bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational and Functional Analyses of HER2 Mutations Reveal Allosteric Activation Mechanisms and Altered Pharmacologic Effects
Authors: Ishiyama Noboru , O'Connor Matthew , Salomatov Andrei , Romashko Darlene , Thakur Shalabh , Mentes Ahmet , Hopkins Julia F. , Frampton Garrett M. , Albacker Lee A. , Kohlmann Anna , Roberts Christopher , Buck Elizabeth 
Published: May 2022

Abstract

Amplification of HER2 can drive the proliferation of cancer cells, and several inhibitors of HER2 have been successfully developed. Recent advances in next-generation sequencing now reveal that HER2 is subject to mutation, with over 2,000 unique variants observed in human cancers. Several examples of oncogenic HER2 mutations have been described, and these primarily occur at allosteric sites outside the ATP-binding site. To identify the full spectrum of oncogenic HER2 driver mutations aside from a few well-studied mutations, we developed mutation-allostery-pharmacology (MAP), an in silico prediction algorithm based on machine learning. By applying this computational approach to 820 single-nucleotide variants, a list of 222 known and potential driver mutations was produced. Of these 222 mutations, 111 were screened by Ba/F3-retrovirus proliferation assays; 37 HER2 mutations were experimentally determined to be driver mutations, comprising 15 previously characterized and 22 newly identified oncogenic mutations. These oncogenic mutations mostly affected allosteric sites in the extracellular domain (ECD), transmembrane domain, and kinase domain of HER2, with only a single mutation in the HER2 orthosteric ATP site. Covalent homodimerization was established as a common mechanism of activation among HER2 ECD allosteric mutations, including the most prevalent HER2 mutation, S310F. Furthermore, HER2 allosteric mutants with enhanced covalent homodimerization were characterized by altered pharmacology that reduces the activity of existing anti-HER2 agents, including the mAb trastuzumab and the tyrosine kinase inhibitor lapatinib. Overall, the MAP-scoring and functional validation analyses provided new insights into the oncogenic activity and therapeutic targeting of HER2 mutations in cancer.

Significance:
This study identified new oncogenic HER2 allosteric mutations, including ECD mutations that share covalent dimerization as a mechanism of oncogenicity, suggesting the need for novel inhibitors to treat HER2-mutant cancers.
JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA
Authors: Ni Zegui , Sun Pengli , Zheng Jin , Wu Mingqing , Yang Congcong , Cheng Maosheng , Yin Mingwei , Cui Chengying , Wang Guangxian , Yuan Lin , Gao Qian , Li Yang 
Published: May 2022

Abstract

The RNA N6-methyladenosine (m6A) writer methyltransferase-like 3 (METTL3) is upregulated in many types of cancer and promotes cancer progression by increasing expression of several oncogenes. Therefore, a better understanding of the mechanisms regulating METTL3 expression and the key targets of METTL3 in cancer cells could provide new therapeutic targets. In this study, we found that activated JNK signaling is associated with increased METTL3 expression in bladder cancer. Knockdown of JNK1 or administration of a JNK inhibitor impaired the binding of c-Jun with the METTL3 promoter, thereby decreasing the expression of METTL3 and global RNA m6A levels. Moreover, RNA m6A sequencing indicated enrichment of m6A in the 3′-UTR of immune checkpoint PD-L1 mRNA, which could be recognized by the m6A reader IGF2BP1 to mediate RNA stability and expression levels of PD-L1. Inhibition of JNK signaling suppressed m6A abundance in PD-L1 mRNA, leading to decreased PD-L1 expression. Functionally, METTL3 was essential for bladder cancer cells to resist the cytotoxicity of CD8+ T cells by regulating PD-L1 expression. Additionally, JNK signaling contributed to tumor immune escape in a METTL3-dependent manner both in vitro and in vivo. These data reveal the JNK/METTL3 axis as a mechanism of aberrant m6A modification and immune regulation in bladder cancer.

Significance:
The identification of a novel m6A-dependent mechanism underlying immune system evasion by bladder cancer cells reveals JNK signaling as a potential target for bladder cancer immunotherapy.
Whole-Genome Duplication Shapes the Aneuploidy Landscape of Human Cancers
Authors: Prasad Kavya , Bloomfield Mathew , Levi Hagai , Keuper Kristina , Bernhard Sara V. , Baudoin Nicolaas C. , Leor Gil , Eliezer Yonatan , Giam Maybelline , Wong Cheng Kit , Rancati Giulia , Storchová Zuzana , Cimini Daniela , Ben-David Uri 
Published: May 2022

Abstract

Aneuploidy is a hallmark of cancer with tissue-specific prevalence patterns that suggest it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on both cellular and genomic contexts. Whole-genome duplication (WGD) is a common macroevolutionary event that occurs in more than 30% of human tumors early in tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy, it remains unknown whether WGD also affects aneuploidy prevalence patterns. Here we analyzed clinical tumor samples from 5,586 WGD− tumors and 3,435 WGD+ tumors across 22 tumor types and found distinct patterns of aneuploidy in WGD− and WGD+ tumors. WGD+ tumors were characterized by more promiscuous aneuploidy patterns, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD− and WGD+ tumors, giving rise to distinct cooccurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy compared with arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Finally, induction of WGD and assessment of aneuploidy in isogenic WGD−/WGD+ human colon cancer cell lines under standard or selective conditions validated key findings from the clinical tumor analysis, supporting a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors and propose that this interaction contributes to tumor evolution.

Significance:
These findings suggest that the interactions between whole-genome duplication and aneuploidy are important for tumor evolution, highlighting the need to consider genome status in the analysis and modeling of cancer aneuploidy.
Comprehensive Analysis of Metabolic Isozyme Targets in Cancer
Authors: Marczyk Michal , Gunasekharan Vignesh , Casadevall David , Qing Tao , Foldi Julia , Sehgal Raghav , Shan Naing Lin , Blenman Kim R.M. , O'Meara Tess A. , Umlauf Sheila , Surovtseva Yulia V. , Muthusamy Viswanathan , Rinehart Jesse , Perry Rachel J. , Kibbey Richard , Hatzis Christos , Pusztai Lajos 
Published: May 2022

Abstract

Metabolic reprogramming is a hallmark of malignant transformation, and loss of isozyme diversity (LID) contributes to this process. Isozymes are distinct proteins that catalyze the same enzymatic reaction but can have different kinetic characteristics, subcellular localization, and tissue specificity. Cancer-dominant isozymes that catalyze rate-limiting reactions in critical metabolic processes represent potential therapeutic targets. Here, we examined the isozyme expression patterns of 1,319 enzymatic reactions in 14 cancer types and their matching normal tissues using The Cancer Genome Atlas mRNA expression data to identify isozymes that become cancer-dominant. Of the reactions analyzed, 357 demonstrated LID in at least one cancer type. Assessment of the expression patterns in over 600 cell lines in the Cancer Cell Line Encyclopedia showed that these reactions reflect cellular changes instead of differences in tissue composition; 50% of the LID-affected isozymes showed cancer-dominant expression in the corresponding cell lines. The functional importance of the cancer-dominant isozymes was assessed in genome-wide CRISPR and RNAi loss-of-function screens: 17% were critical for cell proliferation, indicating their potential as therapeutic targets. Lists of prioritized novel metabolic targets were developed for 14 cancer types; the most broadly shared and functionally validated target was acetyl-CoA carboxylase 1 (ACC1). Small molecule inhibition of ACC reduced breast cancer viability in vitro and suppressed tumor growth in cell line– and patient-derived xenografts in vivo. Evaluation of the effects of drug treatment revealed significant metabolic and transcriptional perturbations. Overall, this systematic analysis of isozyme expression patterns elucidates an important aspect of cancer metabolic plasticity and reveals putative metabolic vulnerabilities.

Significance:
This study exploits the loss of metabolic isozyme diversity common in cancer and reveals a rich pool of potential therapeutic targets that will allow the repurposing of existing inhibitors for anticancer therapy.
See related commentary by Kehinde and Parker, p. 1695
Be Easy and Chill: Melanoma Cells Tell Lymph Node Fibroblasts to Relax
Authors: Lund Amanda W. 
Published: May 2022

Abstract
Melanomas coopt tumor-draining lymph nodes to support metastatic potential and install immunosuppression. The specific mechanisms that mediate lymph node education, however, remain incompletely understood. In this issue, Rovera and colleagues describe the deactivation of contractile lymph node fibroblasts by dedifferentiated melanoma cells, leading to lymph node expansion and enhanced melanoma invasive potential. Fibroblastic reticular cell relaxation depended upon inhibition of constitutive JAK1/STAT3 and YAP/TAZ signaling, which was mediated in part by tumor secretion of the inflammatory cytokine, IL1. These data support an emerging hypothesis that intrinsic melanoma heterogeneity feeds forward to drive microenvironmental adaptations that mediate invasion and progression.
See related article by Rovera et al., p. 1774
Exploiting Dependence of Castration-Resistant Prostate Cancer on the Arginine Vasopressin Signaling Axis by Repurposing Vaptans
Authors: Heidman Laine M. , Peinetti Nahuel , Copello Valeria A. , Burnstein Kerry L. 
Published: May 2022

Abstract

Men with advanced prostate cancer are treated by androgen deprivation therapy but the disease recurs as incurable castration-resistant prostate cancer (CRPC), requiring new treatment options. We previously demonstrated that the G protein–coupled receptor (GPCR) arginine vasopressin receptor type1A (AVPR1A) is expressed in CRPC and promotes castration-resistant growth in vitro and in vivo. AVPR1A is part of a family of GPCR's including arginine vasopressin receptor type 2 (AVPR2). Interrogation of prostate cancer patient sample data revealed that coexpression of AVPR1A and AVPR2 is highly correlated with disease progression. Stimulation of AVPR2 with a selective agonist desmopressin promoted CRPC cell proliferation through cAMP/protein kinase A signaling, consistent with AVPR2 coupling to the G protein subunit alpha s. In contrast, blocking AVPR2 with a selective FDA-approved antagonist, tolvaptan, reduced cell growth. In CRPC xenografts, antagonizing AVPR2, AVPR1A, or both significantly reduced CRPC tumor growth as well as decreased on-target markers of tumor burden. Combinatorial use of AVPR1A and AVPR2 antagonists promoted apoptosis synergistically in CRPC cells. Furthermore, we found that castration-resistant cells produced AVP, the endogenous ligand for arginine vasopressin receptors, and knockout of AVP in CRPC cells significantly reduced proliferation suggesting possible AVP autocrine signaling. These data indicate that the AVP/arginine vasopressin receptor signaling axis represents a promising and clinically actionable target for CRPC.

Implications:
The arginine vasopressin signaling axis in CRPC provides a therapeutic window that is targetable through repurposing safe and effective AVPR1A and AVPR2 antagonists.
Combinatorial Treatment with PARP-1 Inhibitors and Cisplatin Attenuates Cervical Cancer Growth through Fos-Driven Changes in Gene Expression
Authors: Gupte Rebecca , Lin Ken Y. , Nandu Tulip , Lea Jayanthi S. , Kraus W. Lee 
Published: May 2022

Abstract

Cervical cancer continues to be a significant cause of cancer-related deaths in women. The most common treatment for cervical cancer involves the use of the drug cisplatin in conjunction with other therapeutics. However, the development of cisplatin resistance in patients can hinder the efficacy of these treatments, so alternatives are needed. In this study, we found that PARP inhibitors (PARPi) could attenuate the growth of cells representing cervical adenocarcinoma and cervical squamous cell carcinoma. Moreover, a combination of PARPi with cisplatin increased cisplatin-mediated cytotoxicity in cervical cancer cells. This was accompanied by a dramatic alteration of the transcriptome. The FOS gene, which encodes the transcription factor Fos, was one of the most highly upregulated genes in the dual treatment condition, leading to increased Fos protein levels, greater Fos binding to chromatin, and the subsequent induction of Fos target genes. Increased expression of Fos was sufficient to hinder cervical cancer growth, as shown by ectopic expression of Fos in cervical cancer cells. Conversely, Fos knockdown enhanced cell growth. Collectively, these results indicate that by inducing FOS expression, PARPi treatment in combination with cisplatin leads to inhibition of cervical cancer proliferation, likely through a Fos-specific gene expression program.

Implications:
Our observations, which link the gene regulatory effects of PARPi + cisplatin to the growth inhibitory effects of FOS expression in cervical cancer cells, strengthen the rationale for using PARPi with cisplatin as a therapy for cervical cancer.
Lessons Learned from the Impact of COVID-19 on NCI-sponsored Cancer Prevention Clinical Trials: Moving Toward Participant-centric Study Designs
Authors: Samimi Goli , House Margaret , Benante Kelly , Bengtson Lisa , Budd Troy , Dermody Bridget , DeShong Katina , Dyer Valerie , Kimler Bruce F. , Sahasrabuddhe Vikrant V. , Siminski Suzanne , Ford Leslie G. , Vilar Eduardo , Szabo Eva 
Published: May 2022

Abstract
The COVID-19 pandemic overloaded health care systems around the globe and brought travel restrictions and other mandates. These effects critically impacted cancer care and conduct of clinical trials, and required medical and research communities to incorporate changes and novel flexible workflows within clinical trials and regulations to improve efficiency. We report the impact of the pandemic on cancer prevention clinical trials managed by the Division of Cancer Prevention within the NCI, focusing on participant-centric, study staff-centric and regulatory elements. Learning lessons from this challenging period, the cancer prevention community has the opportunity to incorporate many of these necessitated novel approaches to future design of clinical trials, to streamline and improve clinical trial efficiency and impact.
Report from an NCI Roundtable: Cancer Prevention in Primary Care
Authors: Samimi Goli , Douglas Jasmine , Heckman-Stoddard Brandy M. , Ford Leslie G. , Szabo Eva , Minasian Lori M. 
Published: May 2022

Abstract
The Division of Cancer Prevention in the NCI sponsored a Roundtable with primary care providers (PCP) to determine barriers for integrating cancer prevention within primary care and discuss potential opportunities to overcome these barriers. The goals were to: (i) assess the cancer risk assessment tools available to PCPs; (ii) gather information on use of cancer prevention resources; and (iii) understand the needs of PCPs to facilitate the implementation of cancer prevention interventions beyond routine screening and interventions. The Roundtable discussion focused on challenges and potential research opportunities related to: (i) cancer risk assessment and management of high-risk individuals; (ii) cancer prevention interventions for risk reduction; (iii) electronic health records/electronic medical records; and (iv) patient engagement and information dissemination. Time constraints and inconsistent/evolving clinical guidelines are major barriers to effective implementation of cancer prevention within primary care. Social determinants of health are important factors that influence patients' adoption of recommended preventive interventions. Research is needed to determine the best means for implementation of cancer prevention across various communities and clinical settings. Additional studies are needed to develop tools that can help providers collect clinical data that can enable them to assess patients' cancer risk and implement appropriate preventive interventions.
Validating a Simulated Emergency Course for Nurses Working in ENT
Authors: de Cates Catherine , Swords Chloe , Kenyon Olivia , MacGinley-Kerr, RN Karen , Watson, BSc, RN Katy , Smith Matthew E. , Bhargava Eishaan , Tysome James R. 
Published: May 2022

Objectives: Nurses are increasingly providing routine and emergency ENT care; yet there are often limited training opportunities. The aim of this study was to validate an intensive 1-day ENT emergency simulation course for nurses. Methods: The course included short lectures, practical skills stations and mannequin simulation scenarios. Sixteen nurse participants were video-recorded managing simulated scenarios before and after the course. Two assessors scored individual participant performance on a 15-point competency grid (maximum score 30), blinded to the timing of the recording. Participants also rated their confidence and skill before and immediately following the course across 11 items using a 5-point Likert score (maximum score 55). Results: Blinded assessor ratings for performance were significantly improved after the course compared to baseline (overall score 12 vs 7, respectively; P = .015). There was strong assessor inter-rater reliability ( R = 0.965). Self-rated skills and confidence also increased following the course (46.7 vs 24.4 at baseline; P < .01). Conclusion: Simulation-based training is an effective and desirable method of teaching ENT emergency management to nurses, with greatest impact on participant confidence. Future courses need to refine the content and increase the validation sample size using a nurse-specific scoring system.
Pediatric Low-Grade Spindle Cell Neoplasm With A Novel AK5::ALK Fusion: A Case Report
Authors: Kikawa Caroline , Ketterl Tyler G. , Liu PhD Yajuan J. , Reed Robyn C. , Dahl John P. 
Published: May 2022

Objectives: Spindle cell neoplasms (SCN) share a single commonality of spindle-shaped cells on histopathology but are diverse in etiology. Expanding our collective knowledge of these neoplasms could further research in targeted therapies. We present a case of pediatric cutaneous SCN with a novel etiology, and the methods used to identify its origination. Case Presentation and Results: A 1.5-year-old child presented with a 7-month history of a rapidly enlarging, erythematous, non-painful scalp mass without ulceration or bleeding. The child underwent ultrasound and magnetic resonance imaging, revealing a 2.9 × 3 × 2 cm vascular mass without intracranial connections. The mass was successfully resected at surgery. Subsequent histopathologic and genetic testing indicated a SCN harboring a previously undescribed gene rearrangement between adenylate kinase 5 (AK5) and anaplastic lymphoma kinase (ALK). The patient received close clinical follow-up and at 6 months post-surgery had no recurrent disease. Conclusions: ALK rearrangements are common amongst many tumor types, but to our knowledge, AK5::ALK rearrangement has never been reported in SCN. Considering the rapid development of targeted clinical therapies, including those targeting ALK activity, this finding could be significant in the treatment of future patients with similar clinicopathologic and genetic presentation.
Stensen's Duct Stenosis Balloon Dilatation: Long‐term Evaluation of Clinical Outcomes and Quality of Life Impacts
Authors: de Boutray Marie , Pons Mélanie , Graillon Nicolas , Chossegros Cyrille , Reyre Anthony , Chagnaud Christophe , Varoquaux Arthur 
Published: May 2022

AbstractObjectiveTo conduct a long‐term retrospective evaluation of the safety and effectiveness of sialographic balloon dilatation in Stensen's duct stenosis (SDS).Study DesignRetrospective cohort.SettingSingle‐institution academic tertiary referral center.MethodsAll SDS balloon dilatations (SSBDs) performed from 2011 to 2017 were monitored. Pain relief was evaluated by a numeric rating scale at 3‐year follow‐up at least. Long‐term glandular swelling frequency patterns, quality of life (QoL), and drug consumption were retrospectively assessed. Procedure‐related complications were recorded.ResultsTwenty‐one SSBD procedures were recorded (mean ± SD age, 55 ± 12 years), all performed under local anesthesia. SSBD led to complete dilatation in 7 patients (33%), residual stenosis in 8 (38%), and no dilatation (failure) in 6 (29%). Retrospective analysis of clinical outcomes was possible for 17 patients, 71% of whom presented with long‐term pain relief, at a mean relief of 3.2 points on the numeric rating scale (P < .001). Long after SSBD, patients presented with a mean decrease of 15.4 glandular swellings per month (P < .001). Medical consumption was reduced to 18% of patients taking some drugs because of SDS after SSBD vs 71% before. SSBD showed an impact on QoL in >80% of patients, with mean improvements of 26% and 25% in the percentage point reduction of physical and mental QoL, respectively (P < .001). No complications were noted except temporary discomfort due to the procedure.ConclusionDespite the advent of sialendoscopy‐guided techniques, SSBD should be considered for SDS treatment, as it is a safe procedure and provides sustained pain relief.
Effectiveness of Surgical Mandibular Advancement in Improving Airway Dimensions in Nongrowing Skeletal Class II Patients With Obstructive Sleep Apnea—A CBCT Study
Authors: Waghchaure Saurabh S. , Bhad Wasundhara A. , Chavan Santosh J. , Mehta Niyati , Baheti Nikita 
Published: May 2022

Background: Skeletal nongrowing class II patients with retrognathic mandible are often at risk of developing obstructive sleep apnea (OSA). This skeletal discrepancy, when severe enough, is often addressed by surgical mandibular advancement which not only achieves aesthetics, structural balance, and functional efficiency but also improves the airway function. Objective: The aim of the study was to evaluate the effectiveness of surgical mandibular advancement on airway dimensions, in nongrowing skeletal class II patients with mandibular retrognathism associated with OSA. Materials and Methods: The sample consisted of 8 patients with skeletal class II due to retrognathic mandible associated with OSA. Screening was done with functional outcomes of sleep questionnaire (FOSQ) score and confirmed with polysomnography. Pretreatment and posttreatment airway dimensions/volume were assessed and calculated on cone beam computed tomography (CBCT). Three months post surgery, oxygen saturation was recorded. Results: A statistically significant improvement in mean oxygen saturation level was observed from 87.62 ± 7.70 to 97.75 ± 0.46 and mean increase in airway volume was from 48.60 ± 7.17 to 69.48 ± 26.22. The smallest cross section increased from 137 ± 74.37 to 253.75 ± 76.67. Anteroposterior dimensions increased significantly from 6.17 ± 1.78 to 9.33 ± 2.07 and transversed from 24.56 ± 6.41 to 30.14 ± 3.35. FOSQ score improved from 9.37 ± 2.61 to 15.25 ± 0.88. Conclusion: Surgical mandibular advancement is an effective treatment option in improving airway dimensions in nongrowing skeletal class II patients with mandibular retrognathism associated with OSA.