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Pi3k Inhibition Enhances The Anti-Tumor Effect Of Eribulin In Triple Negative Breast Cancer, Sandeep Rajput, Zhanfang Guo, Shunqiang Li, Cynthia X. Ma

Open Access Publications

Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) is commonly observed in triple negative breast cancer (TNBC), leading to activation of the phosphoinositide 3-kinase (PI3K) signaling to promote tumor cell growth and chemotherapy resistance. In this study, we investigated whether adding a pan-PI3K inhibitor could improve the cytotoxic effect of eribulin, a non-taxane microtubule inhibitor, in TNBC patient-derived xenograft models (PDX) with loss of PTEN, and the underlying molecular mechanisms. Three TNBC-PDX models (WHIM6, WHIM12 and WHIM21), all with loss of PTEN expression, were tested for their response to BKM120 and eribulin, alone or in combination

Survey On The Prevalence Of Dyspepsia And Practices Of Dyspepsia Management In Rural Eastern Uganda, Yang Jae Lee, Gautam Adusumilli, Francis Kyakulaga, Peter Muwereza, Rauben Kazungu, Timothy Scott Blackwell, Jose Saenz, Moonkyung Cho Schubert

Open Access Publications

Aim: To investigate the current prevalence and management of dyspepsia in rural Eastern Uganda.

Methods: Residents older than 18 years of age across 95 study sites in Namutumba District, Eastern Uganda were surveyed. Each respondent was administered a questionnaire about dyspepsia and pertinent health-seeking behaviors. Health workers at 12 different clinics were also assessed on their competence in managing dyspepsia. Proportion-based analysis was used to determine self-reported outcome variables reported in this study, including: prevalence of dyspepsia; breakdown of symptoms; initial diagnosis location; management strategies; and appropriate medication usage.

Results: 397 residents (average age of 41.2 years) participated in this …

The Constances Job Exposure Matrix Based On Self-Reported Exposure To Physical Risk Factors: Development And Evaluation, Bradley A Evanoff, Marcus Yung, Skye Buckner-Petty, Johan Hviid Andersen, Yves Roquelaure, Alexis Descatha, Ann Marie Dale

Open Access Publications

OBJECTIVES: Job exposure matrices (JEMs) can be constructed from expert-rated assessments, direct measurement and self-reports. This paper describes the construction of a general population JEM based on self-reported physical exposures, its ability to create homogeneous exposure groups (HEG) and the use of different exposure metrics to express job-level estimates.

METHODS: The JEM was constructed from physical exposure data obtained from the Cohorte des consultants des Centres d'examens de santé (CONSTANCES). Using data from 35 526 eligible participants, the JEM consisted of 27 physical risk factors from 407 job codes. We determined whether the JEM created HEG by performing non-parametric multivariate …

Genetic Approaches To Metabolic Bone Diseases, Fadil M Hannan, Paul J Newey, Michael P Whyte, Rajesh V Thakker

Open Access Publications

Metabolic bone diseases comprise a diverse group of disorders characterized by alterations in skeletal homeostasis, and are often associated with abnormal circulating concentrations of calcium, phosphate or vitamin D metabolites. These diseases commonly have a genetic basis and represent either a monogenic disorder due to a germline or somatic single gene mutation, or an oligogenic or polygenic disorder that involves variants in more than one gene. Germline single gene mutations causing Mendelian diseases typically have a high penetrance, whereas the genetic variations causing oligogenic or polygenic disorders are each associated with smaller effects with additional contributions from environmental factors. Recognition …

Ddr2 Controls Breast Tumor Stiffness And Metastasis By Regulating Integrin Mediated Mechanotransduction In Cafs, Samantha V.H. Bayer, Whitney R. Grither, Audrey Brenot, Priscilla Y. Hwang, Craig E. Barcus, Melanie Ernst, Patrick Pence, Christopher Walter, Amit Pathak, Gregory D. Longmore

Open Access Publications

Biomechanical changes in the tumor microenvironment influence tumor progression and metastases. Collagen content and fiber organization within the tumor stroma are major contributors to biomechanical changes (e., tumor stiffness) and correlated with tumor aggressiveness and outcome. What signals and in what cells control collagen organization within the tumors, and how, is not fully understood. We show in mouse breast tumors that the action of the collagen receptor DDR2 in CAFs controls tumor stiffness by reorganizing collagen fibers specifically at the tumor-stromal boundary. These changes were associated with lung metastases. The action of DDR2 in mouse and human CAFs, and tumors …

The Subjective Value Of Cognitive Effort Is Encoded By A Domain-General Valuation Network, Andrew Westbrook, Bidhan Lamichhane, Todd Braver

Open Access Publications

Cognitive control is necessary for goal-directed behavior, yet people treat cognitive control demand as a cost, which discounts the value of rewards in a similar manner as other costs, such as delay or risk. It is unclear, however, whether the subjective value (SV) of cognitive effort is encoded in the same putatively domain-general brain valuation network implicated in other cost domains, or instead engages a distinct frontoparietal network, as implied by recent studies. Here, we provide rigorous evidence that the valuation network, with core foci in the ventromedial prefrontal cortex and ventral striatum, also encodes SV during cognitive effort-based decision-making …

Celltag Indexing: Genetic Barcode-Based Sample Multiplexing For Single-Cell Genomics, Chuner Guo, Wenjun Kong, Kenji Kamimoto, Guillermo C Rivera-Gonzalez, Xue Yang, Yuhei Kirita, Samantha A Morris

Open Access Publications

High-throughput single-cell assays increasingly require special consideration in experimental design, sample multiplexing, batch effect removal, and data interpretation. Here, we describe a lentiviral barcode-based multiplexing approach, CellTag Indexing, which uses predefined genetic barcodes that are heritable, enabling cell populations to be tagged, pooled, and tracked over time in the same experimental replicate. We demonstrate the utility of CellTag Indexing by sequencing transcriptomes using a variety of cell types, including long-term tracking of cell engraftment and differentiation in vivo. Together, this presents CellTag Indexing as a broadly applicable genetic multiplexing tool that is complementary with existing single-cell technologies.

Comparison Of Opioid Prescribing By Dentists In The United States And England, Katie J. Suda, Michael J. Durkin, Gregory S. Calip, Walid F. Gellad, Hajwa Kim, Peter B. Lockhart, Susan A. Rowan, Martin H. Thornhill

Open Access Publications

Importance: The United States consumes most of the opioids worldwide despite representing a small portion of the world's population. Dentists are one of the most frequent US prescribers of opioids despite data suggesting that nonopioid analgesics are similarly effective for oral pain. While oral health and dentist use are generally similar between the United States and England, it is unclear how opioid prescribing by dentists varies between the 2 countries.

Objective: To compare opioid prescribing by dentists in the United States and England.

Design, Setting, and Participants: Cross-sectional study of prescriptions for opioids dispensed from outpatient pharmacies and health care …

Reaching The End Of The Line: Urinary Tract Infections, Kevin O Tamadonfar, Natalie S Omattage, Caitlin N Spaulding, Scott J Hultgren

Open Access Publications

Urinary tract infections (UTIs) cause a substantial health care burden. UTIs (i) are most often caused by uropathogenic

Partial Adaptation To The Value Range In The Macaque Orbitofrontal Cortex, Katherine E. Conen, Camillo Padoa-Schioppa

Open Access Publications

Values available for choice in different behavioral contexts can vary immensely. To compensate for this variability, neuronal circuits underlying economic decisions undergo adaptation. In orbitofrontal cortex (OFC), neurons encode the subjective value of offered and chosen goods in a quasilinear way. Previous experiments found that the gain of the encoding is lower when the value range is wider. However, the parameters OFC neurons adapted to remained unclear. Furthermore, previous studies did not examine additive changes in neuronal responses. Computational considerations indicate that these factors can directly impact choice behavior. Here we investigated how OFC neurons adapt to changes in the …

Genome-Wide Association Study In Finnish Twins Highlights The Connection Between Nicotine Addiction And Neurotrophin Signaling Pathway, Jenni Hällfors, Teemu Palviainen, Ida Surakka, Richa Gupta, Jadwiga Buchwald, Anu Raevuori, Samuli Ripatti, Tellervo Korhonen, Pekka Jousilahti, Pamela A F Madden, Jaakko Kaprio, Anu Loukola

Open Access Publications

The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we …

Threat Sensitivity Is Associated With The Healthcare Source Used Most Often: Doctor's Office, Emergency Room, Or None At All, Stephen Ristvedt, Kathryn Trinkaus, Erika Waters, Aimee James

Open Access Publications

A significant proportion of American adults do not have a regular source of healthcare and the reasons for this shortfall are not fully understood. The objective of this study was to examine the relationship between individual differences in threat sensitivity and healthcare utilization in a survey of 483 African American men. Demographics, psychological characteristics, and health behaviors were assessed. The primary outcomes were: 1) most frequent source of healthcare utilization (doctor's office or clinic vs. emergency room vs. no place), and 2) frequency of healthcare utilization (one or more vs. no healthcare visits in the previous year). Data were analyzed …

Brain Tumors In Neurofibromatosis Type 1, Amanda De Andrade Costa, David H Gutmann

Open Access Publications

As a cancer predisposition syndrome, individuals with neurofibromatosis type 1 (NF1) are at increased risk for the development of both benign and malignant tumors. One of the most common locations for these cancers is the central nervous system, where low-grade gliomas predominate in children. During early childhood, gliomas affecting the optic pathway are most frequently encountered, whereas gliomas of the brainstem and other locations are observed in slightly older children. In contrast, the majority of gliomas arising in adults with NF1 are malignant cancers, typically glioblastoma, involving the cerebral hemispheres. Our understanding of the pathogenesis of NF1-associated gliomas has been …

Regulation Of Cilia Abundance In Multiciliated Cells, Rashmi Nanjundappa, Dong Kong, Kyuhwan Shim, Tim Stearns, Steven L. Brody, Jadranka Loncarek, Moe R. Mahjoub

Open Access Publications

Multiciliated cells (MCC) contain hundreds of motile cilia used to propel fluid over their surface. To template these cilia, each MCC produces between 100-600 centrioles by a process termed centriole amplification. Yet, how MCC regulate the precise number of centrioles and cilia remains unknown. Airway progenitor cells contain two parental centrioles (PC) and form structures called deuterosomes that nucleate centrioles during amplification. Using an ex vivo airway culture model, we show that ablation of PC does not perturb deuterosome formation and centriole amplification. In contrast, loss of PC caused an increase in deuterosome and centriole abundance, highlighting the presence of …

Mutant Huntingtin Enhances Activation Of Dendritic Kv4 K+ Channels In Striatal Spiny Projection Neurons, Luis Carrillo-Reid, Michelle Day, Zhong Xie, Alexandria E. Melendez, Jyothisri Kondapalli, Joshua L. Plotkin, David L. Wokosin, Yu Chen, Geraldine J. Kress, Michael Kaplitt, Ema Ilijic, Jaime N. Guzman, C Savio Chan, D James Surmeier

Open Access Publications

Huntington's disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued …

Systematic Sampling Of Adults As A Sensitive Means Of Detecting Persistence Of Lymphatic Filariasis Following Mass Drug Administration In Sri Lanka, Ramakrishna U. Rao, Sandhya D. Samarasekera, Kumara C. Nagodavithana, Manjula W. Punchihewa, Udaya S. B. Ranasinghe, Gary J. Weil

Open Access Publications

No abstract provided.

The Effect Of Bpifa1/Splunc1 Genetic Variation On Its Expression And Function In Asthmatic Airway Epithelium, Niccolette Schaefer, Mario Castro, Andrea M. Coverstone, Jonathan Boomer, Et Al

Open Access Publications

Bacterial permeability family member A1 (BPIFA1), also known as short palate, lung, and nasal epithelium clone 1 (SPLUNC1), is a protein involved in the antiinflammatory response. The goal of this study was to determine whether BPIFA1 expression in asthmatic airways is regulated by genetic variations, altering epithelial responses to type 2 cytokines (e.g., IL-13). Nasal epithelial cells from patients with mild to severe asthma were collected from the National Heart, Lung, and Blood Institute Severe Asthma Research Program centers, genotyped for rs750064, and measured for BPIFA1. To determine the function of rs750064, cells were cultured at air-liquid interface and treated …

An Obligatory Role For Club Cells In Preventing Obliterative Bronchiolitis In Lung Transplants, Zhiyi Liu, Fuyi Liao, Davide Scozzi, Yuka Furuya, Kaitlyn N Pugh, Ramsey Hachem, Delphine L Chen, Marlene Cano, Jonathan M Green, Alexander S Krupnick, Daniel Kreisel, Anne Karina T Perl, Howard J Huang, Steven L Brody, Andrew E Gelman

Open Access Publications

Obliterative bronchiolitis (OB) is a poorly understood airway disease characterized by the generation of fibrotic bronchiolar occlusions. In the lung transplant setting, OB is a pathological manifestation of bronchiolitis obliterans syndrome (BOS), which is a major impediment to long-term recipient survival. Club cells play a key role in bronchiolar epithelial repair, but whether they promote lung transplant tolerance through preventing OB remains unclear. We determined if OB occurs in mouse orthotopic lung transplants following conditional transgene-targeted club cell depletion. In syngeneic lung transplants club cell depletion leads to transient epithelial injury followed by rapid club cell-mediated repair. In contrast, allogeneic …

Significance Of Her2 Protein Expression And Her2 Gene Amplification In Colorectal Adenocarcinomas, Xin-Yu Wang, Zhi-Xue Zheng, Yu Sun, Yan-Hua Bai, Yun-Fei Shi, Li-Xin Zhou, Yun-Feng Yao, Ai-Wen Wu, Deng-Feng Cao

Open Access Publications

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. While the role of HER2 as a prognostic biomarker in colorectal adenocarcinomas (CRCs) remains uncertain, its relevance as a therapeutic target has been established. We undertook the present study to evaluate the frequency of HER2 expression in CRC and to correlate it with various clinicopathological variables.

AIM: To correlate HER2 protein expression and

METHODS: About 1195 consecutive surgically resected CRCs were analyzed by immunohistochemical staining (IHC) to assess HER2 protein expression, and 141 selected tumors were further evaluated …

Detection Of Pediatric Upper Extremity Motor Activity And Deficits With Accelerometry, Catherine R. Hoyt, Andrew N. Van, Mario Ortega, Jonathan M. Koller, Elyse A. Everett, Annie L. Nguyen, Catherine E. Lang, Bradley L. Schlaggar, Nico U.F. Dosenbach

Open Access Publications

Importance: Affordable, quantitative methods to screen children for developmental delays are needed. Motor milestones can be an indicator of developmental delay and may be used to track developmental progress. Accelerometry offers a way to gather real-world information about pediatric motor behavior.

Objective: To develop a referent cohort of pediatric accelerometry from bilateral upper extremities (UEs) and determine whether movement can accurately distinguish those with and without motor deficits.

Design, Setting, and Participants: Children aged 0 to 17 years participated in a prospective cohort from December 8, 2014, to December 29, 2017. Children were recruited from Ranken Jordan Pediatric Bridge Hospital, …

A Survey Of Risk Tolerance To Multiple Sclerosis Therapies, Robert J Fox, Carol Cosenza, Lauren Cripps, Paul Ford, Marybeth Mercer, Sneha Natarajan, Amber Salter, Tuula Tyry, Stacey S Cofield

Open Access Publications

OBJECTIVE: To determine tolerance to various risk scenarios associated with current multiple sclerosis (MS) therapies.

METHODS: People with MS from the North American Research Committee on Multiple Sclerosis Registry's online cohort and the National Multiple Sclerosis Society were invited to complete a questionnaire on tolerance to real-world risks associated with a hypothetical therapy. Multiple risks levels were presented, including skin rash, infection, kidney injury, thyroid injury, liver injury, and progressive multifocal leukoencephalopathy (PML).

RESULTS: Both PML and kidney injury had the lowest risk tolerance (RT) at 1:1,000,000, and thyroid and infection risks had the highest tolerance at 1:1,000. Men, younger …

Subsequent Event Risk In Individuals With Established Coronary Heart Disease, Riyaz S. Patel, Petra A. Lenzini, Sharon Cresci, Et Al

Open Access Publications

No abstract provided.

The Structure Of Cognition In 9 And 10 Year-Old Children And Associations With Problem Behaviors: Findings From The Abcd Study's Baseline Neurocognitive Battery, Wesley K Thompson, Deanna M Barch, James M Bjork, Raul Gonzalez, Bonnie J Nagel, Sara Jo Nixon, Monica Luciana

Open Access Publications

The Adolescent Brain Cognitive Development (ABCD) study is poised to be the largest single-cohort long-term longitudinal study of neurodevelopment and child health in the United States. Baseline data on N= 4521 children aged 9-10 were released for public access on November 2, 2018. In this paper we performed principal component analyses of the neurocognitive assessments administered to the baseline sample. The neurocognitive battery included seven measures from the NIH Toolbox as well as five other tasks. We implemented a Bayesian Probabilistic Principal Components Analysis (BPPCA) model that incorporated nesting of subjects within families and within data collection sites. We extracted …

A Mixture Of U.S. Food And Drug Administration-Approved Monoaminergic Drugs Protects The Retina From Light Damage In Diverse Models Of Night Blindness, Henri Leinonen, Elliot H. Choi, Anthony Gardella, Vladimir J. Kefalov, Krzysztof Palczewski

Open Access Publications

Purpose: The purpose of this study was to test the extent of light damage in different models of night blindness and apply these paradigms in testing the therapeutic efficacy of combination therapy by drugs acting on the Gi, Gs, and Gq protein-coupled receptors.

Methods: Acute bright light exposure was used to test susceptibility to light damage in mice lacking the following crucial phototransduction proteins: rod transducin (GNAT1), cone transducin (GNAT2), visual arrestin 1 (ARR1), and rhodopsin kinase 1 (GRK1). Mice were intraperitoneally injected with either vehicle or drug combination consisting of metoprolol (β1-receptor antagonist), bromocriptine (dopamine family-2 receptor agonist) and …

Suppression Of Ilc2 Differentiation From Committed T Cell Precursors By E Protein Transcription Factors, Liangyue Qian, Sandra Bajana, Constantin Georgescu, Vincent Peng, Hong-Cheng Wang, Indra Adrianto, Marco Colonna, Jose Alberola-Ila, Jonathan D. Wren, Xiao-Hong Sun

Open Access Publications

Current models propose that group 2 innate lymphoid cells (ILC2s) are generated in the bone marrow. Here, we demonstrate that subsets of these cells can differentiate from multipotent progenitors and committed T cell precursors in the thymus, both in vivo and in vitro. These thymic ILC2s exit the thymus, circulate in the blood, and home to peripheral tissues. Ablation of E protein transcription factors greatly promotes the ILC fate while impairing B and T cell development. Consistently, a transcriptional network centered on the ZBTB16 transcription factor and IL-4 signaling pathway is highly up-regulated due to E protein deficiency. Our results …

Neurotransmitter Identity Is Acquired In A Lineage-Restricted Manner In The Drosophila Cns, Haluk Lacin, Hui-Min Chen, Xi Long, Robert H. Singer, Tzumin Lee, James W. Truman

Open Access Publications

The vast majority of the adult fly ventral nerve cord is composed of 34 hemilineages, which are clusters of lineally related neurons. Neurons in these hemilineages use one of the three fast-acting neurotransmitters (acetylcholine, GABA, or glutamate) for communication. We generated a comprehensive neurotransmitter usage map for the entire ventral nerve cord. We did not find any cases of neurons using more than one neurotransmitter, but found that the acetylcholine specific gene ChAT is transcribed in many glutamatergic and GABAergic neurons, but these transcripts typically do not leave the nucleus and are not translated. Importantly, our work uncovered a simple …

Skin Cancer Precursor Immunotherapy For Squamous Cell Carcinoma Prevention, Abby R Rosenberg, Mary Tabacchi, Kenneth H Ngo, Michael Wallendorf, Ilana S Rosman, Lynn A Cornelius, Shadmehr Demehri

Open Access Publications

BACKGROUND: Topical calcipotriol plus 5-fluorouracil (5-FU) combination is an effective immunotherapy against actinic keratosis (AK), which is a precursor to squamous cell carcinoma (SCC). However, the long-term effectiveness of calcipotriol plus 5-FU treatment for SCC prevention is unknown.

METHODS: We performed a blinded prospective cohort study on participants of a randomized double-blind clinical trial in which a 4-day course of topical calcipotriol plus 5-FU combination was compared to Vaseline plus 5-FU (control) for AK treatment. SCC and basal cell carcinoma (BCC) incidences were assessed at 1, 2, and 3 years after trial. Tissues were analyzed for calcipotriol plus 5-FU-induced T …

A Novel Pathogenic Variant In Osbpl2 Linked To Hereditary Late-Onset Deafness In A Mongolian Family, Ningjin Wu, Husile Husile, Liqing Yang, Yaning Cao, Xing Li, Wenyan Huo, Haihua Bai, Yangjian Liu, Qizhu Wu

Open Access Publications

BACKGROUND: To investigate the clinical features and the underlying causal gene of a family with hereditary late-onset deafness in Inner Mongolia of China, and to provide evidence for the early genetic screening and diagnosis of this disease.

METHODS: Family data were collected to draw a pedigree. Audiological testing and physical examination of the family members were conducted following questionnaire. Genomic DNA was extracted from peripheral blood of 5 family members (3 patients and 2 normal control) and subjected to whole genome sequencing for identifying deafness casual genes. The pathogenic variant in the deafness gene was further confirmed by Sanger sequencing. …

Network Meta-Analysis Of Randomised Trials Of Pharmacological, Psychotherapeutic, Exercise And Collaborative Care Interventions For Depressive Symptoms In Patients With Coronary Artery Disease: Hybrid Systematic Review Of Systematic Reviews Protocol, Frank Doyle, Kenneth Freedland, Robert Carney, Peter De Jonge, Chris Dickens, Susanne Pedersen, Jan Sorensen, Martin Dempster

Open Access Publications

BACKGROUND: Depression is common in patients with coronary artery disease (CAD) and is associated with poorer outcomes and higher costs. Several randomised controlled trials (RCTs) targeting depression, of various modalities (including pharmacological, psychotherapeutic and other approaches), have been conducted and summarised in pairwise meta-analytic reviews. However, no study has considered the cumulative evidence within a network, which can provide valuable indirect comparisons and information about the relative efficacy of interventions. Therefore, we will adopt a review of review methodology to develop a network meta-analysis (NMA) of depression interventions for depression in CAD.

METHODS: We will search relevant databases from inception …

Follicular Lymphoma Patients With Kir2dl2 And Kir3dl1 And Their Ligands (Hla-C1 And Hla-Bw4) Show Improved Outcome When Receiving Rituximab, Amy K Erbe, Wei Wang, Lakeesha Carmichael, Anna Hoefges, Bartosz Grzywacz, Patrick K Reville, Erik A Ranheim, Jacquelyn A Hank, Kyungmann Kim, Songwon Seo, Eneida A Mendonca, Yiqiang Song, Vaishalee P Kenkre, Fangxin Hong, Randy D Gascoyne, Elisabeth Paietta, Sandra J Horning, Jeffrey S Miller, Brad Kahl, Paul M Sondel

Open Access Publications

BACKGROUND: The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ("maintenance") vs. no additional rituximab until progression ("non-maintenance"). Based on "time-to-rituximab-failure (TTRF)", the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated …