Digital Commons Network^™

Adjuvant Chemotherapy And Survival Among Patients 70 Years Of Age And Younger With Node-Negative Breast Cancer And The 21-Gene Recurrence Score Of 26-30, Seho Park, Yunan Han, Ying Liu, Adetunji T Toriola, Lindsay L Peterson, Graham A Colditz, Seung Il Kim, Young Up Cho, Byeong-Woo Park, Yikyung Park

Open Access Publications

BACKGROUND: The benefits of chemotherapy in node-negative, hormone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients with the 21-gene recurrence score (RS) of 18-30, particularly those with RS 26-30, are not known.

METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) data, we retrospectively identified 29,137 breast cancer patients with the 21-gene RS of 18-30 diagnosed between 2004 and 2015. Mortality risks according to the RS and chemotherapy use were compared by the Kaplan-Meier method and Cox's proportional hazards model.

RESULTS: Among the breast cancer patients with the RS 18-30, 21% of them had RS 26-30. …

Pragmatic Randomised Clinical Trial Of Proton Versus Photon Therapy For Patients With Non-Metastatic Breast Cancer: The Radiotherapy Comparative Effectiveness (Radcomp) Consortium Trial Protocol, Justin E Bekelman, Walter Bosch, Et Al

Open Access Publications

INTRODUCTION: A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer.

METHODS: We are conducting a large …

Staphylococcus Aureus Infects Osteoclasts And Replicates Intracellularly, Jennifer L Krauss, Philip M Roper, Anna Ballard, Chien-Cheng Shih, James A J Fitzpatrick, James E Cassat, Pei Ying Ng, Nathan J Pavlos, Deborah J Veis

Open Access Publications

Osteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. OM is predominantly caused by

Chitosan Biosynthesis And Virulence In The Human Fungal Pathogen Cryptococcus Gattii, Woei C Lam, Rajendra Upadhya, Charles A Specht, Abigail E Ragsdale, Camaron R Hole, Stuart M Levitz, Jennifer K Lodge

Open Access Publications

No abstract provided.

Mutation Of The Co-Chaperone Tsc1 In Bladder Cancer Diminishes Hsp90 Acetylation And Reduces Drug Sensitivity And Selectivity, Mark R. Woodford, Michael Hughes, Rebecca A. Sager, Sarah J. Backe, Alexander J. Baker-Williams, Michael S. Bratslavsky, Joseph M. Jacob, Oleg Shapiro, Michael Wong, Gennady Bratslavsky, Dimitra Bourboulia, Mehdi Mollapour

Open Access Publications

The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 …

Structured Inhibitory Activity Dynamics In New Virtual Environments, Moises Arriaga, Edward B. Han

Open Access Publications

Inhibition plays a powerful role in regulating network excitation and plasticity; however, the activity of defined interneuron types during spatial exploration remain poorly understood. Using two-photon calcium imaging, we recorded hippocampal CA1 somatostatin- and parvalbumin-expressing interneurons as mice performed a goal-directed spatial navigation task in new visual virtual reality (VR) contexts. Activity in both interneuron classes was strongly suppressed but recovered as animals learned to adapt the previously learned task to the new spatial context. Surprisingly, although there was a range of activity suppression across the population, individual somatostatin-expressing interneurons showed consistent levels of activity modulation across exposure to multiple …

Stimulation Of Piezo1 By Mechanical Signals Promotes Bone Anabolism, Xuehua Li, Li Han, Intawat Nookaew, Erin Mannen, Matthew J. Silva, Maria Almeida, Jinhu Xiong

Open Access Publications

Mechanical loading, such as caused by exercise, stimulates bone formation by osteoblasts and increases bone strength, but the mechanisms are poorly understood. Osteocytes reside in bone matrix, sense changes in mechanical load, and produce signals that alter bone formation by osteoblasts. We report that the ion channel Piezo1 is required for changes in gene expression induced by fluid shear stress in cultured osteocytes and stimulation of Piezo1 by a small molecule agonist is sufficient to replicate the effects of fluid flow on osteocytes. Conditional deletion of

Ilc3s Integrate Glycolysis And Mitochondrial Production Of Reactive Oxygen Species To Fulfill Activation Demands, Blanda Di Luccia, Susan Gilfillan, Marina Cella, Marco Colonna, Stanley Ching-Cheng Huang

Open Access Publications

Group 3 innate lymphoid cells (ILC3s) are the innate counterparts of Th17 that require the transcription factor RORγt for development and contribute to the defense against pathogens through IL-22 and IL-17 secretion. Proliferation and effector functions of Th17 require a specific mTOR-dependent metabolic program that utilizes high-rate glycolysis, while mitochondrial lipid oxidation and production of reactive oxygen species (mROS) support alternative T reg cell differentiation. Whether ILC3s employ a specific metabolic program is not known. Here, we find that ILC3s rely on mTOR complex 1 (mTORC1) for proliferation and production of IL-22 and IL-17A after in vitro activation and Citrobacter …

Htlv-1 Viral Oncogene Hbz Drives Bone Destruction In Adult T Cell Leukemia, Jingyu Xiang, Daniel A Rauch, Devra D Huey, Amanda R Panfil, Xiaogang Cheng, Alison K Esser, Xinming Su, John C Harding, Yalin Xu, Gregory C Fox, Francesca Fontana, Takayuki Kobayashi, Junyi Su, Hemalatha Sundaramoorthi, Wing Hing Wong, Yizhen Jia, Thomas J Rosol, Deborah J Veis, Patrick L Green, Stefan Niewiesk, Lee Ratner, Katherine N Weilbaecher

Open Access Publications

Osteolytic bone lesions and hypercalcemia are common, serious complications in adult T cell leukemia/lymphoma (ATL), an aggressive T cell malignancy associated with human T cell leukemia virus type 1 (HTLV-1) infection. The HTLV-1 viral oncogene HBZ has been implicated in ATL tumorigenesis and bone loss. In this study, we evaluated the role of HBZ on ATL-associated bone destruction using HTLV-1 infection and disease progression mouse models. Humanized mice infected with HTLV-1 developed lymphoproliferative disease and continuous, progressive osteolytic bone lesions. HTLV-1 lacking HBZ displayed only modest delays to lymphoproliferative disease but significantly decreased disease-associated bone loss compared with HTLV-1-infected mice. …

Irak4 Mediates Colitis-Induced Tumorigenesis And Chemoresistance In Colorectal Cancer, Qiong Li, Yali Chen, Daoxiang Zhang, Julie Grossman, Lin Li, Namrata Khurana, Hongmei Jiang, Patrick M Grierson, John Herndon, David G Denardo, Grant A Challen, Jingxia Liu, Marianna B Ruzinova, Ryan C Fields, Kian-Huat Lim

Open Access Publications

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor-associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have …

Sr9009 Administered For One Day After Myocardial Ischemia-Reperfusion Prevents Heart Failure In Mice By Targeting The Cardiac Inflammasome, Cristine J Reitz, Faisal J Alibhai, Tarak N Khatua, Mina Rasouli, Byram W Bridle, Thomas P Burris, Tami A Martino

Open Access Publications

Reperfusion of patients after myocardial infarction (heart attack) triggers cardiac inflammation that leads to infarct expansion and heart failure (HF). We previously showed that the circadian mechanism is a critical regulator of reperfusion injury. However, whether pharmacological targeting using circadian medicine limits reperfusion injury and protects against HF is unknown. Here, we show that short-term targeting of the circadian driver REV-ERB with SR9009 benefits long-term cardiac repair post-myocardial ischemia reperfusion in mice. Gain and loss of function studies demonstrate specificity of targeting REV-ERB in mice. Treatment for just one day abates the cardiac NLRP3 inflammasome, decreasing immunocyte recruitment, and thereby …

Association Of Acquired And Heritable Factors With Intergenerational Differences In Age At Symptomatic Onset Of Alzheimer Disease Between Offspring And Parents With Dementia, Gregory S. Day, Carlos Cruchaga, Thomas Wingo, Suzanne E. Schindler, Dean Coble, John C. Morris

Open Access Publications

Importance: Acquired and heritable traits are associated with dementia risk; however, how these traits are associated with age at symptomatic onset (AAO) of Alzheimer disease (AD) is unknown. Identifying the associations of acquired and heritable factors with variability in intergenerational AAO of AD could facilitate diagnosis, assessment, and counseling of the offspring of parents with AD.

Objective: To quantify the associations of acquired and heritable factors with intergenerational differences in AAO of AD.

Design, Setting, and Participants: This nested cohort study used data from the Knight Alzheimer Disease Research Center that included community-dwelling participants with symptomatic AD, parental history of …

Keep The Cat, Change The Care Pathway: A Transformational Approach To Managing Fel D 1, The Major Cat Allergen, Ebenezer Satyaraj, Harold James Wedner, Jean Bousquet

2010-2019 OA Pubs

BACKGROUND: Allergies to cats are the most common animal-origin allergy, and affect approximately 1 in 5 adults worldwide. The prevalence of allergy to furry animals has been increasing, and allergy to cats is a major risk factor for the development of asthma and rhinitis. The diagnosis of cat allergy is now well established. The exact significance of component-resolved diagnosis in the diagnosis of cat allergy remains to be fully understood. Allergen avoidance is effective but often has a psychologic impact. Allergen immunotherapy is not well demonstrated. There is a need for innovative approaches to better manage cat allergens. Next-generation care …

Stub1 Suppresseses Tumorigenesis And Chemoresistance Through Antagonizing Yap1 Signaling, Dong-E Tang, Yong Dai, Lie-Wen Lin, Yong Xu, Dong-Zhou Liu, Xiao-Ping Hong, Hao-Wu Jiang, Song-Hui Xu

Open Access Publications

Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. …

Association Of Circulating Ceramides With Cardiac Structure And Function In The Community: The Framingham Heart Study, Chike C Nwabuo, Meredith Duncan, Vanessa Xanthakis, Linda R Peterson, Gary F Mitchell, David Mcmanus, Susan Cheng, Ramachandran S. Vasan

Open Access Publications

Background A higher circulating plasma ceramide ratio (C16:0/C24:0) is associated with an increased risk of heart failure, even after accounting for standard risk factors including lipid markers. However, the pathobiological mechanisms that underlie this association are incompletely understood. We tested the hypothesis that plasma ceramide ratio (C16:0/C24:0) is associated with adverse cardiac remodeling in the community. Methods and Results We evaluated 2652 Framingham Offspring Study participants (mean age, 66±9 years; 55% women) who attended their eighth examination cycle and underwent routine echocardiography and liquid chromatography-tandem mass spectrometry-based assays for circulating ceramide concentrations. We used multivariable linear regression models to relate …

Astrovirus Replication In Human Intestinal Enteroids Reveals Multi-Cellular Tropism And An Intricate Host Innate Immune Landscape, Abimbola O. Kolawole, Andrew B Janowski, David Wang, Christiane E. Wobus, Et Al.

Open Access Publications

Human astroviruses (HAstV) are understudied positive-strand RNA viruses that cause gastroenteritis mostly in children and the elderly. Three clades of astroviruses, classic, MLB-type and VA-type have been reported in humans. One limitation towards a better understanding of these viruses has been the lack of a physiologically relevant cell culture model that supports growth of all clades of HAstV. Herein, we demonstrate infection of HAstV strains belonging to all three clades in epithelium-only human intestinal enteroids (HIE) isolated from biopsy-derived intestinal crypts. A detailed investigation of infection of VA1, a member of the non-canonical HAstV-VA/HMO clade, showed robust replication in HIE …

Intermediate-High Risk Pulmonary Embolism, Rosa Mirambeaux, Francisco León, Behnood Bikdeli, Raquel Morillo, Deisy Barrios, Edwin Mercedes, Lisa Moores, Victor Tapson, Roger D. Yusen, David Jiménez

Open Access Publications

Limited information exists about the prevalence, management, and outcomes of intermediate-high risk patients with acute pulmonary embolism (PE). In a prospective cohort study, we evaluated consecutive patients with intermediate-high risk PE at a large, tertiary, academic medical center between January 1, 2015 and March 31, 2019. Adjudicated outcomes included PE-related mortality and a complicated course through 30 days after initiation of PE treatment. Repeat systolic blood pressure (SBP), heart rate (HR), brain natriuretic peptide (BNP), and cardiac troponin I (cTnI) measurements, and echocardiography were performed within 48 hours after diagnosis. Among 1,015 normotensive patients with acute PE, 97 (9.6%) had …

Sequence Specificity Despite Intrinsic Disorder: How A Disease-Associated Val/Met Polymorphism Rearranges Tertiary Interactions In A Long Disordered Protein, Ruchi Lohia, Reza Salari, Grace Brannigan

Open Access Publications

The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) in precursor brain-derived neurotrophic factor (BDNF) is one of the earliest SNPs to be associated with neuropsychiatric disorders, and the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica-exchange molecular dynamics (MD) simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence. The simulations were able to correctly reproduce the location of both local and …

Open-Sourced Civic Annotation Pipeline To Identify And Annotate Clinically Relevant Variants Using Single-Molecule Molecular Inversion Probes, Erica K Barnell, Adam Waalkes, Matt C Mosior, Kelsi Penewit, Kelsy C Cotto, Arpad M Danos, Lana M Sheta, Katie M Campbell, Kilannin Krysiak, Damian Rieke, Nicholas C Spies, Zachary L Skidmore, Colin C Pritchard, Todd A Fehniger, Ravindra Uppaluri, Ramaswamy Govindan, Malachi Griffith, Stephen J Salipante, Obi L Griffith

Open Access Publications

PURPOSE: Clinical targeted sequencing panels are important for identifying actionable variants for patients with cancer; however, existing approaches do not provide transparent and rationally designed clinical panels to accommodate the rapidly growing knowledge within oncology.

MATERIALS AND METHODS: We used the Clinical Interpretations of Variants in Cancer (CIViC) database to develop an Open-Sourced CIViC Annotation Pipeline (OpenCAP). OpenCAP provides methods to identify variants within the CIViC database, build probes for variant capture, use probes on prospective samples, and link somatic variants to CIViC clinical relevance statements. OpenCAP was tested using a single-molecule molecular inversion probe (smMIP) capture design on 27 …

Optimizing Postprandial Glucose Management In Adults With Insulin-Requiring Diabetes: Report And Recommendations, John (Jack) L. Leahy, Grazia Aleppo, Vivian A. Fonseca, Satish K. Garg, Irl B. Hirsch, Anthony L. Mccall, Janet B. Mcgill, William H. Polonsky

Open Access Publications

Faster-acting insulins, new noninsulin drug classes, more flexible insulin-delivery systems, and improved continuous glucose monitoring devices offer unprecedented opportunities to improve postprandial glucose (PPG) management and overall care for adults with insulin-treated diabetes. These developments led the Endocrine Society to convene a working panel of diabetes experts in December 2018 to assess the current state of PPG management, identify innovative ways to improve self-management and quality of life, and align best practices to current and emerging treatment and monitoring options. Drawing on current research and collective clinical experience, we considered the following issues for the ∼200 million adults worldwide with …

A Human Stat1 Gain-Of-Function Mutation Impairs Cd8 + T Cell Responses Against Gammaherpesvirus 68, Wei Qian, Cathrine A Miner, Harshad Ingle, Derek J Platt, Megan T Baldridge, Jonathan J Miner

Open Access Publications

Autosomal dominant STAT1 mutations in humans have been associated with chronic mucocutaneous candidiasis (CMC), as well as with increased susceptibility to herpesvirus infections. Prior studies have focused on mucosal and Th17-mediated immunity against

Phase I, Open-Label, Dose-Escalation Study Of The Safety, Pharmacokinetics, Pharmacodynamics, And Efficacy Of Gsk2879552 In Relapsed/Refractory Sclc, Todd M Bauer, Benjamin Besse, Alex Martinez-Marti, Jose Manuel Trigo, Victor Moreno, Pilar Garrido, Geraldine Ferron-Brady, Yuehui Wu, Jennifer Park, Therese Collingwood, Ryan G Kruger, Helai P Mohammad, Marc S Ballas, Arindam Dhar, Ramaswamy Govindan

Open Access Publications

INTRODUCTION: This first-time-in-humans study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of GSK2879552 in patients with relapsed or refractory SCLC.

METHODS: This phase I, multicenter, open-label study (NCT02034123) enrolled patients (≥18 years old) with relapsed or refractory SCLC (after ≥1 platinum-containing chemotherapy or refusal of standard therapy). Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Dose escalations were based on safety, PK, and PD. The primary end point (Part 1) was to determine the safety, tolerability, and recommended dose and regimen of GSK2879552. Secondary end points were to characterize PK and PD parameters …

Casein Kinase 1 Family Proteins Promote Slimb-Dependent Expanded Degradation, Alexander D. Fulford, Maxine V. Holder, David Frith, Ambrosius P. Snijders, Nicolas Tapon, Paulo S. Ribeiro

Open Access Publications

Hippo signalling integrates diverse stimuli related to epithelial architecture to regulate tissue growth and cell fate decisions. The Hippo kinase cascade represses the growth-promoting transcription co-activator Yorkie. The FERM protein Expanded is one of the main upstream Hippo signalling regulators in

Feasibility Of Detecting Change In Backscattered Energy Of Acoustic Harmonics In Locally Heated Tissues, Borna Maraghechi, Michael C Kolios, Jahan Tavakkoli

Open Access Publications

No abstract provided.

Bjc Today

BJC Today

No abstract provided.

Inhibition Of 4-Aminobutyrate Aminotransferase Protects Against Injury-Induced Osteoarthritis In Mice, Jie Shen, Cuicui Wang, Jun Ying, Taotao Xu, Audrey Mcalinden, Regis J. O'Keefe

Open Access Publications

Recently we demonstrated that ablation of the DNA methyltransferase enzyme, Dnmt3b, resulted in catabolism and progression of osteoarthritis (OA) in murine articular cartilage through a mechanism involving increased mitochondrial respiration. In this study, we identify 4-aminobutyrate aminotransferase (Abat) as a downstream target of Dnmt3b. Abat is an enzyme that metabolizes γ-aminobutyric acid to succinate, a key intermediate in the tricarboxylic acid cycle. We show that Dnmt3b binds to the Abat promoter, increases methylation of a conserved CpG sequence just upstream of the transcriptional start site, and inhibits Abat expression. Dnmt3b deletion in articular chondrocytes results in reduced methylation of the …

Multispectral Tracing In Densely Labeled Mouse Brain With Ntracer, Douglas H Roossien, John M Webb, Cristina Mazuski, Erik D Herzog, Et Al.

2010-2019 OA Pubs

SUMMARY: This note describes nTracer, an ImageJ plug-in for user-guided, semi-automated tracing of multispectral fluorescent tissue samples. This approach allows for rapid and accurate reconstruction of whole cell morphology of large neuronal populations in densely labeled brains.

AVAILABILITY AND IMPLEMENTATION: nTracer was written as a plug-in for the open source image processing software ImageJ. The software, instructional documentation, tutorial videos, sample image and sample tracing results are available at https://www.cai-lab.org/ntracer-tutorial.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Race And Risk Of Subsequent Aggressive Breast Cancer Following Ductal Carcinoma In Situ, Ying Liu, Robert West, Jason D Weber, Graham A Colditz

Open Access Publications

BACKGROUND: General populations of black women have a higher risk of developing breast cancer negative for both estrogen receptor (ER) and progesterone receptor (PR) in comparison with white counterparts. Racial differences remain unknown in the risk of developing aggressive invasive breast cancer (IBC) that is characterized by negativity for both ER and PR (ER-PR-) or higher 21-gene recurrence scores after ductal carcinoma in situ (DCIS).

METHODS: This study identified 163,892 women (10.5% black, 9.8% Asian, and 8.6% Hispanic) with incident DCIS between 1990 and 2015 from the Surveillance, Epidemiology, and End Results data sets. Cox proportional hazards regression was used …

Identification Of 4-Amino-Thieno[2,3-D]Pyrimidines As Qcrb Inhibitors In Mycobacterium Tuberculosis, Gregory A Harrison, Anne E Mayer Bridwell, Megh Singh, Keshav Jayaraman, Leslie A Weiss, Rachel L Kinsella, Janessa S Aneke, Kelly Flentie, Miranda E Schene, Margaret Gaggioli, Samantha D Solomon, Scott A Wildman, Marvin J Meyers, Christina L Stallings

Open Access Publications

Antibiotic resistance is a global crisis that threatens our ability to treat bacterial infections, such as tuberculosis, caused by

Virus-Induced Cochlear Inflammation In Newborn Mice Alters Auditory Function, Cathy Yea Won Sung, Maria C. Seleme, Shelby Payne, Stipan Jonjic, Keiko Hirose, William Britt

Open Access Publications

Although human cytomegalovirus (HCMV) is a known cause of sensorineural hearing loss in infants with congenital HCMV (cCMV) infections, mechanisms that contribute to sensorineural hearing loss (SNHL) in infants with cCMV infection are not well defined. Using a murine model of CMV infection during auditory development, we have shown that peripheral infection of newborn mice with murine CMV (MCMV) results in focal infection of the cochlea and virus-induced cochlear inflammation. Approximately 50%-60% of infected mice exhibited increased auditory brainstem response (ABR) thresholds across a range of sound frequencies. Histological analyses of the cochlea in MCMV-infected mice with elevated ABR thresholds …