bluuebunny/crossref_metadata_2025_split huggingface dataset:
Teachers' and Black students' views on the incorporation of African American children's literature in an after‐school book club: collaborative and culturally based learning
Authors: Jones Brittney , Lynch Jacqueline 
Published: May 2023

AbstractIt has been suggested that culturally relevant literature can be beneficial to elementary school students' learning. Yet, less research has focused on African American students' perspectives of that literature, including aspects of that engagement that may benefit their learning. Therefore, the main goal centred on US elementary school students' perspectives of African American children's literature in an after‐school book club. There were 15 second‐ and third‐grade African American students from a low‐income area who participated in the 6‐week book club. The book club sessions were recorded, student artefacts were collected and a focus group was held with students. Following the book club, there were two classroom teachers interviewed along with an after‐school teacher facilitator. Based on the analysis, four themes were found. These focused on increased reading motivation, the role of cultural and personal associations with literature for comprehending, engagement in communal learning and improved access to culturally relevant texts. The results extend previous research on the importance of social collaboration and culturally relevant books to promote motivation and reading comprehension among learners and highlight the value of collaborative and culturally based learning for Black children in the American context.
Confirmation of Neoporphyra cf. dentata on Shikinejima, Izu Islands, southcentral Japan, and comparison with co‐occurring Neoporphyra haitanensis
Authors: Okamoto Miku , Ikeura Airi , Tamaki Motoya , Niwa Kyosuke 
Published: May 2023

SUMMARYThe Izu Islands of southcentral Japan are thought to fall within the distribution range of Neoporphyra dentata. However, the gametophytic blades of Bangiales collected from Shikinejima and Hachijojima, Izu Islands, were identified as Neoporphyra haitanensis in our previous study. Thus, it became uncertain whether N. dentata is distributed in the Izu Islands, including Shikinejima. To clarify whether N. dentata grows on Shikinejima, we conducted a further distribution survey of N. dentata on the island. The morphological features of the blade samples collected from an additional sampling site on Shikinejima were more similar to those of N. dentata than to those of N. haitanensis: the blade thickness and the division formula of spermatangia resembled those of the former species rather than the latter species. However, the division formula of zygotosporangia was different from those of either species. The phylogenetic analyses of the rbcL gene indicated that the samples were resolved in a clade including N. dentata collected from Shirahama, Chiba Prefecture, and Enoshima, Kanagawa Prefecture, Honshu, Japan. The p‐distances of the chloroplast rbcL gene and nuclear 18S rRNA also supported identification of the samples as N. dentata. The results demonstrated that N. dentata is also distributed on Shikinejima with co‐occurring N. haitanensis, and that the island materials of the two species are genetically different from other materials of the two species, respectively.
Contemporary Concise Review 2022: Interstitial lung disease
Authors: Smith David J. F. , Jenkins R. Gisli 
Published: May 2023

SUMMARY OF KEY POINTS
Novel genetic associations for idiopathic pulmonary fibrosis (IPF) risk have been identified. Common genetic variants associated with IPF are also associated with chronic hypersensitivity pneumonitis.
The characterization of underlying mechanisms, such as pathways involved in myofibroblast differentiation, may reveal targets for future treatments.
Newly identified circulating biomarkers are associated with disease progression and mortality.
Deep learning and machine learning may increase accuracy in the interpretation of CT scans.
Novel treatments have shown benefit in phase 2 clinical trials.
Hospitalization with COVID‐19 is associated with residual lung abnormalities in a substantial number of patients.
Inequalities exist in delivering and accessing interstitial lung disease specialist care.
Therapeutic effects of mesoderm introduction of compound glycyrrhizin injection on the treatment of rosacea
Authors: Li Shanshan , Zhao Xu , Chen Yun , Liu Jipeng 
Published: May 2023

AbstractObjectivesThis study aims to introduce compound glycyrrhizin injection for the treatment of rosacea by mesoderm therapy, and further analyze the therapeutic and aesthetic effects of this treatment method and its impact on the dermatological quality of life index, which provides new ideas and methods for cosmetic dermatology treatment of rosacea.MethodsThe recruited rosacea patients were divided into Control group (n = 58) and observation group (n = 58) according to the random number table. The control group was treated with topical metronidazole clindamycin liniment, and the study group was additionally used mesoderm introduction of compound glycyrrhizin injection. The transepidermal water loss (TEWL), water content in corneum, and dermatology life quality index (DLQI) in rosacea patients were evaluated.ResultsOur results showed that the scores of erythema, flushing, telangiectasia, and papulopustule were significantly reduced in the observation group. In addition, the observation group significantly decreased TEWL and increased the water content of the stratum corneum. Furthermore, the observation group significantly reduced the DLQI of rosacea patients compared to the control group.ConclusionThe use of mesoderm therapy combined with compound glycyrrhizic acid has a therapeutic effect on facial rosacea and improves patient satisfaction.
Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes
Authors: Hwang Justin , Shi Xiaolei , Elliott Andrew , Arnoff Taylor E. , McGrath Julie , Xiu Joanne , Walker Phillip , Bergom Hannah E. , Day Abderrahman , Ahmed Shihab , Tape Sydney , Makovec Allison , Ali Atef , Shaker Rami M. , Toye Eamon , Passow Rachel , Lozada John R. , Wang Jinhua , Lou Emil , Mouw Kent W. , Carneiro Benedito A. , Heath Elisabeth I. , McKay Rana R. , Korn W. Michael , Nabhan Chadi , Ryan Charles J. , Antonarakis Emmanuel S. 
Published: May 2023

Abstract

Purpose:
In patients with metastatic prostate cancer (mPC), ATM and BRCA2 mutations dictate differences in PARPi inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions.

Experimental Design:
We examined a novel set of 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on ATM (n = 88) or BRCA2 (n = 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-BRCA2/ATM HRR-deficient (HRDother, n = 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; n = 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data.

Results:
In noncastrate mPCs, only BRCA2-mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations and harbored coamplification of 11q13 genes, including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often tumor mutational burden high. BRCA2-mutated mPCs had upregulation of cell-cycle genes and were enriched in cell-cycle signaling programs. This was distinct from ATM-mutated tumors.

Conclusions:
Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments, including hormonal or taxane therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.
Abstract A004: KRAS allelic imbalance drives an epithelial MAPK-dependent tumor initiation program that is inefficient in provoking metastasis in colorectal cancer in vivo
Authors: Najumudeen Arafath K. , Fey Sigrid K. , Campbell Andrew D. , Sansom Owen J. 
Published: May 2023

Abstract
Allelic imbalance is reported to be a frequent event in cancers and a common feature associated with oncogenes such as KRAS and BRAF. However the functional and therapeutic consequences of such imbalances are poorly understood. Mutations in the KRAS oncogene are one of the most prevalent events in human cancers and heterozygous KRAS mutations are well-described functionally and are thus viewed as sufficient for tumorigenesis. Recent evidence shows high incidence of KRAS gene dosage changes in human cancers, including loss of the normal wild-type allele of KRAS. However, there is still much debate over the function of wild-type KRAS in tumour initiation, progression and therapy response. Using advanced genetically engineered mouse models of colorectal cancer (VillinCRE Apcfl/fl; LSL-KrasG12D/+ (AK), LSL-KrasG12D/+; Trp53fl/fl; Rosa26N1iCD/+ (KPN)) we investigated the functional impact of wild-type Kras in oncogenic Kras driven tumour initiation (AK), progression and metastasis (KPN) in vivo. Mechanistically, wild-type Kras restrains oncogenic Kras signalling and significantly affects the efficiency of the oncogenic Kras induced transformation and response to therapy. We demonstrate a suppressive role for wild-type Kras during tumorigenesis and highlight the critical impact of wild-type Kras upon therapeutic response and tumour progression in Kras mutant CRC. Wild-type KRAS-deficient colorectal tumours are characterized by increased MAPK signalling and transcriptional activation of MAPK regulators. Importantly, loss of wild-type Kras in oncogenic KRAS-driven aggressive KPN tumours significantly alter tumour progression and liver metastasis, showing increased immune infiltration and WNT signalling. In addition, loss of wild-type Kras modulates response to therapeutic intervention and sensitizes wild-type Kras deficient tumours to MEK1/2 inhibition. This study demonstrates a suppressive role for wild-type Kras during tumour initiation and highlights the critical impact of wild-type Kras upon therapeutic response to MAPK and tumour progression in KRAS mutant CRC.
Citation Format: Arafath K. Najumudeen, Sigrid K. Fey, Andrew D. Campbell, Owen J. Sansom. KRAS allelic imbalance drives an epithelial MAPK-dependent tumor initiation program that is inefficient in provoking metastasis in colorectal cancer in vivo [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 A004.
Abstract A026: Stochastic phenotypes in RAS-dependent developmental diseases
Authors: Marmion Robert A. , Simpkins Alison G. , Barrett Lena A. , Schottenfeld-Roames Jodi , Schüpbach Trudi , Shvartsman Stanislav Y. 
Published: May 2023

Abstract
Germline mutations upregulating RAS signaling are associated with multiple developmental disorders. A hallmark of these conditions is that the same mutation may present vastly different phenotypes in different individuals, even in monozygotic twins. We demonstrate how the origins of such largely unexplained phenotypic variations may be dissected using highly controlled studies in Drosophila that have been gene edited to carry activating variants of MEK, a core enzyme in the RAS pathway. This allowed us to measure the small but consistent increase in signaling output of such alleles in vivo. The fraction of mutation carriers reaching adulthood was strongly reduced, but most surviving animals had normal RAS-dependent structures. We rationalize these results using a stochastic signaling model and support it by quantifying cell fate specification errors in bilaterally symmetric larval trachea, a RAS-dependent structure that allows us to isolate the effects of mutations from potential contributions of genetic modifiers and environmental differences. We propose that the small increase in signaling output shifts the distribution of phenotypes into a regime, where stochastic variation causes defects in some individuals, but not in others. Our findings shed light on phenotypic heterogeneity of developmental disorders caused by deregulated RAS signaling and offer a framework for investigating causal effects of other pathogenic alleles and mild mutations.
Citation Format: Robert A. Marmion, Alison G. Simpkins, Lena A. Barrett, Jodi Schottenfeld-Roames, Trudi Schüpbach, Stanislav Y. Shvartsman. Stochastic phenotypes in RAS-dependent developmental diseases [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 A026.
Abstract A029: Unfolding the role of cell state on stress granule heterogeneity and function in KRAS-driven pancreatic cancer
Authors: Redding Alexandra , Fonteneau Guillaume , Grabocka Elda 
Published: May 2023

Abstract
Phenotypic and functional heterogeneity is a common feature of cancer cells that poses as a major therapeutic challenge. Previous work has implicated the phase-separation organelles, stress granules (SGs), as important mediators of tumorigenesis that function as a mutant KRAS-driven stress-adaptive mechanism to enhance cellular fitness. We have found that mutant KRAS pancreatic cancer cells show a high degree of intercellular heterogeneity in SG formation, ranging from no SGs to markedly high levels. Given the function of SGs in cancer cell fitness and the role of cancer cell heterogeneity in tumor progression and therapeutic response, we sought to understand the determinants of SG heterogeneity and its role in KRAS-driven tumorigenesis. Here, we show that the capability of KRAS mutant pancreatic cancer cells to form SGs is dependent on the cell cycle state, with cells in G2 phase showing markedly enhanced SG formation. We demonstrate that this heterogeneity in SG formation is determined by a cell cycle specific interplay between the activator of cell death, Caspase 3, and the SG regulator molecule 15-deoxy-delta-12,14-prostaglandin J2 (15-d-PGJ2). We show that 15-d-PGJ2 production in G2 is driven by calcium-dependent phospholipase A2 (cPLA2) activity and is subject to regulation by Caspase 3. Importantly, we show that heterogeneity in SG levels translates into a functional heterogeneity whereby SG inhibition preferentially sensitizes cells in G2 to stress stimuli. Altogether these data support a model whereby SG formation integrates cues from cell death and proliferative signals and indicate that SG levels may be critical to achieve a clear signal for cell cycle progression at the G2/M border. Furthermore, our findings suggest that KRAS-driven cancer cells may show differential sensitivity to anti-SG therapy as they progress through the cell cycle, and pairing such therapy with G2-synchronizing chemotherapeutics may increase susceptibility and thus treatment efficacy.
Citation Format: Alexandra Redding, Guillaume Fonteneau, Elda Grabocka. Unfolding the role of cell state on stress granule heterogeneity and function in KRAS-driven pancreatic 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 A029.
Abstract A036: Oncogenic mutations in BRAF and MEK weaken the ATP-stabilized inactive conformation of RAF to promote RAF dimerization and MAPK pathway activation
Authors: Wendorff Timothy J. , Kung Jennifer , Sudhamsu Jawahar 
Published: May 2023

Abstract
The RAS-RAF-MEK-ERK signaling axis is upregulated in many human cancers due to its central role in cell growth, differentiation and survival. Oncogenic transformation frequently arises from RAS, BRAF and MEK mutations that activate the pathway. In the clinic, similar transformations also recur as resistance mutations to KRAS.G12C inhibitor treatment. BRAF mutations at V600 (Class I) activate BRAF by releasing the kinase’s activation segment and rendering BRAF activity dimerization-independent. Yet, it remains unclear how a diverse set of dimerization-dependent BRAF mutations (Class II/III) activate the pathway. MEK mutations are assumed to bypass the RAF node entirely. We previously reported a 2.9-Å-resolution crystal structure of human BRAF kinase domain (BRAFKD) in complex with MEK and the ATP analog AMP-PCP, revealing interactions between BRAF and ATP that stabilize an inactive, pre-signaling monomeric conformation of BRAFKD and explain how ATP breaks RAF dimers in solution. Surprisingly, the β3-αC loop of MEK provides additional stabilizing interactions to the BRAF-bound AMP-PCP molecule. Utilizing an in vitro RAF dimerization assay, we find that MEK not only modulates RAF-RAF dimerization, it also enhances both the dimer-breaking effect ATP and the dimer-forming effect of paradoxical activator molecules, such as GDC-0879. Structural analysis reveals that all common oncogenic BRAF mutations alter key interactions with ATP that stabilize the inactive monomer conformation. We find ATP is unable to break RAF dimers containing Class I, II or III mutations, confirming these mutants counteract the inhibitory effects of ATP binding by lowering the threshold for RAF dimerization and thus pathway activation. We further find that oncogenic MEK mutants, in particular β3-αC loop deletions, favor RAF-RAF dimerization, even in the presence of ATP. Our study establishes a framework for rationalizing oncogenic BRAF mutations, and suggests that oncogenic MEK mutants can act, at least in part, by promoting RAF dimerization. This model provides a better understanding of activation mechanisms in the context of constantly evolving resistance mutations where oncogenesis continues to depend on the MAPK pathway.
Citation Format: Timothy J. Wendorff, Jennifer Kung, Jawahar Sudhamsu. Oncogenic mutations in BRAF and MEK weaken the ATP-stabilized inactive conformation of RAF to promote RAF dimerization and MAPK pathway activation [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 A036.
Abstract B003: Combined inhibition of the MAPK and Hippo pathways drives efficacious tumor suppression in a faithful model of mutant Kras (KPC) PDAC
Authors: Chakravarti Deepavali , Muller Florian , Gyuris Jeno , Baloglu Erkun , Kunnimalayiaan Selvi , Olson Jill , Shacham Sharon 
Published: May 2023

Abstract
Oncogenic mutations in the KRAS oncogene hyperactivate the MAPK pathway, a key driver of oncogenesis in the majority of human malignancies. KRAS-driven tumors are aggressive and highly refractory to standard-of-care treatments, thus intense efforts have been devoted to developing inhibitors of its activity. However, pioneering studies in engineered conditional mKras driven mouse models of pancreatic ductal adenocarcinoma (KPC) have demonstrated that while mKras is necessary for tumor maintenance, the anti-neoplastic effects of mKras extinction can be counteracted by activation of the Hippo pathway. These data strongly suggest that the full realization of MAPK pathway (including KRAS) inhibitors’ clinical potential requires the concomitant suppression of the function of YAP/TEAD, the effectors of Hippo pathway. Here, we directly test this hypothesis utilizing Sporos BioDiscovery’s next generation TEAD inhibitor (SPR1) - optimized to maximize anti-neoplastic activity and minimize toxicity through fine-tuning of TEAD paralog specificity. Using mKras murine (KrasG12D mutant, p53 null, PDAC) and human cell lines - we demonstrated strong interaction between SPR1 TEAD inhibitors and the clinical MEK inhibitors (since no G12D inhibitor is yet approved) Trametinib/Binimetinib in vitro. Functional TEAD inhibition was also shown by the reduced expression of the YAP/TEAD transcriptional targets CTGF and CYR61. Further, using a well-established murine orthotopic model, KPC (KrasG12D;p53-/-;p48Cre), that faithfully mimics human PDAC, we demonstrated robust combined efficacy of Trametinib and SPR1 TEAD inhibitors in vivo in suppressing tumor growth and strikingly doubling the survival time of the tumor-bearing mice. To our knowledge, this is the first preclinical demonstration of the therapeutic potential of a MAPK + TEAD inhibitor combination in a mKras G12D-driven orthotopic PDAC; given the high barrier for efficacy of this KPC model –we believe these results favorably presage generalization to MAPK/TEAD inhibitor combinations in other cancer setting and translatability to the clinic.
Citation Format: Deepavali Chakravarti, Florian Muller, Jeno Gyuris, Erkun Baloglu, Selvi Kunnimalayiaan, Jill Olson, Sharon Shacham. Combined inhibition of the MAPK and Hippo pathways drives efficacious tumor suppression in a faithful model of mutant Kras (KPC) PDAC [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 B003.