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Sidra Zafar,1 Jack S Parker,2,3 Christa de Kort,3,4 Gerrit Melles,3,4 Shameema Sikder11Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD, USA; 2Parker Cornea, Birmingham, AL, USA; 3Netherlands Institute for Innovative Ocular Surgery-United States of America, San Diego, CA, USA; 4Melles Cornea Clinic, Rotterdam, NetherlandsPurpose: To determine barriers related to implementation of Descemet’s membrane endothelial keratoplasty (DMEK) among corneal surgeons.Methods: This was a multicenter survey study of all corneal surgeons who participated in a DMEK wet lab organized by the Netherlands Institute for Innovative Ocular Surgery. Data related to barriers limiting uptake of DMEK surgery, self-perceived levels of competence, and difficulty with different steps of DMEK surgery were analyzed.Results: The survey response rate was 31% (22 of 72). The most common barrier to uptake of DMEK surgery identified was anxiety related to incorrect insertion of the tissue and the need to regraft (64%, 14 of 22), followed by anxiety related to tissue preparation (50%, eleven of 22). Surgeons also felt anxious regarding the possibility of rebubbling with initial DMEK (41%, nine of 22). Steps related to DMEK graft (76%) preparation, tissue insertion (41%), and graft unfolding (72%) were identified as the most difficult steps to learn by the respondents.Conclusion: The DMEK learning curve, especially for the novice surgeon, may be shortened by seeking educational resources, including wet labs and surgical videos. Eye banks may facilitate adoption of DMEK by making validated DMEK tissue more accessible to surgeons globally.Keywords: DMEK, uptake, barriers, difficulties

Basal-like breast cancers represent approximately 15%-20% of all breast carcinomas, are aggressive, have variable responses to chemotherapy, and associated with poor clinical outcome. The molecular mechanisms governing the biological behavior of basal-like breast cancers are not well understood. Hence, it is difficult to predict which chemotherapeutics are most likely to be effective and to determine appropriate management strategies for individual patients. Transcriptomic analysis may allow further stratification of basal-like breast cancers enabling prediction of 1) cancer recurrence after surgery; 2) likelihood of metastatic spread; 3) probable tissue sites for metastatic spread; and 4) responses to specific therapies and treatment modalities. Furthermore, careful examination of microarray-based gene expression profiles may identify new molecular targets (or pathways) for the development of targeted therapeutics. Targeted therapies may prove to be more efficacious in basal-like breast cancer treatment than the cytotoxic chemotherapeutics currently employed. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this study was to explore if and then how nurse practitioners (NPs) living in federally designated nonmetropolitan areas of North Carolina integrated spiritual care into their practices. Participants identified the frequency in which they utilize spiritual care practices, specific spiritual interventions, and their definitions of spiritual care. DATA SOURCES: A sample of 101 NPs was chosen through systematic sampling from 507 eligible NPs. Each participant was mailed a demographic data sheet and the Nurse Practitioner Spiritual Care Perspective Survey (NPSCPS). The NPSCPS was modified from the Oncology Nurse Spiritual Care Perspective Scale developed by Taylor and colleagues. Of the 101 mailings, 65 were returned and included in the analysis. CONCLUSIONS: Although most of the NPs in this study felt that spiritual care was an important part of nursing practice, 73% did not routinely provide spiritual care to their patients. Barriers and limitations to the provision of spiritual care must be explored. IMPLICATIONS FOR PRACTICE: As providers of holistic care, NPs should be proficient and comfortable in providing spiritual care to their patients. Educational programs should provide NPs and NP students with knowledge and skills to provide spiritual care. [ABSTRACT FROM AUTHOR]

A multiple case questionnaire/interview study was used to investigate Extraordinary Experiences (EEs) reported by bereaved individuals. Its purpose was to describe the grief processes of 12 bereaved individuals who had reported EEs. Content analysis consisted of a series of individual case data displays and causal networks from which an overall causal network that described participants' grief processes was derived. Despite some ongoing grief work and complicated grief patterns, 11 participants had reached an adaptive grief outcome. For these individuals, EEs played specific roles and fulfilled specific needs within and outside of the context of bereavement. EEs also facilitated the assimilation/accommodation of death by reinforcing participants' 'personal mythologies' regarding death and an after-life. The findings of this study support the emerging model of grief that posits that maintaining continuing bonds with the deceased can be adaptive. They also support the assertion that spiritual and/or religious belief systems are associated with adaptive outcomes of grief. [ABSTRACT FROM AUTHOR]

The present study examined parental support and monitoring as they relate to adolescent outcomes. It was hypothesized that support and monitoring would be associated with higher self-esteem and less risky behavior during adolescence. The diverse sample included 16,749 adolescents assessed as part of the National Educational Longitudinal Study. Both high parental support and parental monitoring were related to greater self-esteem and lower risk behaviors. The findings partially confirm, as well as extend, propositions in attachment theory. [ABSTRACT FROM AUTHOR]

Discusses four closely replication origin activator-related cDNA isolated from maize, ZmROA1-4, along with a promoter sequence for one of them. Protein localization in cycling cells; Cloning of the cDNA encoding full-length protein; Genomic cloning; Imnmunocytochemistry.

Background: Identification of biomarkers to optimize treatment strategies for early-stage triple-negative breast cancer (TNBC) is crucial. This study presents the development and validation of TNBC-DX, a novel test aimed at predicting both short- and long-term outcomes in early-stage TNBC., Methods: Information from 1,259 patients with early-stage TNBC (SCAN-B, CALGB-40603, and BrighTNess) were used to establish the TNBC-DX scores. Independent validation of TNBC-DX was carried out in 3 studies: i) WSG-ADAPT-TN, ii) MMJ-CAR-2014-01, and iii) NeoPACT, including 527 patients with stage I-III TNBC undergoing neoadjuvant chemotherapy. In WSG-ADAPT-TN, patients were randomized to receive nab-paclitaxel plus gemcitabine or carboplatin. In MMJ-CAR-2014-01, patients received carboplatin plus docetaxel. In NeoPACT, patients received carboplatin plus docetaxel and pembrolizumab. The objective of this study was to evaluate the association between TNBC-DX and efficacy outcomes (pCR, distant disease-free survival [DDFS] or event-free survival [EFS], and overall survival [OS]) in the validation cohorts., Results: TNBC-DX test was created incorporating 10-gene core immune gene module, 4-gene tumor cell proliferation signature, tumor size, and nodal staging. In the 2 independent validation cohorts without pembrolizumab, the TNBC-DX pCR score was significantly associated with pCR after adjustment for clinicopathological variables and treatment regimen (odds ratio per 10-units increment=1.34, 95% CI 1.20-1.52, p<0.001). pCR rates for the TNBC-DX pCR-high, -medium, and -low categories were 56.3%, 53.6%, and 22.5% respectively (odds ratio for pCR-high vs pCR-low=3.48 [95% CI 1.72-7.15], p<0.001). Additionally, the TNBC-DX risk score was significantly associated with DDFS (hazard ratio [HR] high-risk vs low-risk=0.24, 95% CI 0.15-0.41, p<0.001) and OS (HR=0.19, 95% CI 0.11-0.35, p<0.001). In the validation cohort with pembrolizumab, the TNBC-DX scores were significantly associated with pCR, EFS, and OS., Conclusions: TNBC-DX predicts pCR to neoadjuvant taxane-carboplatin in stage I-III TNBC and helps to forecast the patient´s long-term survival in the absence of neoadjuvant anthracycline/cyclophosphamide, and independent of pembrolizumab use., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

It is important for researchers to understand the factors that attract marginalized community members to participate in youth service intervention programs, considering their historic mistrust in White-dominated systems (i.e., education and mental health). We employed a hermeneutic phenomenology study to understand 15 Black caregivers' experiences of a university-church partnership program that was grounded in a school mental health paradigm. Using individual interviews and a structured coding process, we examined factors that informed participants' engagement with the program from start to finish. First, caregivers initiated involvement with the program due to their children's holistic needs, the accessibility of the program, and the trust they had in program leaders (including church representatives) and processes. Second, caregivers sustained involvement in the program due to graduate interventionists/mentors displaying professional competence, cultural responsiveness, and an ethic of care. Finally, caregivers viewed the program as helping the children, family, and community thrive , which influenced their desire to see the program grow and expand. As informed by the present study and related literature, recommendations for school mental health professionals involved in culturally responsive and equity-centered community partnership work are offered. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Purpose: The purpose of this study was to assess the predictive capability of HER2DX assay following (neo)adjuvant trastuzumab-pertuzumab (HP)-based therapy in HER2-positive (HER2+) early breast cancer., Experimental Design: HER2DX was analyzed in baseline pretreatment tumors from the PHERGain trial. Patients with stage I-IIIA HER2+ early breast cancer were randomized to group A [docetaxel, carboplatin, and HP (TCHP)] and group B (HP ± endocrine therapy). PET response was evaluated after two cycles. Group A received TCHP for six cycles regardless of PET response. Group B continued with HP ± endocrine therapy for six cycles (PET responders) or with TCHP for six cycles (PET nonresponders). The primary objective of this retrospective study was to associate the HER2DX pathologic complete response (pCR) score with pCR. The secondary objective was the association of the HER2DX risk score with 3-year invasive disease-free survival (iDFS)., Results: HER2DX was performed on 292 (82.0%) tumors. The overall pCR rate was 38.0%, with pCR rates of 56.4% in group A and 33.8% in group B. In multivariable analysis including treatment and clinicopathologic factors, the HER2DX pCR score (continuous variable) significantly correlated with pCR [OR, 1.29; 95% confidence interval (CI), 1.10-1.54; P < 0.001]. HER2DX-defined pCR-high, -med, and -low groups exhibited pCR rates of 50.4%, 35.8%, and 23.2%, respectively (pCR-high vs. pCR-low OR, 3.27; 95% CI, 1.54-7.09; P < 0.001). In patients with residual disease, the HER2DX high-risk group demonstrated numerically worse 3-year iDFS than the low-risk group (89.8% vs. 100%; HR, 2.70; 95% CI, 0.60-12.18; P = 0.197)., Conclusions: HER2DX predicts pCR in the context of neoadjuvant HP-based therapy, regardless of chemotherapy addition, and might identify patients at higher risk of recurrence among patients with residual disease., (©2024 The Authors; Published by the American Association for Cancer Research.)

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., (© 2024. The Author(s).)

Annotation of the cis -regulatory elements that drive transcriptional dysregulation in cancer cells is critical to improving our understanding of tumor biology. Herein, we present a compendium of matched chromatin accessibility (scATAC-seq) and transcriptome (scRNA-seq) profiles at single-cell resolution from human breast tumors and healthy mammary tissues processed immediately following surgical resection. We identify the most likely cell-of-origin for luminal breast tumors and basal breast tumors and then introduce a novel methodology that implements linear mixed-effects models to systematically quantify associations between regions of chromatin accessibility (i.e. regulatory elements) and gene expression in malignant cells versus normal mammary epithelial cells. These data unveil regulatory elements with that switch from silencers of gene expression in normal cells to enhancers of gene expression in cancer cells, leading to the upregulation of clinically relevant oncogenes. To translate the utility of this dataset into tractable models, we generated matched scATAC-seq and scRNA-seq profiles for breast cancer cell lines, revealing, for each subtype, a conserved oncogenic gene expression program between in vitro and in vivo cells. Together, this work highlights the importance of non-coding regulatory mechanisms that underlie oncogenic processes and the ability of single-cell multi-omics to define the regulatory logic of BC cells at single-cell resolution., Competing Interests: Declaration of interests C.M.P is an equity stockholder and consultant of BioClassifier LLC; C.M.P is also listed as an inventor on patent applications for the Breast PAM50 Subtyping assay.

Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus, often diagnosed late because of its challenging symptoms and costly and invasive diagnostic methods. 1,2 To address the need for more accessible biomarkers in EoE, 3 we aimed to investigate the potential of whole-blood RNA expression as a noninvasive biomarker for diagnosing and monitoring EoE, hypothesizing that genetic signatures in blood could distinguish EoE cases, correlate with disease activity, and predict treatment responses., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Early-stage triple-negative breast cancer (TNBC) displays clinical and biological diversity. From a biological standpoint, immune infiltration plays a crucial role in TNBC prognosis. Currently, there is a lack of genomic tools aiding in treatment decisions for TNBC. This study aims to assess the effectiveness of a B-cell/immunoglobulin signature (IGG) alone, or in combination with tumor burden, in predicting prognosis and treatment response in patients with TNBC., Methods: Genomic and clinical data were retrieved from 7 cohorts: SCAN-B (N = 874), BrighTNess (n = 482), CALGB-40603 (n = 389), METABRIC (n = 267), TCGA (n = 118), GSE58812 (n = 107), GSE21653 (n = 67). IGG and a risk score integrating IGG with tumor/nodal staging (IGG-Clin) were assessed for event-free survival (EFS) and overall survival (OS) in each cohort. Random effects model was used to derive pooled effect sizes. Association of IGG with pathological complete response (pCR) was assessed in CALGB-40603 and BrighTNess. Immune significance of IGG was estimated through CIBERSORTx and EcoTyper., Findings: IGG was associated with improved EFS (pooled HR = 0.77, [95% CI = 0.70-0.85], I 2  = 18%) and OS (pooled HR = 0.79, [0.73-0.85], I 2  = 0%) across cohorts, and was predictive of pCR in CALGB-40603 (OR 1.25, [1.10-1.50]) and BrighTNess (OR 1.57 [1.25-1.98]). IGG-Clin was predictive of recurrence (pooled HR = 2.11, [1.75-2.55], I 2  = 0%) and death (pooled HR = 1.99, 95% [0.84-4.73], I 2  = 79%) across cohorts. IGG was associated with adaptive immune response at CIBERSORTx and EcoTyper analysis., Interpretation: IGG is linked to improved prognosis and pCR in early-stage TNBC. The integration of IGG alongside tumor and nodal staging holds promise as an approach to identify patients benefitting from intensified or de-intensified treatments., Funding: This study received funding from: Associació Beca Marta Santamaria, European Union's Horizon 2020 research and innovation and Marie Skłodowska-Curie Actions programs, Fundación FERO, Fundación CRIS contra el cáncer, Agència de Gestó d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Fundación Contigo, Asociación Cáncer de Mama Metastásico IV, Breast Cancer Research Foundation, RESCUER, Fundación científica AECC and FSEOM., Competing Interests: Declaration of interests B. Conte reports speaker fees from Veracyte and payment for educational events from Medsite and Novartis. A. Prat reports consulting fees from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc and Lilly, lecture fees from Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies and Daiichi Sankyo; patents filed PCT/EP2016/080056, PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369; stockholder and consultant of Reveal Genomics, SL; and institutional financial interests from Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, Medica Scientia Innovation Research, SL, Celgene, Astellas and Pfizer. F. Schettini has declared consulting fees from Pfizer, honoraria for lectures from Novartis, Gilead and Daiichy Sankyo, and travel expenses from Novartis and Daiichy Sankyo. O. Martínez-Sáez has declared institutional grants from Roche; personal consulting fees from Roche and Reveal Genomics; honoraria for presentations by Daiichi Sankyo, Pierre Fabre, and Reveal Genomics; and travel expenses by Gilead, Pierre Fabre, Novartis, and MSD. A. Vivancos has declared institutional grants from Bristol Meyers Squibb, Incyte, and Roche; personal consulting fees from Bayer, Bristol Meyers Squibb (BMS); Guardant, Incyte, and Roche; and personal stock options from Reveal Genomics. F. Brasó-Maristany has patents filed: PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369. J. Parker as declared individual and institutional royalties from Veracyte–Prosigna, consulting fees from Bristol Meyers Squibb, Reveal Genomics, and GeneCentric, and holds a patent for breast cancer subtyping. Additionally, he has an equity interest in Reveal Genomics. M. Vidal has declared honoraria for presentations from Novartis, Roche, Pfizer, and Daichii, and travel expenses from Roche and Pfizer. Additionally, she has participated on a Data Safety Monitoring Board or Advisory Board for Novartis and Roche. C. Perou has declared consulting fees and personal stock options from Reveal Genomics. T. Pascual has declared consulting fees from Novartis; honoraria from Novartis, Astra-zeneca, Veracyte, and Argenetics. I. Garcia-Fructuoso has declared honoraria for presentations from Novartis, Daiichi Sankyo, Esteve, GSK; and travel expenses from Novartis, Gilead, Daiichi Sankyo, Lilly, and BMS. L. Paré has declared contract from Reveal Genomics, a HER2DX patent filed (PCT/EP2022/086493), and the TNBCDX patent filed (EP23382703.9). M. Marín-Aguilera has declared contract from Reveal Genomics. P. Villagrasa has declared contract and personal stock options from Reveal Genomics, the HER2DX patent filed (PCT/EP2022/086493), and the DNADX patent filed (EP22382387.3). G. Villacampa has received a speaker's fee from Merck Sharp & Dohme, Pfizer, GlaxoSmithKline and Pierre Fabrer, and received consultant fees from Reveal Genomics. C. Falato is currently employed in AstraZeneca. The remaining authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: HER2DX, a multianalyte genomic test, has been clinically validated to predict breast cancer recurrence risk (relapse risk score), the probability of achieving pathological complete response post-neoadjuvant therapy (pCR likelihood score), and individual ERBB2 messenger RNA (mRNA) expression levels in patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This study delves into the comprehensive analysis of HER2DX's analytical performance., Materials and Methods: Precision and reproducibility of HER2DX risk, pCR, and ERBB2 mRNA scores were assessed within and between laboratories using formalin-fixed paraffin-embedded (FFPE) tumor tissues and purified RNA. Robustness was appraised by analyzing the impact of tumor cell content and protocol variations including different instruments, reagent lots, and different RNA extraction kits. Variability was evaluated across intratumor biopsies and genomic platforms [RNA sequencing (RNAseq) versus nCounter], and according to protocol variations., Results: Precision analysis of 10 FFPE tumor samples yielded a maximal standard error of 0.94 across HER2DX scores (1-99 scale). High reproducibility of HER2DX scores across 29 FFPE tumors and 20 RNAs between laboratories was evident (correlation coefficients >0.98). The probability of identifying score differences >5 units was ≤5.2%. No significant variability emerged based on platform instruments, reagent lots, RNA extraction kits, or TagSet thaw/freeze cycles. Moreover, HER2DX displayed robustness at low tumor cell content (10%). Intratumor variability across 212 biopsies (106 tumors) was <4.0%. Concordance between HER2DX scores from 30 RNAs on RNAseq and nCounter platforms exceeded 90.0% (Cohen's κ coefficients >0.80)., Conclusions: The HER2DX assay is highly reproducible and robust for the quantification of recurrence risk, pCR likelihood, and ERBB2 mRNA expression in early-stage HER2-positive breast cancer., Competing Interests: Disclosure MMA is an employee at Reveal Genomics; GV has received a speaker’s fee from MSD, Pfizer, GSK, and Pierre Fabrer, has held an advisory role with AstraZeneca, and received consultant fees from Reveal Genomics; FBM has a HER2DX patent application EP21383165; PG is an employee at Reveal Genomics; OMS has declared travel expenses and consulting fees from Roche and Reveal, and speaker fees from Eisai, Daiichi, and Novartis; KP serves on the Scientific Advisory Board of Novartis, Ideaya Biosciences, and Scorpion Therapeutics, holds equity options in Scorpion Therapeutics and Ideaya Biosciences, and receives sponsored research funding from Novartis through DFCI; and has patents on S100A7 antibody and BET inhibitor resistance held by DFCI; JM is an employee at Reveal Genomics; WB is an employee at Reveal Genomics; CMP is an equity stockholder and consultant of BioClassifier LLC, and for Reveal Genomics, is also listed as an inventor on patent applications for the Breast PAM50 assay; PVG is one of the stockholders of Reveal Genomics; AP reports advisory and consulting fees from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc, and Lilly, lecture fees from Roche, Pfizer, Novartis, Amgen, BMS, and Daiichi Sankyo, institutional financial interests from Novartis, Roche, and Pfizer, stockholder and consultant of Reveal Genomics, SL; AP is also listed as an inventor on patent applications for the HER2DX assay; JSP is an equity stockholder and consultant for Reveal Genomics and is also listed as an inventor on patent applications for the Breast PAM50 assay; LP is listed as an inventor on HER2DX patent PCT/EP2021/070788 and is an employee at Reveal Genomics. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The HER2DX risk-score has undergone rigorous validation in prior investigations involving patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer. In this study, we present the outcomes of the HER2DX risk-score within the most recent release of the Sweden Cancerome Analysis Network-Breast (SCAN-B) HER2+ cohort. This updated examination benefits from a larger patient sample, an extended follow-up duration, and detailed treatment information., Materials and Methods: Clinical and RNAseq data from the SCAN-B dataset were retrieved from Gene Expression Omnibus (GSE81538). Among the 6600 patients, 819 had HER2+ breast cancer, with 757 individuals with research-based HER2DX risk-scores and corresponding survival outcomes. The HER2DX risk-score was evaluated (i) as a continuous variable and (ii) using predefined cut-offs. The primary endpoint for this study was overall survival (OS). The Kaplan-Meier method and Cox models were used to estimate OS and a multistate model with four states was fitted to better characterize patients' follow-up., Results: The median follow-up time was 7.5 years (n = 757). The most common systemic therapy was chemotherapy with trastuzumab (82.0%) and most tumors were classified as T1-T2 (97.1%). The HER2DX risk-score as a continuous variable was significantly associated with OS after adjustment for clinical variables and treatment regimen [hazard ratios (HR) per 10-unit increment = 1.31, 95% confidence interval (CI) 1.13-1.51, P < 0.001] as well as within predefined risk groups (high versus low; HR = 2.57, 95% CI 1.36-4.85, P < 0.001). Patients classified as HER2DX high-risk also had higher risk of (i) breast cancer recurrence and (ii) death without previous recurrence. Within the subgroup of HER2+ T1N0 tumors (n = 297), those classified as high-risk demonstrated inferior OS compared to low-risk tumors (7-year OS 77.8% versus 96.8%, P < 0.001). The HER2DX mRNA ERBB2 score was associated with clinical HER2 status (area under the receiver operating characteristic curve = 0.91)., Conclusions: In patients with early-stage HER2+ breast cancer, HER2DX risk-score provides prognostic information beyond clinicopathological variables, including treatment regimen with or without trastuzumab., Competing Interests: Role of the funder In addition to financial support, the funders actively contributed to various aspects of the research, including study design, data collection, analysis, interpretation, and report writing. Disclosure GV has received a speaker’s fee from MSD, Pfizer, GSK, and Pierre Fabre; has held an advisory role with AstraZeneca; and received consultant fees from Reveal Genomics. TP has received honoraria for speaker activities from AstraZeneca, Pfizer, Novartis, Veracyte, and Argenetics, and has held an advisory role with Novartis. FBM has a patent application (EP21383165). LP is listed as an inventor on patent PCT/EP2021/070788. OMS has declared travel expenses and consulting fees from Roche and Reveal, and speaker fees from Eisai, Daiichi-Sankyo, and Novartis. JC has ownership interests in MedSIR, Nektar, and Leuko; has held consulting or advisory roles in Celgene, Cellestia Biotech, AstraZeneca, Roche, Seattle Genetics, Daiichi-Sankyo, ERYTECH Pharma, Polyphor, Athenex, Lilly, Servier, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Clovis Oncology, Bioasis, Boehringer Ingelheim, Ellipses Pharma, HiberCell, Bioinvent, GEMoaB, Gilead Sciences, Menarini, Zymeworks, and Reveal Genomics; has received research funding from ARIAD, AstraZeneca, Baxalta, Bayer, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, Puma Biotechnology, Queen Mary University of London, Roche, and Piqur; has patents, royalties, or other intellectual property from pharmaceutical combinations of a Pi3k Inhibitor and a microtubule destabilizing agent (Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A, Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés. US 2019/ 0338368 A1); and has received travel expenses from Roche, Pfizer, Eisai, Novartis, Daiichi-Sankyo, and Gilead Sciences. EC has received honoraria for advisory roles from Pfizer, AstraZeneca, Daiichi-Sankyo, Roche, Novartis, Lilly, and MSD; and has received a speaker’s fee from Roche and Lilly. MM reports research grants from Puma; consulting/advisory fees from Roche, Novartis, AstraZeneca, Daiichi-Sankyo, Seagen, Lilly, and Sanofi; speakers’ honoraria from Seagen, Lilly, AstraZeneca, Pfizer, Daiichi-Sankyo, and Roche; a leadership or fiduciary role as Chairman, GEICAM and as a member of the Board of Directors for TRIO. PC reports speakers’ bureaus with AstraZeneca, GlaxoSmithKline, Novartis, and Roche; travel, accommodation, and expenses from Celgene, GlaxoSmithKline, and Novartis; and research funding from Merck Serono, Novartis, and Roche. LAC reports participation on a Data Safety Monitoring Board or Advisory Board of Sanofi Aventis, Novartis, Genentech/Roche, GSK, AstraZeneca/Daiichi-Sankyo, and Aptitude Health; and has a spouse serving on the board of Falcon Therapeutics and spouse involvement in a neural stem cell therapy patent. NH received consulting fees from Pierre Fabre and Roche. AV has the DNADX patent filed (EP22382387.3). GC served as consultant or advisor for Roche, Lilly, and Bristol-Myers Squibb; served on the speaker’s bureau for Roche, Pfizer, and Lilly; received travel funding from Pfizer and Roche; and received honoraria from Roche, Pfizer, Lilly, Novartis, and Seagen, all outside the submitted work. PV is one of the stockholders of Reveal Genomics, and also reports personal fees from NanoString. JSP is an equity stockholder and consultant for Reveal Genomics and is listed as an inventor on patent applications for the Breast PAM50 assay. CMP is an equity stockholder and consultant of BioClassifier LLC and Reveal Genomics, and is listed as an inventor on patent applications for the Breast PAM50 assay. AP reports advisory and consulting fees from Roche, Pfizer, Novartis, Amgen, Bristol-Myers Squibb, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc, and Lilly; lecture fees from Roche, Pfizer, Novartis, Amgen, Bristol-Myers Squibb, NanoString Technologies, and Daiichi-Sankyo; institutional financial interests from Boehringer, Novartis, Roche, NanoString, Sysmex Europa GmbH, Medica Scientia Innovation Research, SL, Celgene, Astellas, and Pfizer; is a stockholder and consultant of Reveal Genomics and SL; and is listed as an inventor on patent applications for the HER2DX assay. SMT reports consulting or advisory roles for Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol-Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi-Sankyo, Gilead, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Sumitovant Biopharma, Zetagen, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Biopharma, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, and Hengrui USA; research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol-Myers Squibb, Eisai, AstraZeneca, Gilead, NanoString Technologies, Seattle Genetics, and OncoPep; and travel support from Eli Lilly, Sanofi, Gilead, and Pfizer. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Biphenyl-fused-dioxacyclodecynes are a promising class of strained alkyne for use in Cu-free 'click' reactions. In this paper, a series of functionalised derivatives of this class of reagent, containing fluorescent groups, are described. Studies aimed at understanding and increasing the reactivity of the alkynes are also presented, together with an investigation of the bioconjugation of the reagents with an azide-labelled protein.

The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease., (© 2023. The Author(s).)

Purpose: The TNT trial (NCT00532727) showed no evidence of carboplatin superiority over docetaxel in metastatic triple-negative breast cancer (mTNBC), but carboplatin benefit was observed in the germline BRCA1/2 mutation subgroup. Broader response-predictive biomarkers are needed. We explored the predictive ability of DNA damage response (DDR) and immune markers., Experimental Design: Tumor-infiltrating lymphocytes were evaluated for 222 of 376 patients. Primary tumors (PT) from 186 TNT participants (13 matched recurrences) were profiled using total RNA sequencing. Four transcriptional DDR-related and 25 immune-related signatures were evaluated. We assessed their association with objective response rate (ORR) and progression-free survival (PFS). Conditional inference forest clustering was applied to integrate multimodal data. The biology of subgroups was characterized by 693 gene expression modules and other markers., Results: Transcriptional DDR-related biomarkers were not predictive of ORR to either treatment overall. Changes from PT to recurrence were demonstrated; in chemotherapy-naïve patients, transcriptional DDR markers separated carboplatin responders from nonresponders (P values = 0.017; 0.046). High immune infiltration was associated with docetaxel ORR (interaction P values < 0.05). Six subgroups were identified; the immune-enriched cluster had preferential docetaxel response [62.5% (D) vs. 29.4% (C); P = 0.016]. The immune-depleted cluster had preferential carboplatin response [8.0% (D) vs. 40.0% (C); P = 0.011]. DDR-related subgroups were too small to assess ORR., Conclusions: High immune features predict docetaxel response, and high DDR signature scores predict carboplatin response in treatment-naïve mTNBC. Integrating multimodal DDR and immune-related markers identifies subgroups with differential treatment sensitivity. Treatment options for patients with immune-low and DDR-proficient tumors remains an outstanding need. Caution is needed using PT-derived transcriptional signatures to direct treatment in mTNBC, particularly DDR-related markers following prior chemotherapy., (©2023 The Authors; Published by the American Association for Cancer Research.)

Obesity promotes triple-negative breast cancer (TNBC), and effective interventions are urgently needed to break the obesity-TNBC link. Epidemiologic studies indicate that bariatric surgery reduces TNBC risk, while evidence is limited or conflicted for weight loss via low-fat diet (LFD) or calorie restriction (CR). Using a murine model of obesity-driven TNBC, we compared the antitumor effects of vertical sleeve gastrectomy (VSG) with LFD, chronic CR, and intermittent CR. Each intervention generated weight and fat loss and suppressed tumor growth relative to obese mice (greatest suppression with CR). VSG and CR regimens exerted both similar and unique effects, as assessed using multiomics approaches, in reversing obesity-associated transcript, epigenetics, secretome, and microbiota changes and restoring antitumor immunity. Thus, in a murine model of TNBC, bariatric surgery and CR each reverse obesity-driven tumor growth via shared and distinct antitumor mechanisms, and CR is superior to VSG in reversing obesity's procancer effects.

Purpose: To improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit by developing a risk model that incorporates the gene expression-based "intrinsic" subtypes luminal A, luminal B, HER2-enriched, and basal-like., Methods: A 50-gene subtype predictor was developed using microarray and quantitative reverse transcriptase polymerase chain reaction data from 189 prototype samples. Test sets from 761 patients (no systemic therapy) were evaluated for prognosis, and 133 patients were evaluated for prediction of pathologic complete response (pCR) to a taxane and anthracycline regimen., Results: The intrinsic subtypes as discrete entities showed prognostic significance ( P = 2.26E-12) and remained significant in multivariable analyses that incorporated standard parameters (estrogen receptor status, histologic grade, tumor size, and node status). A prognostic model for node-negative breast cancer was built using intrinsic subtype and clinical information. The C-index estimate for the combined model (subtype and tumor size) was a significant improvement on either the clinicopathologic model or subtype model alone. The intrinsic subtype model predicted neoadjuvant chemotherapy efficacy with a negative predictive value for pCR of 97%., Conclusion: Diagnosis by intrinsic subtype adds significant prognostic and predictive information to standard parameters for patients with breast cancer. The prognostic properties of the continuous risk score will be of value for the management of node-negative breast cancers. The subtypes and risk score can also be used to assess the likelihood of efficacy from neoadjuvant chemotherapy.

Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sanz, Weideman, Ward, Clohosey, Garcia-Recio, Selitsky, Mann, Iannone, Whitworth, Chitrakar, Garrido, Kirchherr, Coffey, Tsai, Samir, Xu, Copertino, Bosque, Jones, Parker, Hudgens, Goonetilleke and Soriano-Sarabia.)

Background: The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status., Materials and Methods: Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status., Results: HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk., Conclusions: HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)