізіологічні механізми, що призводять до розвитку уражень серцево-судинної і нервової систем.
Висновки. Визначення терміну Long-COVID як окремого стану у перебігу коронавірусної хвороби відбувалось у кілька етапів. Симптоми Long-COVID пов’язані з ураженням майже всіх систем органів. Ураження серцево-судинної системи є одними з домінуючих, при цьому є дані, що механізм таких уражень пов’язаний з порушеннями у системі згортання крові з утворенням мікротромбів. Також ураження серцево-судинної системи є основною причиною смерті хворих з Long-COVID. Співвідношення за статтю у випадку уражень серцево-судинної системи однакове, у той час як ураження нервової системи, інших органів та систем відбувається переважно у жінок. Деякі з існуючих даних вже знайшли додаткове підтвердження у результатах останніх досліджень, інші потребують його.
EVALUATION OF THE EFFECTIVENESS OF DENTAL COMPLACATIONS PREVENTION AGAINST THE BACKGROUND OF CHEMOTHERAPY IN ONCOLOGICAL PATIENTS IN ZAPORIZHZHIA
Authors: Filon A. M. 
Published: May 2023

SUMMARY. The aim – to investigate the condition of the oral cavity in patients with malignant neoplasms of the mammary gland and lungs before and after chemotherapy and to analyze the effectiveness of dental prophylaxis.
Material and methods. To achieve this goal, a statistical study of oncological patients undergoing chemotherapy at the ONCOLIFE medical center (Zaporizhzhia) was performed. 60 patients, both men and women, were enrolled in the study. All respondents were divided into groups according to cancer type: group 1 consisted of 30 lung cancer patients, group 2 comprised 30 breast cancer patients, and group 3, the control group, included 30 people without cancer. Research results have been processed with modern statistical methods on a PC with Statistica 13 software package.
Results. The data were checked for normality of distribution since the distribution of most data differs from normal; the median and interquartile range (Me(Q25; Q75)) of data presentation were designed. A comparison of indicators in three independent groups was performed with the Kruskall – Wallis test, in two independent groups – with the Mann – Whitney test, and the non-parametric Wilcoxon test was used to determine the effect of prophylactic treatment. The Chi-square test was used to compare qualitative data. Differences were considered statistically significant at a significance level of p<0.05.
Conclusions. Patients with oncopathology accompanied with unsatisfactory oral hygiene, caries and its complications are more likely to get dental problems during chemotherapy treatment. Oncological patients diagnosed with lung cancer and breast cancer developed relatively similar dental complications, which confirms the negative effect of chemotherapy treatment as is.
PEDAGOGICAL ASPECTS OF FORMING ENGLISH LANGUAGE PROFESSIONALLY ORIENTED COMPETENCE OF FUTURE DOCTORS THROUGH THE PRISM OF COMMUNICATIVE EXERCISES
Authors: Prokop I. A. , Kitura H. Ya. 
Published: May 2023

Abstract. The article covers the issues of the practical use of English language communicative exercises as a constituent of medical students’ professional competence. The core of foreign language competence as an integral part of the professional competence of health care specialist is identified. The development of a medical student’s foreign language competence is an essential concept of the professional education in higher educational medical establishments and is implemented through mastering the specifics of language competence at its phonetic, lexical and grammatical levels of study. The emphasis is placed on the need of educational communicative exercises analysis as a core component of English for Specific Purposes (ESP). The issues of special subject contents within the course of ESP, choice of teaching materials, advance of students’ communicative component in the mastering of the English language skills are reviewed. The main elements of the medical students’ communicative competence are defined; science-based classification system of exercises for the formation of communicative competence is regarded; the necessity of lexical mastering for adequate opinion formation is emphasized. Both theoretical and methodological aspects of testing students’ foreign language professional competence in the process of studying professionally oriented English are highlighted. It has been found that the practical use of the communicative exercises makes it possible to develop speech skills and abilities, thus providing an opportunity to evaluate, express own opinions and promote self-development and self-actualization of medical students.
Catheter-Induced Postextrasystolic Potentiation in the Assessment of Severity of Low-Gradient Aortic Valve Stenosis
Authors: Dehghani Payam , Singh Jyotpal , Singer Zachary , Booker Jeffrey , Lavoie Andrea J. , Zimmermann Rodney H. , Shavadia Jay S. , Webb John G. , Clavel Marie-Annick , Pibarot Philippe 
Published: May 2023

Background:
Deciphering which patients with low-gradient aortic valve disease have severe stenosis can be difficult. We aimed to correlate the postextrasystolic potentiation (PESP) with dobutamine stress echocardiography and multidetector computed tomography in patients with low-gradient aortic valve stenosis.

Methods:

Patients with an aortic valve area ≤1 cm
2
and a mean gradient <40 mm Hg were included. Aortic valve stenosis severity was assessed by a core lab with dobutamine stress echocardiography, followed by a multidetector computed tomography aortic valve score if indeterminate. A premature ventricular contraction was induced by intentional catheter contact with the myocardium within the left ventricle. PESP was calculated as a percent change of pre-to-post mean gradient. Multidetector computed tomography was used to measure the aortic valve calcification score, and subsequently, aortic valve calcification density.

Results:

Twenty-eight patients (age, 77±10 years; 19 female) were included. Dobutamine stress echocardiography increased mean gradient from baseline of 25±7 mm Hg to 36±11 mm Hg; pre-premature ventricular contraction mean gradient was 25±7 mm Hg and increased to post-premature ventricular contraction mean gradient of 32±10 mm Hg, representing a PESP of 24±11%. A ≥20% in PESP resulted in 100% sensitivity, 77% specificity, 83% positive predictive value, and 100% negative predictive value for diagnosing severe aortic valve stenosis. There was a significant correlation between PESP and projected aortic valve area and aortic valve calcification density (R=−0.64,
P
=0.0003; R=0.057,
P
=0.014, respectively).

Conclusions:
In patients with low-gradient aortic valve stenosis, catheter-induced premature ventricular contractions during cardiac catheterization causing ≥20% PESP has a 100% sensitivity for severe aortic valve stenosis. Validation of this 20% cutoff in larger groups with correlation to clinical end points is required.