Landscape Of Alterations Research Articles

Different efficacy of tyrosine kinase inhibitors by KIT and PGFRA mutations identified in circulating tumor DNA for the treatment of refractory gastrointestinal stromal tumors

BackgroundWhile advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST.MethodsWe conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients. We compared patient characteristics analyzed with tissue and blood samples, assessed gene alteration profiles, and evaluated prognostic implications from ctDNA status.ResultsIn 133 patients, tissue and blood samples were analyzed for 89 and 44 patients, respectively. ctDNA was detected in 72.7% of cases; no prior treatment or progressive disease was significantly associated with ctDNA-positivity. ctDNA-positive patients had significantly shorter progression-free survival compared with ctDNA-negative patients (hazard ratio = 3.92; P = 0.007). ctDNA genotyping revealed a complex landscape of gene alterations, characterized by multi-exonic mutations in KIT, compared with tissue-based analysis. Patients who received TKIs matched to the identified KIT mutation in ctDNA demonstrated significantly longer PFS than those with unmatched treatment (median, 8.23 vs. 2.43 months; P < 0.001).ConclusionsctDNA-based analysis facilitates assessment of disease status and genomic profiles, thus potentially assisting in identifying optimal therapeutic strategies for advanced GIST patients.

Effects of landscape changes on urban climate change: A case study in the city of São Paulo

Given the vulnerability of Brazilian cities to climate change, it is imperative to monitor urban areas’ susceptibility to temperature fluctuations. In this article, we employ thermal remote sensing and digital image processing techniques to illustrate a substantial rise in surface temperatures across the Northwest Region of São Paulo City over the past three decades. This surge in surface temperature is closely linked to alterations in the urban landscape. Our findings emphasize that one significant environmental consequence of São Paulo City’s rapid urbanization is the pronounced increase in surface temperatures. These results also underscore the significance of assessing landscape features, such as vegetation cover, to inform the prudent, sustainable, and resilient management of urban centers, thereby mitigating climate change effects in metropolitan areas.

Ancestry-associated co-alteration landscape of KRAS and EGFR-altered non-squamous NSCLC

Racial/ethnic disparities mar NSCLC care and treatment outcomes. While socioeconomic factors and access to healthcare are important drivers of NSCLC disparities, a deeper understanding of genetic ancestry-associated genomic landscapes can better inform the biology and the treatment actionability for these tumors. We present a comprehensive ancestry-based prevalence and co-alteration landscape of genomic alterations and immunotherapy-associated biomarkers in patients with KRAS and EGFR-altered non-squamous (non-Sq) NSCLC. KRAS was the most frequently altered oncogene in European (EUR) and African (AFR), while EGFR alterations predominated in East Asian (EAS), South Asian (SAS), and Admixed American (AMR) groups, consistent with prior studies. As expected, STK11 and KEAP1 alterations co-occurred with KRAS alterations while showing mutual exclusivity with EGFR alterations. EAS and AMR KRAS-altered non-Sq NSCLC showed lower rates of co-occurring STK11 and KEAP1 alterations relative to other ancestry groups. Ancestry-specific co-alterations included the co-occurrence of KRAS and GNAS alterations in AMR, KRAS, and ARID1A alterations in SAS, and the mutual exclusivity of KRAS and NF1 alterations in the EUR and AFR ancestries. Contrastingly, EGFR-altered tumors exhibited a more conserved co-alteration landscape across ancestries. AFR exhibited the highest tumor mutational burden, with potential therapeutic implications for these tumors.

C/EBPβ deletion in macrophages impairs mammary gland alveolar budding during the estrous cycle.

Macrophages have important roles in mammary gland development and tissue homeostasis, but the specific mechanisms that regulate macrophage function need further elucidation. We have identified C/EBPβ as an important transcription factor expressed by multiple macrophage populations in the normal mammary gland. Mammary glands from mice with C/EBPβ-deficient macrophages (Cebpb ΔM) show a significant decrease in alveolar budding during the diestrus stage of the reproductive cycle, whereas branching morphogenesis remains unchanged. Defects in alveolar budding were found to be the result of both systemic hormones and local macrophage-directed signals. RNA sequencing shows significant changes in PR-responsive genes and alterations in the Wnt landscape of mammary epithelial cells of Cebpb ΔM mice, which regulate stem cell expansion during diestrus. Cebpb ΔM macrophages demonstrate a shift from a pro-inflammatory to a tissue-reparative phenotype, and exhibit increased phagocytic capacity as compared to WT. Finally, Cebpb ΔM macrophages down-regulate Notch2 and Notch3, which normally promote stem cell expansion during alveolar budding. These results suggest that C/EBPβ is an important macrophage factor that facilitates macrophage-epithelial crosstalk during a key stage of mammary gland tissue homeostasis.

Sparking Intentional and Antiracist Pedagogy: A Narrative Analysis of COVID-Era Interviews with Public Health Faculty

The COVID-19 pandemic and the racial justice uprisings of 2020–2022 created an altered and challenging landscape for teaching public health. Challenging and direct experiences with these public health issues and their reverberations shaped how some faculty and many students participated in both online and in-person classrooms. In this project, we conducted a narrative analysis of oral history interviews with eight faculty members at a public university in New York City to understand how they reacted to these events and reconsidered their public health teaching during this period. We map what propelled faculty along paths of change and where these paths led. We learn that participating faculty shifted in varied ways toward more intentional and sometimes more antiracist teaching practices. Two experiences were foundational to these shifts: (1) faculty attunement to student realities during this time, and (2) faculty reflection on their own social positionings (i.e., race, gender identity, sexual orientation, class, age, immigration status, etc.) and their development of critical consciousness. These findings provide insights into how faculty conceptualize, support, and change their teaching approaches during periods of upheaval, particularly in the context of limited institutional support for faculty development. Finally, we discuss key issues for institutions seeking to formalize and enhance shifts like those described.

Type II innate lymphoid cell plasticity contributes to impaired reconstitution after allogeneic hematopoietic stem cell transplantation

Type II innate lymphoid cells (ILC2s) maintain homeostasis and barrier integrity in mucosal tissues. In both mice and humans, ILC2s poorly reconstitute after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Determining the mechanisms involved in their impaired reconstitution could improve transplant outcomes. By integrating single-cell chromatin and transcriptomic analyses of transplanted ILC2s, we identify a previously unreported population of converted ILC1-like cells in the mouse small intestine post-transplant. Exposure of ILC2s to proinflammatory cytokines resulted in a mixed ILC1-ILC2 phenotype but was able to convert only a small population of ILC2s to ILC1s, which were found post-transplant. Whereas ILC2s protected against acute graft-versus-host disease (aGVHD) mediated mortality, infusion of proinflammatory cytokine-exposed ILC2s accelerated aGvHD. Interestingly, murine ILC2 reconstitution post-HSCT is decreased in the presence of alloreactive T cells. Finally, peripheral blood cells from human patients with aGvHD have an altered ILC2-associated chromatin landscape compared to transplanted controls. These data demonstrate that following transplantation ILC2s convert to a pro-pathogenic population with an ILC1-like chromatin state and provide insights into the contribution of ILC plasticity to the impaired reconstitution of ILC2 cells, which is one of several potential mechanisms for the poor reconstitution of these important cells after allo-HSCT.

REPRODUCTIVE AGEING: Altered histone modification landscapes underpin defects in uterine stromal cell decidualization in aging females.

Advanced maternal age is associated with a higher rate of pregnancy complications that are unrelated to karyotypic abnormalities of the oocyte. This study shows that the murine uterine stroma undergoes profound epigenetic changes affecting active and repressive histone modification profiles that are associated with impaired endometrial functionality and underpin the decline in reproductive performance of aged females. Decidualization describes the transformation of the uterine stroma in response to an implanting embryo, a process critical for supporting the development of the early embryo, for ensuring normal placentation and ultimately for a healthy reproductive outcome. Maternal age has been found to impede the progression of decidualization, heightening the risk of reproductive problems. Here, we set out to comprehensively characterize this deficit by pursuing transcriptomic and epigenomic profiling approaches specifically in the uterine stromal cell (UtSC) compartment of young and aged female mice. We find that UtSCs from aged females are globally far less responsive to the decidualization stimulus triggered by exposure to the steroid hormones estrogen and progesterone. Despite an overall transcriptional hyperactivation of genes that are differentially expressed as a function of maternal age, the hormonally regulated genes specifically fail to be activated in aged UtSCs. Moreover, even in their unstimulated 'ground' state, UtSCs from aged females are epigenetically distinct, as determined by genomic enrichment profiling for the active and repressive histone marks H3K4me3 and H3K9me3, respectively. We find that many hormone-inducible genes exhibit a profound lack of promoter-associated H3K4me3 in aged UtSCs, implying that a significant enrichment of active histone marks prior to gene stimulation is required to enable the elicitation of a rapid transcriptional response. With this combination of criteria, our data highlight specific deficits in epigenetic marking and gene expression of ion channels and vascular markers. These results point to fundamental defects in muscle-related and perivascular niche functions of the uterine stroma with advanced maternal age.

Landscape Dynamics of the Mu Us Sandy Land Based on Multi-Source Remote Sensing Images

This study meticulously investigates landscape alterations within the Mu Us Sandy Land, a critical region for desertification control in China. The research dissects the dynamic characteristics and inter-conversion of landscape elements across eleven distinct periods by employing multi-source remote sensing imagery spanning 1963 to 2020, alongside visual interpretation, random forest classification, and the desertification difference index (DDI). The analysis uncovers significant landscape transformations within the Mu Us Sandy Land over the past six decades, following a precise chronological sequence. A pivotal shift occurred around 1986, characterized by opposing trends within fixed and shifting sandy land. The earlier stage (pre-1986) witnessed a substantial decrease (66.9%) in the fixed sandy land area, accompanied by a corresponding rise (38.7%) in shifting sandy land. Conversely, the later stage (post-1986) era exhibited a remarkable increase (309.7%) in fixed sandy land, alongside a significant decline (78.9%) in shifting sand land coverage. This study identifies two stages of landscape transformation: a pre-1986 phase dominated by the conversion of fixed sandy land to semi-fixed sandy land and a post-1986 reversal toward shifting sand land into fixed sandy land. These sequential transformations have shaped the landscape pattern alterations observed in the Mu Us Sandy Land since 1963. The dramatic landscape improvements observed after 1986 can be primarily attributed to the implementation and continued investment in large-scale ecological restoration projects. This study’s findings, which reveal the intricate landscape dynamics and their implications for ecosystem management, provide a scientific foundation for refining and formulating comprehensive strategies to control desertification and manage the Mu Us Sandy Land’s unique ecosystem.

Integrative analysis of Anoikis-related genes reveals that FASN is a novel prognostic biomarker and promotes the malignancy of bladder cancer via Wnt/β-catenin pathway

Bladder cancer (BC) exhibits diversity in clinical outcomes and is characterized by heterogeneity. Anoikis, a form of programmed cell death, plays a crucial role in facilitating tumor invasion and metastasis. This study comprehensively investigated the genetic landscape of BC progression, identifying 300 differentially expressed Anoikis-related genes (DE-ARGs) through in-depth analysis of the GSE13507 datasets. Functional enrichment analysis revealed associations with diverse diseases and biological processes. Employing machine learning algorithms, a logistic regression model based on nine marker genes demonstrated superior accuracy in distinguishing BC from normal samples. Validation in TCGA datasets highlighted the prognostic significance of LRP1, FASN, and SIRT6, suggesting their potential as cancer biomarkers. Particularly, FASN emerged as an independent prognostic indicator, regulating BC cell proliferation and metastasis through the Wnt/β-catenin pathway. The study provides crucial insights into altered genetic landscapes and potential therapeutic strategies for BC, emphasizing the significance of FASN in BC prognosis and progression.

Deciphering the landscape of lncRNA-driven ceRNA network in schizophrenia etiology

BackgroundThe unifying hypothesis of competing endogenous RNA (ceRNA) wherein crosstalk between coding (mRNAs) and long non-coding RNAs (lncRNAs) via microRNA (miRNA) response elements, creates a pervasive regulatory network across the transcriptome, has been implicated in complex disorders including schizophrenia. Even with a wide range of high-throughput data, the etiology of schizophrenia remains elusive, necessitating a more holistic understanding of the altered genetic landscape, shifting focus from solely candidate gene studies and protein-coding variants.ObjectiveWe developed lncRNA-associated ceRNA networks to elucidate global molecular/regulatory signatures underlying schizophrenia using diverse data in the public domain.MethodsMicroarray dataset associated with peripheral blood mononuclear cells (PBMCs) of schizophrenia and control patients was used to identify differentially expressed mRNAs. Weighted gene co-expression network analysis (WGCNA) was used to identify highly correlated hubs, and genes from these overlapping Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) term genesets were considered key mRNA players. StarBase, Human MicroRNA Disease Database, and miRWalk were used to derive mRNA-miRNA and miRNA-lncRNA relationships. Finally, the key mRNAs, interacting lncRNAs and miRNAs were chosen to reconstruct sub-ceRNA networks based on network centrality scores.ResultsBioinformatics analysis revealed the involvement of three differentially expressed mRNAs, namely ADRA1A, HAP1 and HOMER3 in the schizophrenia ceRNA networks with lncRNAs NEAT1, XIST, and KCNQ1OT1 modulating their activity by a suggestive sequestering of miR-3163, miR-214-3p and miR-2467-3p, respectively.ConclusionsFurthermore, based on contextual evidence, we propose how ceRNAs could orchestrate crosstalk between neurostructural dynamics and immune/inflammatory processes and enable unifying these disparate models of schizophrenia etiology.

CDK4/6 inhibition enhances T-cell immunotherapy on hepatocellular carcinoma cells by rejuvenating immunogenicity

Hepatocellular carcinoma (HCC) poses a significant clinical challenge, necessitating the integration of immunotherapeutic approaches. Palbociclib, a selective CDK4/6 inhibitor, has demonstrated promising efficacy in preclinical HCC models and is being evaluated as a novel therapeutic option in clinical trials. Additionally, CDK4/6 inhibition induces cellular senescence, potentially influencing the tumor microenvironment and immunogenicity of cancer cells. In this study, we conducted comprehensive bioinformatic analyses using diverse HCC transcriptome datasets, including bulk and single-cell RNA-sequencing data from public databases. We also utilized human and mouse HCC cells to investigate functional aspects. Primary T cells isolated from mouse blood were employed to assess T cell immunity against HCC cells. Results revealed that CD8+ T-cell infiltration correlates with improved outcomes in HCC patients with suppressed CDK4/6 expression. Moreover, CDK4/6 expression was associated with alterations in the immune landscape and immune checkpoint expression within the liver tumor microenvironment. Furthermore, we found that treatment with Palbociclib and Doxorubicin induces cellular senescence and a senescence-associated secretory phenotype in HCC cells. Notably, pretreatment with Palbociclib augmented T cell-mediated cytotoxicity against HCC cells, despite upregulation of PD-L1, surpassing the effects of Doxorubicin pretreatment. In conclusion, our study elucidates a novel mechanism by which CDK4/6 inhibition enhances T-cell-associated cancer elimination and proposes a potential therapeutic strategy to enhance T-cell immunotherapy on HCC.Graphical abstract

New insights gained from cellular landscape changes in myocarditis and inflammatory cardiomyopathy.

Advances in the etiological classification of myocarditis and inflammatory cardiomyopathy (ICM) have reached a consensus. However, the mechanism of myocarditis/ICM remains unclear, which affects the development of treatment and the improvement of outcome. Cellular transcription and metabolic reprogramming, and the interactions between cardiomyocytes and non-cardiomyocytes, such as the immune cells, contribute to the process of myocarditis/ICM. Recent efforts have been made by multi-omics techniques, particularly in single-cell RNA sequencing, to gain a better understanding of the cellular landscape alteration occurring in disease during the progression. This article aims to provide a comprehensive overview of the latest studies in myocarditis/ICM, particularly as revealed by single-cell sequencing.

Comprehensive genomic profiling from C-CAT database unveiled over 80% presence of oncogenic drivers in anaplastic thyroid carcinoma including BRAF, RAS family, NF1, and FGFR1.

Anaplastic thyroid carcinoma (ATC) is considered a very aggressive carcinoma and has been difficult to treat with therapeutic strategies. This study examines the landscape of genomic alteration in ATC, including the BRAF V600E mutation, and its clinical implications. A retrospective observational study was conducted using collected at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan, utilizing comprehensive genomic profiling data from 102 ATC cases. Additionally, AACR-GENIE data from 267 cases were analysed for validation. Statistical methods, including the conditional Kendall tau statistic and χ2 tests, were employed for survival analysis and gene mutation comparisons. Among 102 ATCs, BRAF, RAS, and other driver mutations were found in 83 cases (81.2%). The prevalence of BRAF V600E mutations was as high as 60%. Co-mutation analysis identified different genomic profiles in the BRAF, RAS, and wild-type groups. Despite the diverse molecular backgrounds, no significant differences in clinical variables and overall survival were observed. The analysis considering left-side amputation suggested that RAS mutations had a poorer prognosis. In the BRAF/RAS wild-type group, FGFR1 and NF1 were identified as driver mutations, with an accumulation of copy number variations and less TERT promoter mutations. This molecular subgrouping was also supported by the AACR-GENIE data. Comprehensive genomic analysis of ATC in Japan revealed distinct molecular subgroups, highlighting the importance of BRAF V600E mutations, particularly V600E, as potential therapeutic targets and suggest the relevance of tailor-made therapeutic strategies based on genomic profiling.

Histone Chaperone Deficiency in Arabidopsis Plants Triggers Adaptive Epigenetic Changes in Histone Variants and Modifications

At the molecular scale, adaptive advantages during plant growth and development rely on modulation of gene expression, primarily provided by epigenetic machinery. One crucial part of this machinery is histone posttranslational modifications, which form a flexible system, driving transient changes in chromatin, and defining particular epigenetic states. Posttranslational modifications work in concert with replication-independent histone variants further adapted for transcriptional regulation and chromatin repair. However, little is known about how such complex regulatory pathways are orchestrated and interconnected in cells. In this work, we demonstrate the utility of mass spectrometry–based approaches to explore how different epigenetic layers interact in Arabidopsis mutants lacking certain histone chaperones. We show that defects in histone chaperone function (e.g., chromatin assembly factor-1 or nucleosome assembly protein 1 mutations) translate into an altered epigenetic landscape, which aids the plant in mitigating internal instability. We observe changes in both the levels and distribution of H2A.W.7, altogether with partial repurposing of H3.3 and changes in the key repressive (H3K27me1/2) or euchromatic marks (H3K36me1/2). These shifts in the epigenetic profile serve as a compensatory mechanism in response to impaired integration of the H3.1 histone in the fas1 mutants. Altogether, our findings suggest that maintaining genome stability involves a two-tiered approach. The first relies on flexible adjustments in histone marks, while the second level requires the assistance of chaperones for histone variant replacement.

The pan-cancer landscape of SMARCA4 and SMARCB1 alterations in a large cohort of Chinese patients.

e14636 Background: Alterations of SMARCA4 or SMARCB1 (SMARCA4/B1) proteins have been identified in various aggressive cancers. Recent studies show that tumors harboring deleterious SMARCA4/B1 alterations express PD-L1 and respond to immune checkpoint inhibitor (ICI) therapies. Current ongoing immunotherapy-based clinical trials for cancers deficient in SMARCA4/B1 include combinations of atezolizumab and the TIGIT antibody tiragolumab (Phase II), as well as nivolumab and the CTLA-4 antibody ipilimumab (Phases II &amp; III). Here we present a comprehensive analysis of the pan-cancer landscape of SMARCA4/B1 alterations, based on real-world data from a large cohort of Chinese patients. Methods: From 2021 to 2023, we collected genomic information from 16,113 cancer patients, spanning more than 40 different cancer types. These patients had undergone targeted next-generation sequencing (NGS) through the Med1CDx panel, which targets 601 cancer-associated genes. After excluding 1,034 samples of unidentified tumor origins, 15,079 samples were analyzed further. The analysis included somatic and germline pathogenic/likely pathogenic (P/LP) single-nucleotide variants, insertions/deletions, and copy number alteration in SMARCA4/B1. Results: We identified 421/15079 (2.8%) patients with SMARCA4/B1 alterations, with a median age of 63 years (range 13-90). Cancer types with a higher frequency of SMARCA4/CB1 mutations include: endometrial cancer (9.8%), thyroid cancer (6.9%), gastric cancer (6.2%), cholangiocarcinoma (5.7%), and lung cancer (4.4%). The predominant mutation type is variants of uncertain significance (VUS) gene mutations, constituting 72% (302/421) of the spectrum, with nearly all being missense mutations. These are mainly observed in lung cancer, thyroid cancer, and colorectal cancer. The frequency of pathogenic/likely pathogenic mutations is 28% (119/421), mainly distributed in lung cancer and liver cancer. Q201L, P222L, and E1364del are the most common mutations in SMARCA4, with a mutation rate of approximately 4.1%, occurring across over five cancer types. The most common co-mutations of SMARCA4/B1 were TP53 (47.3%), EGFR (25.4%), KRAS (15.9%), STK11 (7.1%) and CDKN2A (7.4%). Clinicopathological feature of age showed no significant differences between SMARCA4/B1 mutant and wild-type groups. Tissues with SMARCA4/B1 mutations exhibited a higher tumor mutational burden (TMB) (median=8.3) than wild-type tissues (median=4.2) (P &lt; 0.001). Conclusions: Elevated TMB levels in patients with SMARCA4/B1 mutations suggest a significant potential benefit from immunotherapy. The presence of co-mutations may also aid in predicting the efficacy of combination immunotherapy treatments. Furthermore, the high prevalence of VUS emphasizes the need for additional research to determine their clinical relevance.

Characterization of diverse targetable ERBB2 alterations in 512,993 patients with solid tumors.

3129 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has demonstrated activity against a range of HER2-expressing and HER2-mutant (mut) solid tumors. We present an extensive landscape of ERBB2 alterations (alt) that may predict sensitivity to HER2-targeted therapies in development with a focus on mutations and cancer types without approved indications. Methods: We queried institutional databases (MSKCC and Foundation Medicine, Inc.) of comprehensive genomic profiling (CGP) performed on solid tumor tissue samples using either MSK-IMPACT (N=83,332; MSK) or FoundationOne/FoundationOne CDx (N=429,661; FMI) and on patient-matched liquid biopsies using FoundationOne Liquid CDx (N=1,922). ctDNA tumor fraction (ctDNA TF) on FoundationOne Liquid CDx was estimated using a composite algorithm. Clinicopathological characteristics and treatment outcomes were annotated for MSK-IMPACT samples. Results: ERBB2 activating alt were detected in 6.6% (n=28,508) and 5.0% (n=4,133) of tumors in the FMI and MSK cohorts, respectively. In FMI tissue samples, ERBB2 alt were most prevalent in gastroesophageal (GEC; 18.1%), bladder (18.0%), salivary gland (14.1%), breast (12.7%), and uterine (12.1%) cancers. The cancer types with the largest number of ERBB2mut tumors, specifically, included NSCLC (n=1,618, 1.9%), breast (n=1,565, 3.5%), colorectal (CRC; n=1,221, 2.3%), bladder (n=855, 8.8%), and GEC (n=660, 3.4%). Across these 5 cancers, ERBB2 mut were most commonly located in the kinase domain (KD; 58%), followed by the extracellular domain (ECD; 28%) and transmembrane domain (TMD; 2%). Rare splice site mut and in-frame deletions resulting in exon 16 loss (Ex16Alt) were also observed (n=76, &lt;0.1%). ERBB2 mut were found to be mutually exclusive with other RTK/MAPK driver oncogenes including: EGFR, KRAS, ALK, MET, BRAF, and RET in NSCLC; FGFR1 in breast cancer; BRAF in CRC; and FGFR3 in bladder cancer. In patient-matched liquid biopsy samples, sensitivity for detecting ERBB2 amplifications (amp; 33.3%, 43/129) was lower than for detecting ERBB2 mut (72.3%, 47/65) across select cancers. However, sensitivity for detection of both alts was improved in liquid samples with elevated ctDNA TF (≥1%), increasing to 52.6% (40/76) for amp and 97.3% (36/37) for mut. In the MSK cohort, 110 of 986 (11.2%) patients with ERBB2 mut non-NSCLC tumors received one or more HER2-targeted therapies, including ADCs. Clinical responses to HER2-targeted therapies were observed in patients harboring KD mut (n=10), ECD mut (n=6), TMD mut (V659E, n=1), and in 1 patient with a V697L mut. Conclusions: CGP detects diverse ERBB2activating alt at a high incidence in solid tumor types beyond NSCLC. These represent patient populations who may benefit from HER2-directed therapies. Trials of novel HER2-targeted agents are necessary to refine our understanding of the biological dependency of HER2 alterations.

Landscape of genomic alterations in patients with chemoradiation resistant cervical cancer using whole-genome sequencing.

e17531 Background: Cervical cancer is a pressing global health concern and ranks as the second most prevalent female malignancy in India. Unfortunately, 80% of cases are diagnosed at locally advanced stages, leading to significant morbidity and mortality. Standard treatment for locally advanced cervical cancer involves concurrent pelvic radiotherapy and chemotherapy (CCRT). However, a substantial 30%-40% of patients experience CCRT treatment failure. The genomic alterations owing to CCRT resistance are largely unknown. This pilot study aims to identify genomic alterations associated with differential responses to concurrent chemoradiotherapy in cervical cancer patients. Methods: We collected 36 fresh tissue biopsies along with 5 ml of blood from stage IIIB cervical cancer patients. From the total of 36 cervical cancer patients, based on RECIST (Response evaluation criteria in solid tumors) criteria 19 patients were classified as responders and 17 patients were categorized as non-responders to CCRT. Genomic DNA was extracted from both tumor tissue and paired blood samples. Subsequently, whole genome sequencing was performed using the Novaseq 6000 platform, achieving a sequencing depth of 30x-50x coverage with 2x150bp paired reads. The data was further analyzed for Single Nucleotide Variants (SNVs), Copy Number Alterations (CNAs), Structural Variants (SVs), and mutational signatures. Results: In our study, we identified several notable mutated genes, with MUC12 (35%), MUC4 (31%), MACF1 (27%), and OBSCN (27%) being the most prominent. The mutational spectrum encompassed well-known significantly mutated genes such as FBXW7, SPEN, PIK3CA, KMT2C, KMT2D, ARID1A, and STK11, as well as potential novel candidates, genes not previously associated with cervical cancer, such as PKHD1L1, PLEC, and LRP1B. Pathway analysis revealed that several signaling pathways were enriched in cervical cancer, including Notch signaling, Hippo signaling, and RTK/RAS signaling pathways. Mutational signature analysis revealed a prevalence of APOBEC mutagenesis pattern. Copy number alterations displayed amplifications in regions such as 3q, 9p, 14q, and 11p which encompass genes like PIK3CA, JAK2, CD274, and AKT1. Comparative analysis of genomic alterations between chemoradiation resistant and sensitive patients identified mutations in genes related to Notch signaling and TNF signaling, which were exclusively present in the non-responder group. Conclusions: This study represents an initial attempt to understand the genomic landscape of cervical cancer in Indian population using whole genome sequencing approach and its association with responses to CCRT. These findings not only pave the way for further research but also hold promise for the development of targeted therapies, offering potential enhancements in the management of chemoradiation-resistant cervical cancer patients.

236P Oncogenic fusions shape the landscape of actionable genomic alterations in pancreatic acinar cell carcinoma

236P Oncogenic fusions shape the landscape of actionable genomic alterations in pancreatic acinar cell carcinoma

‘Such a Space to Cross’: Lessons Learned(?) from Teaching During a Pandemic

ABSTRACT The COVID-19 Pandemic dramatically impacted the classroom experiences of teachers and students across the globe. This reflexive autobiographical article critically examines the ramifications of this extraordinary event on the experiences of teaching and learning for the teacher-writer and her secondary English and literature students. Through a process of narrative inquiry , the text weaves together stories of praxis during and after the extended lockdowns experienced in Victoria, Australia, with exploration of spatial and geographical metaphors through which the teacher seeks to derive meaning from her experiences of teaching while physically distanced from her students and colleagues. These reflections are theorised using Doreen Massey’s conceptualisation of space as both social and political and Michel de Certeau’s metaphor of the city map in order to illuminate the impacts of the altered learning landscape on the teacher’s professional identity during and after the COVID-19 Pandemic. In this way, the essay also offers a critical reflection on the consequences of reification in school communities that are inevitably shaped by standards-based reforms and institutional power.

Identification of the Incisive Branch of the Inferior Alveolar Nerve of Edentulous Mandibles Using Cone-Beam Computerized Tomography.

This study explored the average length of the incisive branch (IB) of the inferior alveolar nerve on cone-beam computerized tomography (CBCT) with regard to patient demographics in patients with edentulous mandibles. CBCT was used in a retrospective study of edentulous mandibles to assess the presence and anatomical variation for the IB. Three independent observers measured bilateral IB lengths. In addition to demographics, IB length and port of exit data were obtained. A 1-way analysis of variance was used to test whether IB length varied by sex or port of exit, and a standard Pearson correlation was used to test for IB length and age significance, with a significance level of P < .05. Intraclass correlation coefficients showed significant agreement in IB length across all observers. No significant difference was noted between the exit port and IB length. An important effect was reported for sex, indicating women have generally shorter IB lengths (9.43 ± 3.99 vs 10.55 ± 3.92). There was a significant correlation with age, but the relationship was weak. Edentulous mandibles have an altered anatomic landscape, and establishing predictive IB dimensions aids practitioners in surgical planning.