Digital Commons Network^™

Extended Dna Threading Through A Dual-Engine Motor Module Of The Activating Signal Co-Integrator 1 Complex, Junqiao Jia, Tarek Hilal, Katherine E Bohnsack, Aleksandar Chernev, Ning Tsao, Juliane Bethmann, Aruna Arumugam, Lane Parmely, Nicole Holton, Bernhard Loll, Nima Mosammaparast, Markus T Bohnsack, Henning Urlaub, Markus C Wahl

2020-Current year OA Pubs

Activating signal co-integrator 1 complex (ASCC) subunit 3 (ASCC3) supports diverse genome maintenance and gene expression processes, and contains tandem Ski2-like NTPase/helicase cassettes crucial for these functions. Presently, the molecular mechanisms underlying ASCC3 helicase activity and regulation remain unresolved. We present cryogenic electron microscopy, DNA-protein cross-linking/mass spectrometry as well as in vitro and cellular functional analyses of the ASCC3-TRIP4 sub-module of ASCC. Unlike the related spliceosomal SNRNP200 RNA helicase, ASCC3 can thread substrates through both helicase cassettes. TRIP4 docks on ASCC3 via a zinc finger domain and stimulates the helicase by positioning an ASC-1 homology domain next to the C-terminal …

The F-Pilus Biomechanical Adaptability Accelerates Conjugative Dissemination Of Antimicrobial Resistance And Biofilm Formation, Jonasz B Patkowski, Tobias Dahlberg, Himani Amin, Dharmender K Gahlot, Sukhithasri Vijayrajratnam, Joseph P Vogel, Matthew S Francis, Joseph L Baker, Magnus Andersson, Tiago R D Costa

2020-Current year OA Pubs

Conjugation is used by bacteria to propagate antimicrobial resistance (AMR) in the environment. Central to this process are widespread conjugative F-pili that establish the connection between donor and recipient cells, thereby facilitating the spread of IncF plasmids among enteropathogenic bacteria. Here, we show that the F-pilus is highly flexible but robust at the same time, properties that increase its resistance to thermochemical and mechanical stresses. By a combination of biophysical and molecular dynamics methods, we establish that the presence of phosphatidylglycerol molecules in the F-pilus contributes to the structural stability of the polymer. Moreover, this structural stability is important for …

Cross-Sectional Study To Assess Depression Among Healthcare Workers In Lusaka, Zambia During The Covid-19 Pandemic, Sandra Simbeza, Jacob Mutale, Musunge Mulabe, Lazarus Jere, Chama Bukankala, Kombatende Sikombe, Izukanji Sikazwe, Carolyn Bolton-Moore, Aaloke Mody, Elvin H. Geng, Anjali Sharma, Laura K. Beres, Jake M. Pry

2020-Current year OA Pubs

OBJECTIVES: We sought to assess depression among healthcare workers (HCWs) in the context of COVID-19 in Lusaka Province, Zambia.

DESIGN: This cross-sectional study is nested within a larger study, the Person-Centred Public Health for HIV Treatment in Zambia (PCPH), a cluster-randomised trial to assess HIV care and outcomes.

SETTING: The research was conducted in 24 government-run health facilities from 11 August to 15 October 2020 during the first wave of the COVID-19 pandemic in Lusaka, Zambia.

PARTICIPANTS: We used convenience sampling to recruit HCW participants who were previously enrolled in the PCPH study, had more than 6 months' experience working …

Statins Enhance The Efficacy Of Her2-Targeting Radioligand Therapy In Drug-Resistant Gastric Cancers, Yi Rao, Zachary Samuels, Lukas M Carter, Sebastien Monette, Sandeep Surendra Panikar, Patricia M R Pereira, Jason S Lewis

2020-Current year OA Pubs

Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous …

A Dna Damage-Induced Phosphorylation Circuit Enhances Mec1atr Ddc2atrip Recruitment To Replication Protein A, Luke A Yates, Elias A Tannous, R Marc Morgan, Peter M Burgers, Xiaodong Zhang

2020-Current year OA Pubs

The cell cycle checkpoint kinase Mec1

Monocyte Depletion Enhances Neutrophil Influx And Proneural To Mesenchymal Transition In Glioblastoma, Zhihong Chen, David H Gutmann, Et Al.

2020-Current year OA Pubs

Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genome editing, we generate a mouse model that is deficient of all monocyte chemoattractant proteins. Using this strain, we effectively abolish monocyte infiltration in genetically engineered murine models of de novo glioblastoma (GBM) and hepatocellular carcinoma (HCC), which show differential enrichment patterns for monocytes and neutrophils. Eliminating monocyte chemoattraction in monocyte enriched PDGFB-driven GBM invokes a compensatory neutrophil influx, while having no …

Association Of Radiotherapy Duration With Clinical Outcomes In Patients With Esophageal Cancer Treated In Nrg Oncology Trials: A Secondary Analysis Of Nrg Oncology Randomized Clinical Trials, Christopher L Hallemeier, Hyun Kim, Et Al.

2020-Current year OA Pubs

IMPORTANCE: For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes.

OBJECTIVE: To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT).

DESIGN, SETTING, AND PARTICIPANTS: This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology …

Evaluation Of Birth By Cesarean Delivery And Development Of Early-Onset Colorectal Cancer, Yin Cao, Long H Nguyen, Stefani Tica, Ebunoluwa Otegbeye, Xiaoyu Zong, Bjorn Roelstraete, Andrew T Chan, Barbara B Warner, Olof Stephansson, Jonas F Ludvigsson

2020-Current year OA Pubs

IMPORTANCE: The incidence of early-onset colorectal cancer (CRC), diagnosed younger than 50 years of age, has increased worldwide. Gut dysbiosis throughout the life course is hypothesized as a leading mechanism, yet epidemiologic data are limited.

OBJECTIVE: To prospectively examine the association between birth by cesarean delivery and early-onset CRC among offspring.

DESIGN, SETTING, AND PARTICIPANTS: In this population-based, nationwide case-control study in Sweden, adults diagnosed with CRC between 18 and 49 years of age from 1991 to 2017 were identified through the Epidemiology Strengthened by Histopathology Reports in Sweden (ESPRESSO) cohort. Up to 5 general population control individuals without CRC …

Rapid Profiling Of Dna Replication Dynamics Using Mass Spectrometry-Based Analysis Of Nascent Dna, Mohamed E Ashour, Andrea K Byrum, Alice Meroni, Jun Xia, Saurabh Singh, Roberto Galletto, Susan M Rosenberg, Alessandro Vindigni, Nima Mosammaparast

2020-Current year OA Pubs

The primary method for probing DNA replication dynamics is DNA fiber analysis, which utilizes thymidine analog incorporation into nascent DNA, followed by immunofluorescent microscopy of DNA fibers. Besides being time-consuming and prone to experimenter bias, it is not suitable for studying DNA replication dynamics in mitochondria or bacteria, nor is it adaptable for higher-throughput analysis. Here, we present mass spectrometry-based analysis of nascent DNA (MS-BAND) as a rapid, unbiased, quantitative alternative to DNA fiber analysis. In this method, incorporation of thymidine analogs is quantified from DNA using triple quadrupole tandem mass spectrometry. MS-BAND accurately detects DNA replication alterations in both …

The Value And Impacts Of Academic Public Health Departments, Paul C Erwin, Julie H Grubaugh, Stephanie Mazzucca-Ragan, Ross C Brownson

2020-Current year OA Pubs

The academic health department (AHD) is a partnership between an academic institution and a governmental health agency. These partnerships are meant to provide mutual benefits that include opportunities for student field placements and internships, practice-informed curriculum, and practice-based research. The term academic health department dates back only to 2000, although there are several examples of academic-practice partnerships prior to that date. In addition to AHDs that have been established over the past two decades, other forms of academic-practice engagement provide similar mutual benefits, such as prevention research centers and public health training centers. Current research on AHDs explores how these …

Advanced Care Planning For Hospitalized Patients Following Clinician Notification Of Patient Mortality By A Machine Learning Algorithm, Stephen Chi, Seunghwan Kim, Matthew Reuter, Katharine Ponzillo, Debra Parker Oliver, Randi Foraker, Kevin Heard, Jingxia Liu, Kyle Pitzer, Patrick White, Nathan Moore

2020-Current year OA Pubs

IMPORTANCE: Goal-concordant care is an ongoing challenge in hospital settings. Identification of high mortality risk within 30 days may call attention to the need to have serious illness conversations, including the documentation of patient goals of care.

OBJECTIVE: To examine goals of care discussions (GOCDs) in a community hospital setting with patients identified as having a high risk of mortality by a machine learning mortality prediction algorithm.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study took place at community hospitals within 1 health care system. Participants included adult patients with a high risk of 30-day mortality who were admitted to 1 …

Estimated Clinical Outcomes And Cost-Effectiveness Associated With Provision Of Addiction Treatment In Us Primary Care Clinics, Raagini Jawa, Yjuliana Tin, Samantha Nall, Susan L Calcaterra, Alexandra Savinkina, Laura R Marks, Simeon D Kimmel, Benjamin P Linas, Joshua A Barocas

2020-Current year OA Pubs

IMPORTANCE: US primary care practitioners (PCPs) are the largest clinical workforce, but few provide addiction care. Primary care is a practical place to expand addiction services, including buprenorphine and harm reduction kits, yet the clinical outcomes and health care sector costs are unknown.

OBJECTIVE: To estimate the long-term clinical outcomes, costs, and cost-effectiveness of integrated buprenorphine and harm reduction kits in primary care for people who inject opioids.

DESIGN, SETTING, AND PARTICIPANTS: In this modeling study, the Reducing Infections Related to Drug Use Cost-Effectiveness (REDUCE) microsimulation model, which tracks serious injection-related infections, overdose, hospitalization, and death, was used to examine …

Associations Of Combined Physical Activity And Body Mass Index Groups With Colorectal Cancer Survival Outcomes, Caroline Himbert, Matthew G Mutch, Corey Bernadt, Adetunji T Toriola, Et Al.

2020-Current year OA Pubs

BACKGROUND: Physical activity and BMI have been individually associated with cancer survivorship but have not yet been studied in combinations in colorectal cancer patients. Here, we investigate individual and combined associations of physical activity and BMI groups with colorectal cancer survival outcomes.

METHODS: Self-reported physical activity levels (MET hrs/wk) were assessed using an adapted version of the International Physical Activity Questionnaire (IPAQ) at baseline in 931 patients with stage I-III colorectal cancer and classified into 'highly active' and'not-highly active'(≥ / < 18 MET hrs/wk). BMI (kg/m

RESULTS: 'Not-highly active' compared to 'highly active' and 'overweight'/ 'obese' compared to 'normal weight' patients had a 40-50% increased risk …

On-The-Go Adaptation Of Implementation Approaches And Strategies In Health: Emerging Perspectives And Research Opportunities, Elvin H Geng, Aaloke Mody, Byron J Powell

2020-Current year OA Pubs

In many cases, implementation approaches (composed of one or more strategies) may need to change over time to work optimally. We use a literature review to inform a mechanistic analysis of such on-the-go adaptations. We suggest that such adaptations of implementation strategies consist of three necessary steps. The first component is the initial effect of the implementation approach on intended implementation, service delivery, or clinical outcomes. Second, these initial effects must in turn be used to modify, alter, intensify, or otherwise change the implementation approach. Third, the modified approach itself has effects. Conceiving of adaptation as all three steps implies …

Priorities To Promote Participant Engagement In The Participant Engagement And Cancer Genome Sequencing (Pe-Cgs) Network, Anne Lr Schuster, Graham A Colditz, Li Ding, Bettina F Drake, Ryan C Fields, Et Al.

2020-Current year OA Pubs

BACKGROUND: Engaging diverse populations in cancer genomics research is of critical importance and is a fundamental goal of the NCI Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Established as part of the Cancer Moonshot, PE-CGS is a consortium of stakeholders including clinicians, scientists, genetic counselors, and representatives of potential study participants and their communities. Participant engagement is an ongoing, bidirectional, and mutually beneficial interaction between study participants and researchers. PE-CGS sought to set priorities in participant engagement for conducting the network's research.

METHODS: PE-CGS deliberatively engaged its stakeholders in the following four-phase process to set the network's research priorities …

Outcome Prediction By The 2022 European Leukemianet Genetic-Risk Classification For Adults With Acute Myeloid Leukemia: An Alliance Study, Krzysztof Mrózek, Geoffrey L Uy, Et Al.

2020-Current year OA Pubs

Recently, the European LeukemiaNet (ELN) revised its genetic-risk classification of acute myeloid leukemia (AML). We categorized 1637 adults with AML treated with cytarabine/anthracycline regimens according to the 2022 and 2017 ELN classifications. Compared with the 2017 ELN classification, 2022 favorable group decreased from 40% to 35% and adverse group increased from 37% to 41% of patients. The 2022 genetic-risk groups seemed to accurately reflect treatment outcomes in all patients and patients aged <60 years, but in patients aged ≥60 years, relapse rates, disease-free (DFS) and overall (OS) survival were not significantly different between intermediate and adverse groups. In younger African-American patients, DFS and OS did not differ between intermediate-risk and adverse-risk patients nor did DFS between favorable and intermediate groups. In Hispanic patients, DFS and OS did not differ between favorable and intermediate groups. Outcome prediction abilities of 2022 and 2017 ELN classifications were similar. Among favorable-risk patients, myelodysplasia-related mutations did not affect patients with CEBPA

Social Disadvantage During Pregnancy: Effects On Gestational Age And Birthweight, Joan L Luby, Sarah K England, Deanna M Barch, Barbara B Warner, Cynthia Rogers, Christopher D Smyser, Regina Triplett, Jyoti Arora, Tara A Smyser, George M Slavich, Peinan Zhao, Molly Stout, Erik Herzog, J Philip Miller

2020-Current year OA Pubs

OBJECTIVE: Whether psychosocial adversity during pregnancy impacts fetal health outcomes at birth remains underexplored. This is a critical issue given significant social disadvantage and psychosocial stress faced by pregnant women worldwide.

STUDY DESIGN: Measures of social disadvantage and psychological factors, and medical/reproductive and nutritional health status in pregnant women were obtained at each trimester. Using Structural Equation Modeling (SEM), we investigated the relationship of forms of adversity to each other and to infant gestational age, and birthweight.

RESULTS: Among 399 singletons, Social Disadvantage significantly predicted gestational age (p = 0.003), and residual birthweight (p = 0.006). There was a 0.4 …

Understanding Misimplementation In U.S. State Health Departments: An Agent-Based Model, Matt Kasman, Ross A Hammond, Rob Purcell, Louise Farah Saliba, Stephanie Mazzucca-Ragan, Margaret Padek, Peg Allen, Douglas A Luke, Sarah Moreland-Russell, Paul C Erwin, Ross C Brownson

2020-Current year OA Pubs

INTRODUCTION: The research goal of this study is to explore why misimplementation occurs in public health agencies and how it can be reduced. Misimplementation is ending effective activities prematurely or continuing ineffective ones, which contributes to wasted resources and suboptimal health outcomes.

METHODS: The study team created an agent-based model that represents how information flow, filtered through organizational structure, capacity, culture, and leadership priorities, shapes continuation decisions. This agent-based model used survey data and interviews with state health department personnel across the U.S. between 2014 and 2020; model design and analyses were conducted with substantial input from stakeholders between 2019 …

The Who Aware (Access, Watch, Reserve) Antibiotic Book And Prevention Of Antimicrobial Resistance, Veronica Zanichelli, Michael Sharland, Bernadette Cappello, Lorenzo Moja, Haileyesus Getahun, Carmem Pessoa-Silva, Hatim Sati, Catharina Van Weezenbeek, Hanan Balkhy, Mariângela Simão, Sumanth Gandra, Benedikt Huttner

2020-Current year OA Pubs

Guidance on the appropriate use of antibiotics for common infections is lacking in many settings. The World Health Organization (WHO) has recently released

Air Pollution And Acute Kidney Injury In The U.S. Medicare Population: A Longitudinal Cohort Study, Whanhee Lee, Ziyad Al-Aly, Et Al.

2020-Current year OA Pubs

BACKGROUND: Recent studies have reported the association between air pollution exposure and reduced kidney function. However, it is unclear whether air pollution is associated with an increased risk of acute kidney injury (AKI).

OBJECTIVES: To address this gap in knowledge, we investigated the effect estimates of long-term exposures to fine particulate matter [PM

METHODS: This nationwide population-based longitudinal cohort study included 61,300,754 beneficiaries enrolled in Medicare Part A fee-for-service (FFS) who were

RESULTS: Exposure to

DISCUSSION: This study found an association between exposures to air pollution and the risk of the first hospital admission with AKI, and this association persisted …

Axatilimab For Chronic Graft-Versus-Host Disease After Failure Of At Least Two Prior Systemic Therapies: Results Of A Phase I/Ii Study, Carrie L Kitko, Iskra Pusic, Et Al.

2020-Current year OA Pubs

PURPOSE: Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity after allogeneic hematopoietic cell transplantation. Colony-stimulating factor 1 receptor (CSF-1R)-dependent macrophages promote cGVHD fibrosis, and their elimination in preclinical studies ameliorated cGVHD. Axatilimab is a humanized monoclonal antibody that inhibits CSF-1R signaling and restrains macrophage development.

PATIENTS AND METHODS: This phase I (phI)/phase II (phII) open-label study (ClinicalTrials.gov identifier: NCT03604692) evaluated safety, tolerability, and efficacy of axatilimab in patients age ≥ 6 years with active cGVHD after ≥ 2 prior systemic therapy lines. Primary objectives in phI were to identify the optimal biologic and recommended phII dose and …

Myeloid Autophagy Genes Protect Mice Against Fatal Tnf- And Lps-Induced Cytokine Storm Syndromes, Ya-Ting Wang, Amy Sansone, Asya Smirnov, Christina L Stallings, Anthony Orvedahl

2020-Current year OA Pubs

ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CASP1: caspase 1; CASP4/CASP11: caspase 4, apoptosis-related cysteine peptidase; CIM: conditionally immortalized macrophage; CLP: cecal ligation and puncture; CSS: cytokine storm syndrome; DC: dendritic cell; IFNG/IFNγ: interferon gamma; IFNGR1: interferon gamma receptor 1; ip: intraperitoneal; iv: intravenous; IL12/p70: interleukin 12, p70 heterodimer; IL18: Interleukin 18; ITGAX/CD11c: integrin alpha X; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; LYZ2/LYSM: lysozyme 2; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; RB1CC1/FIP200: RB1-inducible coiled-coil 1; S100A8/MRP8: S100 calcium binding protein A8 (calgranulin …

Persistent Molecular Disease In Adult Patients With Aml Evaluated With Whole-Exome And Targeted Error-Corrected Dna Sequencing, Michael J Slade, Reza Ghasemi, Michelle O'Laughlin, Tasha Burton, Robert S Fulton, Haley J Abel, Eric J Duncavage, Timothy J Ley, Meagan A Jacoby, David H Spencer

2020-Current year OA Pubs

PURPOSE: Persistent molecular disease (PMD) after induction chemotherapy predicts relapse in AML. In this study, we used whole-exome sequencing (WES) and targeted error-corrected sequencing to assess the frequency and mutational patterns of PMD in 30 patients with AML.

MATERIALS AND METHODS: The study cohort included 30 patients with adult AML younger than 65 years who were uniformly treated with standard induction chemotherapy. Tumor/normal WES was performed for all patients at presentation. PMD analysis was evaluated in bone marrow samples obtained during clinicopathologic remission using repeat WES and analysis of patient-specific mutations and error-corrected sequencing of 40 recurrently mutated AML genes …

Complete Remission Of Widely Metastatic Human Epidermal Growth Factor Receptor 2-Amplified Pancreatic Adenocarcinoma After Precision Immune And Targeted Therapy With Description Of Sequencing And Organoid Correlates, Daniel A King, S Peter Goedegebuure, Xiuli Zhang, Jasreet Hundal, Malachi Griffith, William E Gillanders, Haeseong Park, Et Al.

2020-Current year OA Pubs

No abstract provided.

Insights Into The Pathogenesis Of Hereditary Angioedema Using Genetic Sequencing And Recombinant Protein Expression Analyses, Zhen Ren, Shuangxia Zhao, Tiandao Li, H James Wedner, John P Atkinson

2020-Current year OA Pubs

BACKGROUND: The pathogenesis of hereditary angioedema (HAE) type I and type II is linked to defective C1 esterase inhibitor (C1-INH) encoded by the SERPING1 gene. There are substantial variabilities in the clinical presentations of patients with HAE that are not directly correlated to the serum levels of C1-INH. The impact of SERPING1 variants on C1-INH expression, structure, and function is incompletely understood.

OBJECTIVE: To investigate the influence of SERPING1 variants on the C1-INH expression, structure, and function of 20 patients with HAE from 14 families with no prior genetic diagnosis.

METHODS: Patients underwent whole-exome sequencing (WES). If no variants were …

Utilization Of Microwave Ablation As A Novel Approach For Refractory Chylothorax Following Esophagectomy: A Case Report, Khashayar Farahnak, Alejandro De Filippis Falcon, Hailey M Shepherd, Carlos J Guevara, Mayank R Patel, G Alexander Patterson, Varun Puri, Daniel Kreisel, Ruben G Nava

2020-Current year OA Pubs

No abstract provided.

Logistical, Technical, And Radiation Safety Aspects Of Establishing A Radiopharmaceutical Therapy Program: A Case In Lutetium-177 Prostate-Specific Membrane Antigen (Psma) Therapy, Jacqueline E Zoberi, Jose Garcia-Ramirez, David Luechtefeld, Nichole M Maughan, Maxwell Amurao, Reiko Oyama, Brian C Baumann, Hiram A Gay, Jeff M Michalski

2020-Current year OA Pubs

Prostate-specific membrane antigen (PSMA) is a cell surface protein highly expressed in nearly all prostate cancers, with restricted expression in some normal tissues. The differential expression of PSMA from tumor to non-tumor tissue has resulted in the investigation of numerous targeting strategies for therapy of patients with metastatic prostate cancer. In March of 2022, the FDA granted approval for the use of lutetium-177 PSMA-617 (Lu-177-PSMA-617) for patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. Therefore, the use of Lu-177-PSMA-617 is expected to increase and become more widespread. Herein, …

Management Of Infusion-Related Reactions (Irrs) In Patients Receiving Amivantamab In The Chrysalis Study, Keunchil Park, Ramaswamy Govindan, Et Al.

2020-Current year OA Pubs

BACKGROUND: Amivantamab, a fully humanized EGFR-MET bispecific antibody, has antitumor activity in diverse EGFR- and MET-driven non-small cell lung cancer (NSCLC) and a safety profile consistent with associated on-target activities. Infusion-related reaction(s) (IRR[s]) are reported commonly with amivantamab. We review IRR and subsequent management in amivantamab-treated patients.

METHODS: Patients treated with the approved dose of intravenous amivantamab (1050 mg, <80 kg; 1400 mg, ≥80 kg) in CHRYSALIS-an ongoing, phase 1 study in advanced EGFR-mutated NSCLC-were included in this analysis. IRR mitigations included split first dose (350 mg, day 1 [D1]; remainder, D2), reduced initial infusion rates with proactive infusion interruption, and steroid premedication before initial dose. For all doses, pre-infusion antihistamines and antipyretics were required. Steroids were optional after the initial dose.

RESULTS: As of 3/30/2021, 380 patients received amivantamab. IRRs were reported in 256 (67%) patients. Signs/symptoms of IRR included chills, dyspnea, flushing, nausea, chest discomfort, and vomiting. Most of the 279 IRRs were grade 1 or 2; grade 3 and 4 …

Mitochondrial Pyruvate Carrier Inhibition Initiates Metabolic Crosstalk To Stimulate Branched Chain Amino Acid Catabolism, Daniel Ferguson, Sophie J Eichler, Nicole K H Yiew, Jerry R Colca, Kevin Cho, Gary J Patti, Trevor M Shew, Andrew J Lutkewitte, Sandip Mukherjee, Kyle S Mccommis, Natalie M Niemi, Brian N Finck

2020-Current year OA Pubs

OBJECTIVE: The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH.

METHODS: Circulating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE; NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n = 94) or 250 mg …

Failure Of Early Mycological Clearance In Hiv-Negative Cryptococcal Meningitis, Zhihui Su, Chongliang Luo, Kai Dai, Dasen Yuan, Bang-E Qin, Meifeng Gu, Junyu Liu, Yong Chen, Fuhua Peng, Ying Jiang

2020-Current year OA Pubs

BACKGROUND: Negative cerebrospinal fluid (CSF) cultures at 2 weeks after antifungal treatment (early mycological clearance [EMC]) should be a treatment goal of cryptococcal meningitis (CM). However, EMC in human immunodeficiency virus (HIV)-negative patients with CM is poorly understood.

METHODS: We conducted a retrospective review of medical records and 1-year follow-up of 141 HIV-negative patients with CM with an initial positive CSF culture for

RESULTS: Of 141 patients, 28 (19.9%) had EMC failure. The 1-year mortality rate was 5.7% (8/141). Multivariate analysis showed that non-amphotericin B (AmB)-based regimens, baseline log

CONCLUSIONS: EMC failure in HIV-negative CM is attributed to non-AmB-based therapy …