Medicine and Health Sciences Commons^™

Tmsb4y Is A Candidate Tumor Suppressor On The Y Chromosome And Is Deleted In Male Breast Cancer., Hong Yuen Wong, Grace M Wang, Sarah Croessmann, Daniel J Zabransky, Anita Aggarwal, Min-Ling Liu, + 10 More

Pathology Faculty Publications

Male breast cancer comprises less than 1% of breast cancer diagnoses. Although estrogen exposure has been causally linked to the development of female breast cancers, the etiology of male breast cancer is unclear. Here, we show via fluorescence in situ hybridization (FISH) and droplet digital PCR (ddPCR) that the Y chromosome was clonally lost at a frequency of ~16% (5/31) in two independent cohorts of male breast cancer patients. We also show somatic loss of the Y chromosome gene TMSB4Y in a male breast tumor, confirming prior reports of loss at this locus in male breast cancers. To further understand …

Atp-Site Binding Inhibitor Effectively Targets Mtorc1 And Mtorc2 Complexes In Glioblastoma, Jayson Neil, Craig Shannon, Avinash Mohan, Dimitri Laurent, Raj Murali, Meena Jhanwar-Uniyal

NYMC Faculty Publications

The PI3K-AKT-mTOR signaling axis is central to the transformed phenotype of glioblastoma (GBM) cells, due to frequent loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10). The mechanistic target of rapamycin (mTOR) kinase is present in two cellular multi-protein complexes, mTORC1 and mTORC2, which have distinct subunit composition, substrates and mechanisms of action. Targeting the mTOR protein is a promising strategy for GBM therapy. However, neither of these complexes is fully inhibited by the allosteric inhibitor of mTOR, rapamycin or its analogs. Herein, we provide evidence that the combined inhibition of mTORC1/2, using the ATP-competitive binding …

Hot Spot Mutation In Tp53 (R248q) Causes Oncogenic Gain-Of-Function Phenotypes In A Breast Cancer Cell Line Derived From An African American Patient, Nataly Shtraizent, Hiroshi Matsui, Alla Polotskaia, Jill Bargonetti

Publications and Research

African American (AA) breast cancer patients often have triple negative breast cancer (TNBC) that contains mutations in the TP53 gene. The point mutations at amino acid residues R273 and R248 both result in oncogenic gain-of-function (GOF) phenotypes. Expression of mutant p53 (mtp53) R273H associates with increased cell elasticity, survival under serum deprivation conditions, and increased Poly (ADP ribose) polymerase 1 (PARP1) on the chromatin in the AA-derived TNBC breast cancer cell line MDA-MB-468. We hypothesized that GOF mtp53 R248Q expression could stimulate a similar phenotype in the AA-derived TNBC cell line HCC70. To test this hypothesis we depleted the R248Q …

Patient-Reported Outcomes Screening For Improved Patient Wellness: A Cancer Center Initiative, Alison Morris

Doctor of Nursing Practice (DNP) Projects

Background: People experiencing serious illness have significant unmet physical, emotional, social and spiritual needs. The Quality Oncology Practice Initiative (QOPI) requires patients to be screened for emotional wellbeing and pain by their second oncology visit. This project details one cancer center’s quality improvement initiative to (a) implement electronic screening of every cancer patient by their second oncology visit, (b) design processes for ongoing assessment and intervention of need(s), and (c) develop measurable and sustainable evaluation metrics to ensure that palliative care needs are met. Methods: In June 2015, we launched electronic collection of patient-reported outcomes (PROs) using the Patient Reported …

Barriers Encountered By Nurses And Nursing Assistants That Prevent Purposeful Rounding, Mar Joseph B. Odias

Master's Projects and Capstones

Purpose: The aim of the study was to identify barriers encountered by registered nurses (RNs) and nursing assistants (NAs) that prevent purposeful (hourly) rounding.

Background: The literature has shown that purposeful rounding improves patient outcomes and safety. However, few studies show the barriers encountered by nursing staff that hinder the purposeful rounding process.

Methods: A pre-post test design was implemented on a 25-bed oncology, urology medical surgical unit with a staff of 38 RNs, 9 NAs, and 4 Unit Secretaries (US). A pre-implementation needs assessment survey was completed by 55% (21/38) of RNs, 33% (3/9) of NAs, and 100% (4/4) …

Phase Ii Clinical Trial Of Concurrent Neoadjuvant Chemotherapy With Radiotherapy In Locally Advanced Breast Cancer, Muriel Brackstone

Electronic Thesis and Dissertation Repository

Locally advanced breast cancer (LABC) represents 15% of all non-metastatic breast cancers, with an overall poor prognosis, despite current guidelines that recommend neoadjuvant chemotherapy followed by surgery and adjuvant radiation. Therefore, a novel treatment paradigm using concurrent neoadjuvant chemoradiotherapy was proposed. A clinical trial was designed, where 32 LABC patients were treated with q3 weekly 5-fluorouracil, epirubicin and cyclophosphamide for three cycles, followed by weekly docetaxel for 9 weeks with concurrent regional radiation (45+5.4Gy) for the first 6 weeks. Patients subsequently underwent modified radical mastectomies. Pathological complete responses (pCR) and 3 year overall survival rates were compared to a matched …

Cyclin D1 Silencing Suppresses Tumorigenicity, Impairs Dna Double Strand Break Repair And Thus Radiosensitizes Androgenindependent Prostate Cancer Cells To Dna Damage., F Marampon, G L Gravina, Xiaoming Ju, A Vetuschi, R Sferra, Mathew C Casimiro, S Pompili, C Festuccia, A Colapietro, E Gaudio, E Di Cesare, V Tombolini, Richard Pestell

Department of Cancer Biology Faculty Papers

Patients with hormone-resistant prostate cancer (PCa) have higher biochemical failure rates following radiation therapy (RT). Cyclin D1 deregulated expression in PCa is associated with a more aggressive disease: however its role in radioresistance has not been determined. Cyclin D1 levels in the androgen-independent PC3 and 22Rv1 PCa cells were stably inhibited by infecting with cyclin D1-shRNA. Tumorigenicity and radiosensitivity were investigated using in vitro and in vivo experimental assays. Cyclin D1 silencing interfered with PCa oncogenic phenotype by inducing growth arrest in the G1 phase of cell cycle and reducing soft agar colony formation, migration, invasion in vitro and tumor …

New Podcast From Radiation Oncology, Daniel G. Kipnis, Msi

Jefferson Digital Commons News

The Department of Radiation Oncology’s first podcast, FAQ: Special focus on the Radiation Oncology Residency Program at Thomas Jefferson University, features a discussion of what separates Jefferson from other residency program and answers commonly asked questions. The podcast is now archived in the Jefferson Digital Commons.

Igf-I Induces Upregulation Of Ddr1 Collagen Receptor In Breast Cancer Cells By Suppressing Mir-199a-5p Through The Pi3k/Akt Pathway., Roberta Matà, Chiara Palladino, Maria Luisa Nicolosi, Anna Rita Lo Presti, Roberta Malaguarnera, Marco Ragusa, Daniela Sciortino, Andrea Morrione, Marcello Maggiolini, Veronica Vella, Antonino Belfiore

Kimmel Cancer Center Faculty Papers

Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine-kinase that contributes to epithelial-to-mesenchymal transition and enhances cancer progression. Our previous data indicate that, in breast cancer cells, DDR1 interacts with IGF-1R and positively modulates IGF-1R expression and biological responses, suggesting that the DDR1-IGF-IR cross-talk may play an important role in cancer.In this study, we set out to evaluate whether IGF-I stimulation may affect DDR1 expression. Indeed, in breast cancer cells (MCF-7 and MDA-MB-231) IGF-I induced significant increase of DDR1 protein expression, in a time and dose dependent manner. However, we did not observe parallel changes in DDR1 mRNA. DDR1 …

‘Much Clearer With Pictures’: Using Community-Based Participatory Research To Design And Test A Picture Option Grid For Underserved Patients With Breast Cancer, Marie-Anne Durand, Shama Alam, Stuart W. Grande, Glyn Elwyn

Dartmouth Scholarship

Women of low socioeconomic status (SES) diagnosed with early stage breast cancer experience decision-making, treatment and outcome disparities. Evidence suggests that decision aids can benefit underserved patients, when tailored to their needs. Our aim was to develop and test the usability, acceptability and accessibility of a pictorial encounter decision aid targeted at women of low SES diagnosed with early stage breast cancer.

Erbeta Regulation Of Nf-Kb Activation In Prostate Cancer Is Mediated By Hif-1, Paul Mak, Jiarong Li, Sanjoy Samanta, Arthur M. Mercurio

Arthur M. Mercurio

We examined the regulation of NF-kappaB in prostate cancer by estrogen receptor beta (ERbeta) based on the inverse correlation between p65 and ERbeta expression that exists in prostate carcinomas and reports that ERbeta can inhibit NF-kappaB activation, although the mechanism is not known. We demonstrate that ERbeta functions as a gate-keeper for NF-kappaB p65 signaling by repressing its expression and nuclear translocation. ERbeta regulation of NF-kappaB signaling is mediated by HIF-1. Loss of ERbeta or hypoxia stabilizes HIF-1alpha, which we found to be a direct driver of IKKbeta transcription through a hypoxia response element present in the promoter of the …

Chronic Ethanol Exposure Enhances The Aggressiveness Of Breast Cancer: The Role Of P38Γ, Mei Xu, Siying Wang, Zhenhua Ren, Jacqueline A. Frank, Xiuwei H. Yang, Zhuo Zhang, Zun-Ji Ke, Xianglin Shi, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12–48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the …

Metabolic Patterns In Cancer Cells And Tumor Micro-Environment In Diffuse Large B¬Cell Lymphoma: Tumor–Stromal Metabolic Coupling, Mahasweta Gooptu, Md, Alina E. Dulau Florea, Md, Benjamin E. Leiby, Phd, Barbara Pro, Md, John David Sprandio, Jr. Md, Diana Whitaker-Menezes, Phd, Paolo Cotzia, Md, Guldeep Uppal, Md, Jaime Caro, Md, Jerald Z. Gong, Md, Ubaldo E. Martinez-Outshoorn, Md

Department of Medical Oncology Posters

It has previously been suggested that the tumor microenvironment in diffuse large B-cell lymphoma (DLBCL) has prognostic significance. Furthermore, gene expression profiling in DLBCL patients has identified separate subsets with glycolytic and mitochondrial (oxidative phosphorylative) metabolic signatures.

Glycolytic metabolism forms the basis for FDG PET scans, widely used in staging and response assessment in DLBCL. While many assume that the tumor as a whole is primarily glycolytic, the metabolic patterns of cancer cells (C) and surrounding cancer-associated stromal cells (CAS) remain relatively unknown. We investigated the in situ metabolic patterns of C and CAS cells as well as tumor-associated macrophages …

Oncology Section Edge Task Force On Breast Cancer Outcomes: A Systematic Review Of Outcome Measures For Functional Mobility, Mary Insana Fisher, Jeannette Lee, Claire Davies, Hannah Geyer, Genevieve Colon, Lucinda Pfalzer

Mary Insana Fisher

Background: Breast cancer treatments in women with breast cancer often result in physical impairments that lead to activity limitations and participation restrictions. These limitations and restrictions manifest in impaired functional mobility skills that may impact survivorship. Thus, evaluation of functional mobility is an important part of survivorship care. Purpose: To identify functional mobility outcome measures that possess strong psychometric properties and are clinically useful for examination of women treated for breast cancer. Methods: Multiple electronic databases were searched for articles published after 1995. Studies were included if they reported psychometric properties, used clinically feasible methods, were performed on adults, and …

The Metastatic Receptor Status Impact On First-Line Treatment Plans And Outcomes For Recurrent Metastatic Breast Cancer, T. Allen Pannell

Doctoral Dissertations

Background: For more than two decades, breast cancer researchers have studied the benefits, risks and clinical importance of testing the receptor status of metastatic tumors. While there is a growing consensus that the status should be re-tested and under what circumstances that re-testing should occur, there is little to no evidence that utilizing test results for metastatic tumor receptor status improves the clinical outcomes of patients. In fact, there is evidence that changes to treatment plans based on this re-testing can be harmful to patient outcomes.

Objective: This dissertation evaluates the current state of evidence related to altering patient treatment …

Nurses’ Perceptions Of Best Practices To Assess Pediatric Patients And Educate Their Families Experiencing Effects Of Cancer Chemotherapy: “Chemo Brain” A Pilot Study, Jennifer A. Tapping

Senior Theses

With more advanced and more aggressive chemotherapy cancer treatment leading to higher survival rates, complications with quality of life are becoming more prominent. Of these complications, delayed cognitive processing, commonly known as “chemo brain,” is becoming a topic of interest. Cognitive changes are some of the most common as well as the most challenging complications associated with central nervous system (CNS) directed treatment, such as chemotherapy. The term “chemo brain” is often used to describe self-reported or observed cognitive processing delays in patients who receive chemotherapy as a form of cancer treatment (Raffa, 2009). Although these cognitive delays have the …

Pamam Dendrimers As Promising Nanocarriers For Rnai Therapeutics, Prashant Kesharwani, Sanjeev Banerjee, Umesh Gupta, Mohd Cairul Iqbal Mohd Amin, Subhash Padhye, Fazlul H. Sarkar, Arun K. Iyer

Pharmaceutical Sciences Faculty Publications

Therapeutics based on RNA interference mechanisms are highly promising for the management of several diseases including multi-drug resistant cancers. However, effective delivery of siRNAs and oligonucleotides still remains challenging. In this regard, hyper-branched, PAMAM dendrimers having unique three-dimensional architecture and nanoscale size, with cationic surface charge can potentially serve as siRNA condensing agents as well as robust nano-vectors for targeted delivery. In addition, their surface functionality permits conjugation of drugs and genes or development of hybrid systems for combination therapy. Thus far, in vitro cellular testing of dendrimer-mediated siRNA delivery has revealed great potential, with reports on their in vivo …

Silibinin-Mediated Metabolic Reprogramming Attenuates Pancreatic Cancer-Induced Cachexia And Tumor Growth., Surendra K. Shukla, Aneesha Dasgupta, Kamiya Mehla, Venugopal Gunda, Enza Vernucci, Joshua J. Souchek, Gennifer Goode, Ryan King, Anusha Mishra, Ibha Rai, Sangeetha Nagarajan, Nina V. Chaika, Fang Yu, Surendra K. Shukla

Journal Articles: Eppley Institute

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic …

Rehabilitation And Cancer Survivorship, Matthew Denning, Samantha Fisk, Alyssa Grigware, Mary Leopold, Erika Lopez, Margaret Masiak, Sebastian Stoltzfus, Ashley Tomaswick

Disease Prevention and Health Promotion Resources

Presentation given at Central Maine Medical Center on December 4, 2015, to build awareness of the role of rehabilitation services in cancer survivor management and discuss strategies to address existing needs. This presentation was based on a project undertaken to determine which physical distress screening tools are most appropriate to trigger a wellness or rehabilitation referral when it is warranted for a survivor. The use of effective screening tools will assist in directing cancer survivors, who experience physical and emotional burdens caused by the disease and subsequent treatment, to access services that will continue to improve their overall quality of …

A Review Of Screening Processes For Physical Distress And Appropriate Outcome Measures For Outpatient Rehabilitation Referral In Cancer Survivorship, Ashley Tomaswick, Sebastian Stoltzfus, Margaret Masiak, Erika Lopez, Mary Leopold, Alyssa Grigware, Samantha Fisk, Matthew Denning

Disease Prevention and Health Promotion Papers

The goal of this project is to determine which physical distress screening tools are most appropriate to trigger a wellness or rehabilitation referral when it is warranted for a survivor. The use of effective screening tools will assist in directing cancer survivors, who experience physical and emotional burdens caused by the disease and subsequent treatment, to access services that will continue to improve their overall quality of life upon completion of cancer treatment or in a setting of ongoing palliative care. These measures should focus on functional mobility, balance, fatigue, and distress. Additionally, there are many common tests used to …

Investigation Of Quatitative Image Features From Pretreatment Ct And Fdg-Pet Scans In Stage Iii Nsclc Patients Undergoing Defintive Radiation Therapy, David Fried

Dissertations & Theses (Open Access)

The purpose of this work was to determine if quantitative image features (QIFs) extracted from computed tomography (CT) and flourodeoxyglucose (FDG) positron emission tomography (PET) could provide prognostic information to improve outcome models. Our goal for this work was to determine if it may one day be feasible to incorporate QIFs into personalized cancer care. QIFs were used to quantitatively characterize patient disease as seen on imaging. A leave-one-out cross-validation procedure was used to assess the prognostic ability of QIFs extracted from CT and PET in addition to conventional prognostic factors (CPFs). QIFs were found to improve model fit for …

Regulation Of The Oxidative Stress Response By Arid1a, Suet Yan Kwan

Dissertations & Theses (Open Access)

SWI/SNF is mutated in about 20% of all human cancers; in particular ARID1A is the most frequently mutated SWI/SNF subunit. ARID1A is a tumor suppressor gene, inactivating mutations in ARID1A are most frequently found in ovarian and endometrial cancers, specifically uterine corpus endometrioid carcinomas (UCEC), ovarian clear cell carcinomas (OCCC) and ovarian endometrioid carcinomas (OEC). The functional roles of ARID1A are not completely understood and there are limited therapeutic strategies that specifically target ARID1A-mutant cancers. Given that ARID1A expression is lost in cancer, ARID1A mutations cannot be targeted directly and novel therapeutic strategies are required to target ARID1A-mutant …

A Synthetic Lethality Screen Using A Focused Sirna Library To Identify Sensitizers To Dasatinib Therapy For The Treatment Of Epithelial Ovarian Cancer., Harsh B Pathak, Yan Zhou, Geetika Sethi, Jeff Hirst, Russell J Schilder, Erica A Golemis, Andrew K Godwin

Department of Medicine Faculty Papers

Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC). The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK) and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to …

Assessment Of Breast Cancer Treatment Delay Impact On Prognosis And Survival: A Look At The Evidence From Systematic Analysis Of The Literature, Faustine Williams

Faustine Williams

Cyclin-Dependent Kinase Inhibitor P1446a Induces Apoptosis In A Jnk/P38 Mapk-Dependent Manner In Chronic Lymphocytic Leukemia B-Cells, Cody Paiva, J. Claire Godbersen, Ryan S. Soderquist, Taylor Rowland, Sumner Kilmarx

Dartmouth Scholarship

CDK (cyclin-dependent kinase) inhibitors have shown remarkable activity in CLL, where its efficacy has been linked to inhibition of the transcriptional CDKs (7 and 9) and deregulation of RNA polymerase and short-lived pro-survival proteins such as MCL1. Furthermore, ER (endoplasmic reticulum) stress has been implicated in CDK inhibition in CLL. Here we conducted a pre-clinical study of a novel orally active kinase inhibitor P1446A in CLL B-cells. P1446A inhibited CDKs at nanomolar concentrations and induced rapid apoptosis of CLL cells in vitro, irrespective of chromosomal abnormalities or IGHV mutational status. Apoptosis preceded inactivation of RNA polymerase, and was accompanied by …

Enormous, Rapidly Growing Breast Mass., Vivek Verma, Sanjay Muttineni, Rajesh R. Kulkarni, Edibaldo Silva, William W. West, Robert B. Thompson

Journal Articles: Oncology and Hematology

BACKGROUND: Signs and symptoms of a rapidly enlarging breast mass are not only important for all clinicians to recognize and assess, but also are not uncommon occurrences. We describe a similar but unique case that developed into an enormous, 36 cm exophytic mass.

CASE PRESENTATION: A 51-year-old woman with history of psychiatric conditions presented for signs and symptoms of sepsis. It was determined that the source was an enormous 36 cm mass originating from the breast/chest wall. After stabilizing the patient with antibiotics, she underwent successful resection. Surgical margins were positive, and histopathology demonstrated bland spindle cells with stromal overgrowth. …

Epithelial Neoplasia Coincides With Exacerbated Injury And Fibrotic Response In The Lungs Of Gprc5a-Knockout Mice Following Silica Exposure, Xiaofei Wang, Dongliang Xu, Yueling Liao, Shuangshuang Zhong, Hongyong Song, Beibei Sun, Binhua P. Zhou, Jiong Deng, Baohui Han

Markey Cancer Center Faculty Publications

Exposure to crystalline silica is suggested to increase the risk for a variety of lung diseases, including fibrosis and lung cancer. However, epidemiological evidences for the exposure-risk relationship are ambiguous and conflicting, and experimental study from a reliable animal model to explore the relationship is lacking. We reasoned that a mouse model that is sensitive to both lung injury and tumorigenesis would be appropriate to evaluate the exposure-risk relationship. Previously, we showed that, Gprc5a^-/- mice are susceptible to both lung tumorigenesis and endotoxin-induced acute lung injury. In this study, we investigated the biological consequences in Gprc5a^-/- mouse model …

Pharmacists On The Front Lines Of Polypharmacy: The Individualized Medication Assessment And Planning (Imap) Project To Improve Medication Use In Senior Adults With Cancer, Ginah Nightingale Pharmd, Bcop, Laura T. Pizzi Pharmd, Mph, Emily Hajjar Pharmd, Bcps, Bcacp, Cgp, Elizabeth Pigott, Margaret Wang, Shannon Doherty, Kristine Swartz Md, Andrew Chapman Do, Facp

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

Breast Cancer Rehabilitation: Clinical Examination And Outcomes Assessment, Nicole L. Stout, Shana Harrington, Lucinda Pfalzer, Mary Insana Fisher

Mary Insana Fisher

Breast cancer is the most commonly diagnosed cancer in women in the United States. The treatment for breast cancer occurs along a protracted time period and includes many different disease treatment modalities. These treatments carry with them a large number of adverse effects that negatively impact function in both the short term and long term. It is necessary for rehabilitation providers to interface with patients being treated for breast cancer throughout the continuum of care so that interval assessments can be conducted to identify emerging impairments and alleviate disability. To achieve this, the rehabilitation provider must have an understanding of …

In Vitro Growth Suppression Of Renal Carcinoma Cells By Curcumin, Santhi D. Konduri, Madhavi Latha Yadav Bangaru, Phu Thanh Do, Shenglin Chen, Jeffrey Woodliff, Sanjay Kansra

Journal of Patient-Centered Research and Reviews

Purpose

Malignant clear cell renal carcinoma (ccRCC) is an aggressive tumor highly resistant to chemotherapy and radiation. Current therapeutic approaches to management of ccRCC have not significantly improved patient survival, therefore novel therapies are needed. Activated NFκB and STAT3 expression is associated with ccRCC pathogenesis. The dietary polyphenol curcumin is a well-documented antitumor agent and a known inhibitor of NFκB and STAT3 activation. Given the lack of effective therapies that block ccRCC progression, our objective was to examine whether curcumin could suppress the growth and migration of ccRCC cells, and whether this suppression was mediated via inhibition of NFκB and …