Medicine and Health Sciences Commons^™

A Prismatic View Of The Epigenetic-Metabolic Regulatory Axis In Breast Cancer Therapy Resistance, Chandrima Das, Apoorva Bhattacharya, Swagata Adhikari, Atanu Mondal, Payel Mondal, Santanu Adhikary, Siddhartha Roy, Kenneth Ramos, Kamlesh K Yadav, John A Tainer, Tej K Pandita

Faculty, Staff and Student Publications

Epigenetic regulation established during development to maintain patterns of transcriptional expression and silencing for metabolism and other fundamental cell processes can be reprogrammed in cancer, providing a molecular mechanism for persistent alterations in phenotype. Metabolic deregulation and reprogramming are thus an emerging hallmark of cancer with opportunities for molecular classification as a critical preliminary step for precision therapeutic intervention. Yet, acquisition of therapy resistance against most conventional treatment regimens coupled with tumor relapse, continue to pose unsolved problems for precision healthcare, as exemplified in breast cancer where existing data informs both cancer genotype and phenotype. Furthermore, epigenetic reprograming of the …

Understanding The Treatment Paradigm And The Sequencing Of Antiglaucoma Fixed-Dose Combinations In A Tertiary Center In South India, Ronnie George, Praggya Mishra, Balekudaru Shantha, Lingam Vijaya, Nitin Maksane, Neha Gurha

Faculty, Staff and Student Publications

PURPOSE: To analyze the medical management of primary open-angle glaucoma (POAG) and ocular hypertension (OHT) and the placement of fixed-drug combination drugs (FDC) in the treatment paradigm at a tertiary eye care center in South India.

METHODS: Retrospective study (January 2011-December 2015) of newly diagnosed POAG and OHT patients (≥18 years) with ≥5 years follow-up. Primary outcome included percentage use of different antiglaucoma drugs (at initiation) and FDCs at the first, second, and third progression (sequencing). Secondary outcomes: Percentage discontinuation for different FDCs, efficacy parameters (decrease in intraocular pressure (IOP)/visual field), adverse events, and the median number of antiglaucoma medications …

Longitudinal Changes In The Carotid Arteries Of Head And Neck Cancer Patients Following Radiation Therapy: Results From A Prospective Serial Imaging Biomarker Characterization Study, Efstratios Koutroumpakis, Abdallah Sherif Radwan Mohamed, Peter Chaftari, David I Rosenthal, Dorothy Gujral, Christopher Nutting, Serageldin Kamel, Mohamed A Naser, Peter Kim, Roland Bassett, Clifton D Fuller, Elie Mouhayar, Md Anderson Head Neck Radiation Oncology Cardiovascular Working Group

Faculty, Staff and Student Publications

INTRODUCTION: We prospectively evaluated morphologic and functional changes in the carotid arteries of patients treated with unilateral neck radiation therapy (RT) for head and neck cancer.

METHODS: Bilateral carotid artery duplex studies were performed at 0, 3, 6, 12, 18 months and 2, 3, 4, and 5 years following RT. Intima media thickness (IMT); global and regional circumferential, as well as radial strain, arterial elasticity, stiffness, and distensibility were calculated.

RESULTS: Thirty-eight patients were included. A significant difference in the IMT from baseline between irradiated and unirradiated carotid arteries was detected at 18 months (median, 0.073 mm vs -0.003 mm; …

A Phase I Study Of Tak-659 And Paclitaxel In Patients With Taxane-Refractory Advanced Solid Tumors, M A Gouda, J Shunyakova, A Naing, E Dumbrava, D S Hong, Y Yuan, P Yang, A Myers, Y Liang, J Peng, D Karp, A M Tsimberidou, J Rodon, T A Yap, S A Piha-Paul, F Meric-Bernstam, S Fu

Faculty, Staff and Student Publications

BACKGROUND: Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.

PATIENTS AND METHODS: Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients …

Genome-Wide Association Studies And Mendelian Randomization Analyses Provide Insights Into The Causes Of Early-Onset Colorectal Cancer, R S Laskar, Y Cao, Et Al.

2020-Current year OA Pubs

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed < 50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC.

PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR.

RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH …

Retrospective Multicenter Cohort Study On Safety And Electroencephalographic Response To Lacosamide For Neonatal Seizures, Moninder Kaur, Rejean M Guerriero, Renée A Shellhaas, Et Al.

2020-Current year OA Pubs

BACKGROUND: There is growing evidence supporting the safety and effectiveness of lacosamide in older children. However, minimal data are available for neonates. We aimed to determine the incidence of adverse events associated with lacosamide use and explore the electroencephalographic seizure response to lacosamide in neonates.

METHODS: A retrospective cohort study was conducted using data from seven pediatric hospitals from January 2009 to February 2020. For safety outcomes, neonates were followed for ≤30 days from index date. Electroencephalographic response of lacosamide was evaluated based on electroencephalographic reports for ≤3 days.

RESULTS: Among 47 neonates, 98% received the first lacosamide dose in …

Specific Gravity Improves Identification Of Clinically Significant Quantitative Proteinuria From The Dipstick Urinalysis, Meredith C Mcadams, L Parker Gregg, Pin Xu, Song Zhang, Michael Li, Ella Carroll, Vaishnavi Kannan, Duwayne L Willett, S Susan Hedayati

Faculty, Staff and Students Publications

KEY POINTS: Urine albumin-to-creatinine ratio and urine protein-to-creatinine ratio are frequently obtained and represent possible tools for screening for proteinuria and thus early CKD. Adding specific gravity to dipstick proteinuria improves the ability to screen patients with clinically significant proteinuria and can be used to identify patients with early CKD.

BACKGROUND: CKD is often underdiagnosed during early stages when GFR is preserved because of underutilization of testing for quantitative urine albumin-to-creatinine ratio (UACR) or urine protein-to-creatinine ratio (UPCR). Semiquantitative dipstick proteinuria (DSP) on urinalysis is widely obtained but not accurate for identifying clinically significant proteinuria.

METHODS: We identified all patients …

Kcnk1 Promotes Proliferation And Metastasis Of Breast Cancer Cells By Activating Lactate Dehydrogenase A (Ldha) And Up-Regulating H3k18 Lactylation, Xiangchan Hou, Jiawei Ouyang, Le Tang, Pan Wu, Xiangying Deng, Qijia Yan, Lei Shi, Songqing Fan, Chunmei Fan, Can Guo, Qianjin Liao, Yong Li, Wei Xiong, Guiyuan Li, Zhaoyang Zeng, Fuyan Wang

Faculty, Staff and Students Publications

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in …

Naturalistic Assessment Of Reaction Time Variability In Older Adults At Risk For Alzheimer's Disease, Matthew S Welhaf, Hannah Wilks, Andrew J Aschenbrenner, David A Balota, Suzanne E Schindler, Tammie L S Benzinger, Brian A Gordon, Carlos Cruchaga, Chengjie Xiong, John C Morris, Jason Hassenstab

2020-Current year OA Pubs

OBJECTIVE: Maintaining attention underlies many aspects of cognition and becomes compromised early in neurodegenerative diseases like Alzheimer's disease (AD). The consistency of maintaining attention can be measured with reaction time (RT) variability. Previous work has focused on measuring such fluctuations during in-clinic testing, but recent developments in remote, smartphone-based cognitive assessments can allow one to test if these fluctuations in attention are evident in naturalistic settings and if they are sensitive to traditional clinical and cognitive markers of AD.

METHOD: Three hundred and seventy older adults (aged 75.8 +/- 5.8 years) completed a week of remote daily testing on the …

Efemp1 Haploinsufficiency Causes A Marfan-Like Hereditary Connective Tissue Disorder, Irman Forghani, Steven H Lang, Matthew J Rodier, Stephanie A Bivona, Alejo A Morales, Stephan Zuchner, Guney Bademci, Mustafa Tekin

Faculty, Staff and Students Publications

Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele …

Interfacility Referral Communication For Picu Transfer, Caitlin K Thirnbeck, Elizabeth T Espinoza, Elizabeth A Beaman, Alexis L Rozen, Kimberly C Dukes, Hardeep Singh, Loreen A Herwaldt, Christopher P Landrigan, Heather Schacht Reisinger, Christina L Cifra

Faculty, Staff and Students Publications

Objectives: For patients requiring transfer to a higher level of care, excellent interfacility communication is essential. Our objective was to characterize verbal handoffs for urgent interfacility transfers of children to the PICU and compare these characteristics with known elements of high-quality intrahospital shift-to-shift handoffs.

Design: Mixed methods retrospective study of audio-recorded referral calls between referring clinicians and receiving PICU physicians for urgent interfacility PICU transfers.

Setting: Academic tertiary referral PICU.

Patients: Children 0-18 years old admitted to a single PICU following interfacility transfer over a 4-month period (October 2019 to January 2020).

Interventions: None.

Measurements and main results: We reviewed …

Late-Season Influenza Vaccine Effectiveness Against Medically Attended Outpatient Illness, United States, December 2022-April 2023, Jessie R Chung, Stacey L House, Tara Curley, Et Al.

2020-Current year OA Pubs

BACKGROUND: The 2022-23 US influenza season peaked early in fall 2022.

METHODS: Late-season influenza vaccine effectiveness (VE) against outpatient, laboratory-confirmed influenza was calculated among participants of the US Influenza VE Network using a test-negative design.

RESULTS: Of 2561 participants enrolled from December 12, 2022 to April 30, 2023, 91 laboratory-confirmed influenza cases primarily had A(H1N1)pdm09 (6B.1A.5a.2a.1) or A(H3N2) (3C.2a1b.2a.2b). Overall, VE was 30% (95% confidence interval -9%, 54%); low late-season activity precluded estimation for most subgroups.

CONCLUSIONS: 2022-23 late-season outpatient influenza VE was not statistically significant. Genomic characterization may improve the identification of influenza viruses that circulate postinfluenza peak.

Proteolysis Of The Pericellular Matrix: Pinpointing The Role And Involvement Of Matrix Metalloproteinases In Early Osteoarthritic Remodeling, Marina Danalache, Felix Umrath, Rosa Riester, Maik Schwitalle, Farshid Guilak, Ulf Krister Hoffmann

2020-Current year OA Pubs

The pericellular matrix (PCM) serves a critical role in signal transduction and mechanoprotection in chondrocytes. Osteoarthritis (OA) leads to a gradual deterioration of the cartilage, marked by a shift in the spatial arrangement of chondrocytes from initially isolated strands to large cell clusters in end-stage degeneration. These changes coincide with progressive enzymatic breakdown of the PCM. This study aims to assess the role and involvement of specific matrix metalloproteinases (MMPs) in PCM degradation during OA. We selected cartilage samples from 148 OA patients based on the predominant spatial chondrocyte patterns. The presence of various MMPs (-1,-2,-3,-7,-8,-9,-10,-12,-13) was identified by multiplexed …

Aeeg In The First 3 Days After Extremely Preterm Delivery Relates To Neurodevelopmental Outcomes, Roberta Pineda, Zachary Vesoulis, Nathalie El Ters, Amit Mathur

2020-Current year OA Pubs

OBJECTIVES: Investigate relationships between aEEG in the first 72 h in extremely preterm infants with 1) infant, medical, and environmental factors, and 2) infant feeding and neurobehavioral outcomes at term and school-age.

METHODS: Sixty-four preterm infants (≤28 weeks gestation) were enrolled within the first 24-hours of life and had two-channel aEEG until 72 h of life. Standardized neurobehavioral and feeding assessments were conducted at term, and parent-reported outcomes were documented at 5-7 years.

RESULTS: Lower aEEG Burdjalov scores (adjusted for gestational age) were related to vaginal delivery (p = 0.04), cerebral injury (p = 0.01), Black race (p < 0.01) and having unmarried parents (p = 0.02). Lower Burdjalov scores related to less NICU Network Neurobehavioral Scale arousal (p = 0.002) at term and poorer BRIEF global executive function (p = 0.004), inhibition (p = 0.007), working memory (p = 0.02), material organization (p = 0.0008), metacognition (p = 0.01), and behavioral regulation (p = 0.02) at 5-7 years. We did not observe relationships of early aEEG to feeding outcomes or sensory processing measures.

CONCLUSION: Early …

Validated Clinical Score To Predict Gastroesophageal Reflux In Patients With Chronic Laryngeal Symptoms: Cough Reflux, Amanda J Krause, Alexander M Kaizer, Dustin A Carlson, Walter W Chan, Chien-Lin Chen, C Prakash Gyawali, Andrew Jenkins, John E Pandolfino, Vinathi Polamraju, Ming-Wun Wong, Madeline Greytak, Rena Yadlapati

2020-Current year OA Pubs

BACKGROUND & AIMS: Discerning whether laryngeal symptoms result from gastroesophageal reflux is clinically challenging and a reliable tool to stratify patients is needed. We aimed to develop and validate a model to predict the likelihood of gastroesophageal reflux disease (GERD) among patients with chronic laryngeal symptoms.

METHODS: This multicenter international study collected data from adults with chronic laryngeal symptoms who underwent objective testing (upper gastrointestinal endoscopy and/or ambulatory reflux monitoring) between March 2018 and May 2023. The training phase identified a model with optimal receiver operating characteristic curves, and β coefficients informed a weighted model. The validation phase assessed performance …

Autologous Her2-Specific Car T Cells After Lymphodepletion For Advanced Sarcoma: A Phase 1 Trial, Meenakshi Hegde, Shoba Navai, Christopher Derenzo, Sujith K Joseph, Khaled Sanber, Mengfen Wu, Ahmed Z Gad, Katherine A Janeway, Matthew Campbell, Dolores Mullikin, Zeid Nawas, Catherine Robertson, Pretty R Mathew, Huimin Zhang, Birju Mehta, Raksha R Bhat, Angela Major, Ankita Shree, Claudia Gerken, Mamta Kalra, Rikhia Chakraborty, Sachin G Thakkar, Olga Dakhova, Vita S Salsman, Bambi Grilley, Natalia Lapteva, Adrian Gee, Gianpietro Dotti, Riyue Bao, Ahmed Hamed Salem, Tao Wang, Malcolm K Brenner, Helen E Heslop, Winfried S Wels, M John Hicks, Stephen Gottschalk, Nabil Ahmed

Faculty, Staff and Students Publications

In this prospective, interventional phase I study (NCT00902044) for patients with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T-cells (HER2-CART) after lymphodepletion with cyclophosphamide (Cy) +/− fludarabine (Flu): 1×108 T-cells/m2 after Flu (cohort A) or Flu/Cy (cohort B), and 1×108 CAR-positive T-cells/m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2-CART after lymphodepletion. The determination of antitumor responses was the secondary outcome. Thirteen patients were treated in 14 enrollments with 7 receiving multiple infusions. HER2-CART expanded after 19 of 21 infusions. Nine of 12 patients in cohorts A and …

Improving Access To Exome Sequencing In A Medically Underserved Population Through The Texome Project, Blake Vuocolo, Ryan J German, Seema R Lalani, Chaya N Murali, Carlos A Bacino, Stephanie Baskin, Rebecca Littlejohn, John D Odom, Scott Mclean, Carrie Schmid, Morgan Nutter, Melissa Stuebben, Emily Magness, Olivia Juarez, Dina El Achi, Bailey Mitchell, Kevin E Glinton, Laurie Robak, Sandesh C S Nagamani, Lisa Saba, Adasia Ritenour, Lilei Zhang, Haley Streff, Katie Chan, K Jordan Kemere, Kent Carter, Texome Project, Nichole Owen, Liesbeth Vossaert, Pengfei Liu, Hugo Bellen, Michael F Wangler

Faculty, Staff and Students Publications

PURPOSE: Genomic medicine can end diagnostic odysseys for patients with complex phenotypes; however, limitations in insurance coverage and other systemic barriers preclude individuals from accessing comprehensive genetics evaluation and testing.

METHODS: The Texome Project is a 4-year study that reduces barriers to genomic testing for individuals from underserved and underrepresented populations. Participants with undiagnosed, rare diseases who have financial barriers to obtaining exome sequencing (ES) clinically are enrolled in the Texome Project.

RESULTS: We highlight the Texome Project process and describe the outcomes of the first 60 ES results for study participants. Participants received a genetic evaluation, ES, and return …

Unswitched Memory B Cell Deficiency In Children With Sickle Cell Disease And Response To Pneumococcal Polysaccharide Vaccine, Venée N Tubman, Daniel Maysonet, Norma Estrada, Tripti Halder, Lindsey Ramos, Sameera Bhamidipati, Alexandre F Carisey, Charles G Minard, Carl E Allen

Faculty, Staff and Students Publications

Early mortality in sickle cell disease (SCD) is attributed to increased infections due to loss of splenic function. Marginal zone B cells are important for initial opsonization of pathogens and can be absent in spleen histopathology in SCD. The frequency of unswitched memory B cells (UMBC), the circulating correlate of marginal zone B cells, reflects the immunologic function of the spleen. We hypothesized that asplenia in SCD is associated with alterations in the peripheral blood lymphocyte population and explored whether UMBC deficiency was associated with a clinical phenotype. We analyzed B cell subsets and clinical history for 238 children with …

Egg-Induced Adult Food Protein-Induced Enterocolitis Syndrome: Clinical Phenotypes, Natural History And Immunological Characteristics, Purificación Gonzalez-Delgado, Sara Anvari, Jordi Barrachina, Ana L Jimenez Portillo, Teodorikez Jimenez, Francisco M Marco De La Calle, Javier Fernandez

Faculty, Staff and Students Publications

No abstract provided.

Atrial Fibrillation And Clonal Hematopoiesis In Tet2 And Asxl1, Seyedmohammad Saadatagah, Mohammadreza Naderian, Mesbah Uddin, Ozan Dikilitas, Abhishek Niroula, Art Schuermans, Elizabeth Selvin, Ron C Hoogeveen, Kunihiro Matsushita, Vijay Nambi, Bing Yu, Lin Yee Chen, Alexander G Bick, Benjamin L Ebert, Michael C Honigberg, Na Li, Amil Shah, Pradeep Natarajan, Iftikhar J Kullo, Christie M Ballantyne

Faculty, Staff and Students Publications

Importance: Clonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling.

Objective: To determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes.

Design, setting, and participants: This was a population-based, prospective cohort study in participants of the Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) cohort. Samples were collected and echocardiography was performed from 2011 to 2013 in the ARIC cohort, and samples were collected from 2006 to 2010 in the UKB cohort. Included in this study were adults …

Neighborhood-Level Disadvantage And Delayed Adjuvant Therapy In Head And Neck Cancer, Evan M Graboyes, Joshua Lee Cagle, Salma Ramadan, Kavita Prasad, Flora Yan, John Pearce, Angela L Mazul, Jean-Sebastien Anoma, Elizabeth G Hill, Bhisham S Chera, Sidharth V Puram, Ryan Jackson, Vlad C Sandulache, Samantha Tam, Michael C Topf, Russel Kahmke, Nosayaba Osazuwa-Peters, Brian Nussenbaum, Anthony J Alberg, Katherine R Sterba, Chanita Hughes Halbert

Faculty, Staff and Students Publications

Importance: For patients with head and neck squamous cell carcinoma (HNSCC), initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery is recommended by the National Comprehensive Cancer Network Guidelines and the Commission on Cancer. Although individual-level measures of socioeconomic status are associated with receipt of timely, guideline-adherent PORT, the role of neighborhood-level disadvantage has not been examined.

Objective: To characterize the association of neighborhood-level disadvantage with delays in receiving PORT.

Design, setting, and participants: This retrospective cohort study included 681 adult patients with HNSCC undergoing curative-intent surgery and PORT from 2018 to 2020 at 4 US academic medical …

Hyperkinetic Movement Disorder Caused By The Recurrent C892c>T Nacc1 Variant, Jonna Komulainen-Ebrahim, Salla M Kangas, Estrella López-Martín, Timothy Feyma, Fernando Scaglia, Beatriz Martínez-Delgado, Outi Kuismin, Maria Suo-Palosaari, Lucinda Carr, Reetta Hinttala, Manju A Kurian, Johanna Uusimaa

Faculty, Staff and Students Publications

BACKGROUND: Genetic syndromes of hyperkinetic movement disorders associated with epileptic encephalopathy and intellectual disability are becoming increasingly recognized. Recently, a de novo heterozygous NACC1 (nucleus accumbens-associated 1) missense variant was described in a patient cohort including one patient with a combined mitochondrial oxidative phosphorylation (OXPHOS) deficiency.

OBJECTIVES: The objective is to characterize the movement disorder in affected patients with the recurrent c.892C>T NACC1 variant and study the NACC1 protein and mitochondrial function at the cellular level.

METHODS: The movement disorder was analyzed on four patients with the NACC1 c.892C>T (p.Arg298Trp) variant. Studies on NACC1 protein and mitochondrial function …

Inherited C-Terminal Trex1 Variants Disrupt Homology-Directed Repair To Cause Senescence And Dna Damage Phenotypes In Drosophila, Mice, And Humans, Samuel D Chauvin, Fang R Zhao, W Alexander Stinson, Wei Qian, Prabhakar S Andhey, Maxim N Artyomov, Elisha D O Roberson, Jonathan J Miner, Et Al.

2020-Current year OA Pubs

Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3'-5' DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause …

Co-Aggregation With Apolipoprotein E Modulates The Function Of Amyloid-Β In Alzheimer's Disease, Zengjie Xia, Michael R Strickland, Hong Jiang, David M Holtzman, Et Al.

2020-Current year OA Pubs

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related …

Efficacy And Safety Of A Four-Drug, Quarter-Dose Treatment For Hypertension: The Quartet Usa Randomized Trial, Mark D Huffman, Et Al.

2020-Current year OA Pubs

New approaches are needed to lower blood pressure (BP) given persistently low control rates. QUARTET USA sought to evaluate the effect of four-drug, quarter-dose BP lowering combination in patients with hypertension. QUARTET USA was a randomized (1:1), double-blinded trial conducted in federally qualified health centers among adults with hypertension. Participants received either a quadpill of candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg or candesartan 8 mg for 12 weeks. If BP was >130/>80 mm Hg at 6 weeks in either arm, then participants received open label add-on amlodipine 5 mg. The primary outcome …

Three-Year Outcomes Of Post-Acute Sequelae Of Covid-19, Miao Cai, Yan Xie, Eric J Topol, Ziyad Al-Aly

2020-Current year OA Pubs

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes post-acute sequelae of coronavirus disease 2019 (COVID-19) (PASC) in many organ systems. Risks of these sequelae have been characterized up to 2 years after infection, but longer-term follow-up is limited. Here we built a cohort of 135,161 people with SARS-CoV-2 infection and 5,206,835 controls from the US Department of Veterans Affairs who were followed for 3 years to estimate risks of death and PASC. Among non-hospitalized individuals, the increased risk of death was no longer present after the first year of infection, and risk of incident PASC declined over the 3 …

Plasma Extracellular Vesicle Tau And Tdp-43 As Diagnostic Biomarkers In Ftd And Als, Madhurima Chatterjee, Nicolas R Barthélemy, Randall J Bateman, Et Al.

2020-Current year OA Pubs

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy …

Use Of A Blood Biomarker Test Improves Economic Utility In The Evaluation Of Older Patients Presenting With Cognitive Impairment, William J Canestaro, Randall J Bateman, David M Holtzman, Mark Monane, Joel B Braunstein

2020-Current year OA Pubs

More than 16 million Americans living with cognitive impairment warrant a diagnostic evaluation to determine the cause of this disorder. The recent availability of disease-modifying therapies for Alzheimer's disease (AD) is expected to significantly drive demand for such diagnostic testing. Accurate, accessible, and affordable methods are needed. Blood biomarkers (BBMs) offer advantages over usual care amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in these regards. This study used a budget impact model to assess the economic utility of the PrecivityAD

A Microbiota-Directed Complementary Food Intervention In 12-18-Month-Old Bangladeshi Children Improves Linear Growth, Ishita Mostafa, Matthew C Hibberd, Steven J Hartman, Md Hasan Hafizur Rahman, Mustafa Mahfuz, S M Tafsir Hasan, Per Ashorn, Michael J Barratt, Tahmeed Ahmed, Jeffrey I Gordon

2020-Current year OA Pubs

BACKGROUND: Globally, stunting affects ∼150 million children under five, while wasting affects nearly 50 million. Current interventions have had limited effectiveness in ameliorating long-term sequelae of undernutrition including stunting, cognitive deficits and immune dysfunction. Disrupted development of the gut microbiota has been linked to the pathogenesis of undernutrition, providing potentially new treatment approaches.

METHODS: 124 Bangladeshi children with moderate acute malnutrition (MAM) enrolled (at 12-18 months) in a previously reported 3-month RCT of a microbiota-directed complementary food (MDCF-2) were followed for two years. Weight and length were monitored by anthropometry, the abundances of bacterial strains were assessed by quantifying metagenome-assembled …

Bcar4 Expression As A Predictive Biomarker For Endocrine Therapy Resistance In Breast Cancer, Muheng Liao, Jace Webster, Emily M Coonrod, Katherine N Weilbaecher, Christopher A Maher, Nicole M White

2020-Current year OA Pubs

BACKGROUND: Breast cancer, particularly the estrogen receptor positive (ER+) subtype, remains a leading cause of cancer-related death among women. Endocrine therapy is the most effective treatment for ER+ breast cancer; however, the development of resistance presents a significant challenge. This study explored the role of the breast cancer antiestrogen resistance 4 (BCAR4) gene as a potential driver of resistance and a pivotal biomarker in breast cancer.

PATIENTS AND METHODS: The researchers undertook a comprehensive analysis of 1743 patients spanning 6 independent cohorts. They examined the association of BCAR4 expression with patient outcomes across all breast cancer types and the PAM50 …