tbuckley/cabot-search huggingface dataset:
Abstract 17318: Cardioprotective Microbes and Restorative Sleep Are Reduced and Blood Pressure During Sleep is Increased When Rats Have Fragmented Sleep
Authors: Katherine A Maki, Jennifer J Barb, Ulf G Bronas, Michael W Calik, Stefan Green, Anne M Fink
Journal: Circulation (2020)

Introduction: Sleep that is restless and fragmented impairs cardiovascular (CV) health. Using a rat model, we measured sleep characteristics and assessed bacterial communities in the gut microbiome. We hypothesized poor quality sleep to be associated with a reduction in cardioprotective microbiomes and adverse CV outcomes. Methods: Wistar Kyoto rats had normal sleep (n= 7, controls) or 8-hrs of fragmented sleep (n = 8) for 28 days. Implanted telemetry transmitters recorded blood pressure (BP), heart rate (HR), and cortical electroencephalogram (EEG) signals continuously. Fecal samples were collected daily; microbial composition was determined by 16S rRNA amplicon sequencing. Results: The sleep fragmented (SF) rats could not achieve deep slow-wave sleep (SWS) for 8-hrs each day—compared with controls, relative EEG delta power (a marker of the depth of sleep) was significantly lower (29±3% versus 39±3%, P = 0.04). In addition, SF was associated with a rise in BP and HR. The relative abundance of Parabacteroides (classified to genus level) and Tannerellaceae (classified to family level), both gram-negative anaerobic bacteria from the phylum Bacteroidetes, were decreased in SF rats during late-SF (intervention days 20 &amp; 27), relative to controls. Elevated Parabacteroides levels (%) were significantly and inversely correlated with systolic (R= -0.002, P &lt;0.001) and diastolic (R= -0.003, P &lt;0.001) BP levels recorded during sleep in both groups of rats. Conclusions: Parabacteroides levels in the gut microbiome may contribute to changes in BP. Undesirable changes in sleep from SF are associated with reduced levels of Parabacteroides during the late-SF period in the gut microbiome, compared with controls. The Parabacteroides -BP associations and reactivity of this bacterium to disrupted sleep support Parabacteroides as an exciting cardioprotective biomarker to stratify and prevent negative CV outcomes provoked by SF.
122P Abemaciclib in HR+/HER2- metastatic breast cancer: A real-world experience
Authors: M. Bottosso, T. Giarratano, C. Barbieri, A. Menichetti, E. Cumerlato, F. Miglietta, E. Genovesi, O. Amato, M.V. Dieci, G. Griguolo, V. Guarneri
Journal: Annals of Oncology (2021)
126TiP HER2CLIMB-02: Tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer
Authors: S.A. Hurvitz, N. Harbeck, L. Vahdat, A.C. Wolff, S.M. Tolaney, S. Loi, N. Masuda, J. O'Shaughnessy, D. Xie, L.N. Walker, E. Rustia, V. Borges
Journal: Annals of Oncology (2021)
ミクロビオームの理解:癌に対する個別化医療のための微生物叢を利用するための新たなバイオマーカー【JST・京大機械翻訳】
Authors: Rajpoot Meenakshi, K Sharma Anil, Sharma Anil, Gupta Girish Kumar
Journal: Seminars in Cancer Biology (2018)
구연 : 아포에이 크링글 단백질의 신생혈관 억제 효능과 암의 성장 및 간 전이 억제 효능에 관한 연구
Authors: 김장성, 안진형, 유현경, 이호정, 이석근, 정수일, 박두홍, 윤엽
Journal: Clinical and Molecular Hepatology (2003)

배경/목적: 암세포가 1-2 mm3 크기 이상의 조직으로 성장하려면 새로운 혈관을 형성하여 영양분을 공급받아야 하며 이때 암에 관련된 혈관을 구성하는 내피세포는 급격히 분열 분화해 새로운 혈관을 형성한다. 본 연구에서는 인간의 lipoprotein(a)의 구성요소 중 하나인 apolipoprotein(a)의 Kringle (LK) domain을 대상으로 신혈관형성 억제기능을 규명하며 이를 이용한 항암 효능을 규명하고자 하였다. 특히 암의 전이 억제능을 조사하기 위하여 피부암의 전이 및 직장암의 경우 빈번히 발생하는 간 조직으로의 전이를 억제하는 효능을 규명하고자 하였다. 대상과 방법: apolipoprotein(a)의 Kringle (LK) 단백질은 Pichia pastoris 효모 발현을 통한 재조합 단백질의 형태로 생산 하였고 이들의 신생혈관 억제 효능 및 기전은 혈관 내피세포를 통한 세포성장 및 이동성 저해를 통하여 검증하였다. In vivo 효능 검색은 계융모막의 혈관생성 및 생쥐의 피하에 삽입된 Matrigel을 이용한 혈관 침윤도를 측정하였다. 항암 효능은 인체 암세포를 주입한 면역결핍 생쥐를 이용하였고 암의 전이 억제 효능은 B16F10 melanoma를 이용한 폐 전이 및 CT-26 직장암세포의 비장 내 주입을 통한 간 조직 전이 모델을 이용하였다. 결과: 1) 재조합 apolipoprotein(a)의 Kringle (LK) 단백질은 혈관내피세포의 성장, 이동성, 튜브 형성을 저해함이 확인되었다. 2) LK 단백질은 혈관내피세포의 세포괴사를 유도하며 혈관 이동성에 관련된 Erk(extracellular signal regulated kinase) 단백질의 인산화를 특이하게 저해함이 확인되었다. 3) LK 단백질의 지속적 투여는 인체 암세포가 주입된 면역 결핍 생쥐의 암세포의 성장 및 암의 전이를 효과적으로 저해함과 동시에 생체의 생존율을 증가시키는 효능이 있음이 확인되었다. 4) 유전자 도입을 통한 LK 발현이 유도된 직장암세포는 간 조직으로의 전이능이 현저히 소실되었다. 결론: 이상의 결과로 apolipoprotein(a)의 Kringle (LK) 단백질은 혈관 내피세포를 선택적으로 저해하는 효능이 확립되었고 암의 성장 저해 및 간 조직으로의 전이 억제능이 규명되어 향후 다양한 암의 성장 및 전이를 억제하는 치료제 또는 치료방법의 개발 가능성을 제시한다.
Abstract 13079: An Increase in Circulating Cardiomyocyte-specific Cell-free DNA in Heart Failure
Authors: Tomofumi Misaka, Tetsuro Yokokawa, Yusuke KIMISHIMA, Shimizu Takeshi, Takashi Kaneshiro, Yasuchika Takeishi
Journal: Circulation (2020)

Introduction: Cardiomyocyte cell death is closely linked with the pathophysiology of heart failure. Cell-free DNA (cfDNA) is found in circulating blood as fragmented double-strand DNA, which is released from dying cells. However, the clinical significance of cfDNA in heart failure has not been elucidated. Methods and Results: The present study enrolled 32 heart failure patients and 28 control subjects. Circulating cfDNA was isolated from plasma samples in peripheral blood. The levels of total cfDNA assessed by quantitative PCR using LINE1-specific primers were not different between the two groups (P=0.343). Next, cfDNA was subjected to bisulfite conversion to identify cardiomyocyte-derived cfDNA, based on that FAM101A locus is unmethylated in a cardiac-specific manner. Digital PCR targeting the unmethylated FAM101A locus demonstrated that the copy numbers of cardiomyocyte-specific cfDNA were significantly elevated in heart failure patients compared to controls (0.99 [0.77 - 1.98] vs 0 [0 - 0.91] copies/mL, P=0.003, Figure A ). The receiver operating characteristic curve revealed that cardiomyocyte-specific cfDNA significantly discriminated heart failure patients from control subjects (AUC, 0.716, P=0.003). Correlation analysis showed that the levels of cardiomyocyte-specific cfDNA were significantly correlated with serum levels of high-sensitivity cardiac troponin I (r = 0.438, P = 0.012, Figure B ), but not with BNP (r = 0.275, P = 0.058), suggesting that the elevated cardiomyocyte-specific cfDNA might be associated with enhanced cardiomyocyte death but not with high ventricular filling pressure. Conclusions: A newly developed bisulfite-digital PCR system identified an increase in cardiomyocyte-specific cfDNA in heart failure patients. cfDNA may be a novel biomarker to measure the actual numbers of cardiomyocyte death in heart failure.
GRIDSS2: comprehensive characterisation of somatic structural variation using single breakend variants and structural variant phasing
Authors: Daniel L. Cameron, Jonathan Baber, Charles Shale, Jose Espejo Valle-Inclan, Nicolle Besselink, Arne van Hoeck, Roel Janssen, Edwin Cuppen, Peter Priestley, Anthony T. Papenfuss
Journal: Genome biology (2021)

Abstract GRIDSS2 is the first structural variant caller to explicitly report single breakends—breakpoints in which only one side can be unambiguously determined. By treating single breakends as a fundamental genomic rearrangement signal on par with breakpoints, GRIDSS2 can explain 47% of somatic centromere copy number changes using single breakends to non-centromere sequence. On a cohort of 3782 deeply sequenced metastatic cancers, GRIDSS2 achieves an unprecedented 3.1% false negative rate and 3.3% false discovery rate and identifies a novel 32–100 bp duplication signature. GRIDSS2 simplifies complex rearrangement interpretation through phasing of structural variants with 16% of somatic calls phasable using paired-end sequencing.
Mast cells drive pathologic vascular lesions in Takayasu arteritis
Authors: Alexandre Le Joncour, Anne-Claire Desbois, Aurélie S. Leroyer, Edwige Tellier, Paul Régnier, Anna Maciejewski-Duval, Cloé Comarmond, Stéphane Barete, Michel Arock, Patrick Bruneval, Jean-Marie Launay, Pierre Fouret, Ulrich Blank, Michelle Rosenzwajg, David Klatzmann, Mohamed Jarraya, Laurent Chiche, Fabien Koskas, Patrice Cacoub, Gilles Kaplanski, David Saadoun
Journal: Journal of Allergy and Clinical Immunology (2021)
Abstract 15122: Il18 Uses Both Il18 Receptor and Na-cl Co-transporter to Support Islet β Cell Proliferation and Insulin Secretion
Authors: Xian Zhang, Songyuan Luo, Wang Minjie, Guo-Ping Shi
Journal: Circulation (2020)

Introduction: The regeneration of pancreatic β cells to restore insulin production is a promising therapeutic strategy for insulin-dependent type-1 (T1D) and type-2 diabetes (T2D). Plasma IL18 levels are increased in these patients. Prior studies suggest a role for IL18 in inducing islet insulin production. IL18 administration suppressed autoimmune diabetes in non-obese diabetic mice. We recently discovered that IL18 uses two receptors IL18r and NCC (Na-Cl co-transporter) with equal binding kinetics. Hypothesis: IL18r and NCC use different mechanisms to mediate IL18 activity in islet β cell insulin production. Methods and Results: Immunoblot and immunofluorescent staining localized IL18 on islet α cells, NCC on islet β cells, and IL18r on pancreas acinar cells. Development of T1D or T2D increased the α cell IL18 expression. From high fat diet (HFD)-induced T2D, deficiency of IL18r ( Il18r -/- ) or NCC ( Ncc -/- ), or combined deficiency of both receptors ( Il18r -/- Ncc -/- ) reduced insulin secretion, exacerbated β cell failure, decreased α cell content, reduced islet size, reduced β cell proliferation, and decreased the expression of islet proliferation markers. Deficiency of IL18r in Il18r -/- and Il18r -/- Ncc -/- mice aggravated β cell content and size reductions and glucose metabolism and increased β cell apoptosis after streptozotocin (STZ)-induced T1D. Il18r -/- Ncc -/- mice also showed increased macrophage accumulation in the islets from both T1D and T2D mice. Using α cell-selective IL18-deficient Gcg CreERT2 IL18 fl/fl mice, acinar cell-selective IL18r-deficient Mist1 CreERT2 Il18r fl/fl mice, and β cell NCC-deficient Ins1 Cre Ncc fl/fl mice, we demonstrated that these mice showed impaired insulin secretion and glucose metabolism, exacerbated β cell failure, and aggravated HFD-induced T2D. Mechanistic studies suggested that IL18 uses NCC on β cells to promote insulin secretion and uses IL18r on acinar cells to assist β cell development. Conclusions: Islet α cell IL18 uses NCC on β cells to promote β cell proliferation and uses IL18r on acinar cells to produce inflammatory molecules to assist β cell generation and insulin secretion. Both the IL18r and NCC signaling pathways are essential to β cell function in diabetic patients.
Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults With Overweight or Obesity and Type 2 Diabetes: A 54-Week Randomized Phase 2b Study
Authors: Rajaa Nahra, Tao Wang, Kishore M. Gadde, Jan Oscarsson, Michael Stumvoll, Lutz Jermutus, Boaz Hirshberg, Philip Ambery
Journal: Diabetes Care (2021)

OBJECTIVE Cotadutide, a dual GLP-1 and glucagon receptor agonist, is under development for nonalcoholic steatohepatitis (NASH) and chronic kidney disease with type 2 diabetes. The effects of cotadutide on hepatic and metabolic parameters were evaluated in participants with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS In this phase 2b study, 834 adults with BMI ≥25 kg/m2 and type 2 diabetes inadequately controlled with metformin (glycated hemoglobin A1c [HbA1c] of 7.0%–10.5% [53–91 mmol/mol]) were randomized to double-blind cotadutide 100 μg (n = 100), 200 μg (n = 256), or 300 μg (n = 256); placebo (n = 110); or open-label liraglutide 1.8 mg (n = 110)—all administered subcutaneously. Coprimary end points were changes in HbA1c and body weight at week 14. The originally randomized interventions were continued to week 54. Liver damage biomarkers and liver fibrosis algorithms were assessed. RESULTS Cotadutide significantly decreased HbA1c and body weight at weeks 14 and 54 versus placebo (all P &amp;lt; 0.001). Improvements in lipid profile, AST and ALT levels, propeptide of type III collagen level, fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score were observed with cotadutide 300 μg versus placebo, but not with liraglutide. Weight loss with cotadutide 200 μg was similar to that with liraglutide 1.8 mg and greater with cotadutide 300 μg versus liraglutide 1.8 mg. The most common adverse events with cotadutide (nausea, 35%; vomiting, 17%) decreased over time. CONCLUSIONS Cotadutide treatment for 54 weeks improved glycemic control and weight loss in participants with overweight/obesity and type 2 diabetes. Ad hoc analyses demonstrated improvements in hepatic parameters and support further evaluation of cotadutide in NASH.
60P Real-life use of Oncotype DX Breast Recurrence Score® test for the management of patients with node-negative and node-positive breast cancer in the autonomous community of Galicia (Spain)
Authors: I. Fernandez-Perez, S. Antolin Novoa, L. De Paz Arias, L. Vazquez Tuñas, M.E. Perez Lopez, S. Varela Ferreiro, A.Q. Gonzalez Quintas, C. Senin Estor, J.F. Cueva Banuelos, C. Hagen, L. Inglada-Pérez, D. Pereiro, L. Calvo-Martinez, I. Carou, L. Iglesias Rey, A. Saenz de Miera, T. García-Caballero
Journal: Annals of Oncology (2021)
Abstract 15187: Very Low-density Lipoprotein Signals Through Sphingosine-1-phosphate Receptors Upon Binding to Scavenger Receptor Class B, Type I in Human Adrenocortical Cells
Authors: Shinjini Chowdhury, Vivek Choudhary, Mrunal Choudhary, Wendy B Bollag
Journal: Circulation (2020)

Aldosterone is considered to be a link between hypertension and obesity; obese individuals have high serum levels of both very low-density lipoprotein (VLDL) and sphingosine-1-phosphate (S1P). VLDL has been shown to stimulate aldosterone production in multiple zona glomerulosa cell models. S1P is transported in blood bound to lipoproteins such as VLDL, low-density lipoprotein, and high-density lipoprotein (HDL); the VLDL particle contains the highest levels of S1P. S1P in HDL has been shown to promote interactions between scavenger receptor class B, type I (SR-BI) and S1P receptor 1 (S1PR1). We hypothesized that like HDL, VLDL will signal through S1PRs upon binding to SR-BI; therefore, VLDL-induced aldosterone production will be inhibited by S1PR antagonists. Human adrenocortical cells (HAC15) were treated with VLDL and/or an S1PR1 antagonist (Ex26) for 24 h. The expression of steroidogenic genes and aldosterone production were monitored by qRT-PCR and radioimmunoassay, respectively. Ex26 inhibited VLDL-induced increases in CYP11B2 (22-fold) and StAR (1.5-fold) expression by 43% and 10%, respectively. Ex26 had no effect on VLDL-stimulated increase in NR4A1 expression. In addition, the VLDL-induced 5-fold increase in aldosterone levels was significantly inhibited by Ex26 (36%). Our results indicate that like HDL, VLDL likely signals by binding to SR-BI and activating S1PR1, such that an S1PR1 antagonist reduces VLDL-induced aldosterone production. Further investigation into these steroidogenic signaling pathways is warranted and may lead to the identification of therapeutic targets such as S1PR1 to potentially treat obesity-associated hypertension.
JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views
Authors: Naseema Gangat, Natasha Szuber, Animesh Pardanani, Ayalew Tefferi
Journal: Leukemia (2021)

Abstract JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses both hereditary and acquired conditions. A systematic diagnostic approach begins with documentation of historical hematocrit (Hct)/hemoglobin (Hgb) measurements and classification of the process as life-long/unknown duration or acquired. Further investigation in both categories is facilitated by determination of serum erythropoietin level (EPO). Workup for hereditary/congenital erythrocytosis requires documentation of family history and laboratory screening for high-oxygen affinity hemoglobin variants, 2, 3 biphosphoglycerate deficiency, and germline mutations that are known to alter cellular oxygen sensing (e.g., PHD2, HIF2A, VHL ) or EPO signaling (e.g., EPOR mutations); the latter is uniquely associated with subnormal EPO. Acquired erythrocytosis is often elicited by central or peripheral hypoxia resulting from cardiopulmonary disease/high-altitude dwelling or renal artery stenosis, respectively; EPO in the former instance is often normal (compensated by negative feed-back). Other conditions associated with acquired erythrocytosis include EPO-producing tumors and the use of drugs that promote erythropoiesis (e.g., testosterone, erythropoiesis stimulating agents). “Idiopathic erythrocytosis” loosely refers to an otherwise not explained situation. Historically, management of non-PV erythrocytosis has been conflicted by unfounded concerns regarding thrombosis risk, stemming from limited phenotypic characterization, save for Chuvash polycythemia, well-known for its thrombotic tendency. In general, cytoreductive therapy should be avoided and phlebotomy is seldom warranted where frequency is determined by symptom control rather than Hct threshold. Although not supported by hard evidence, cardiovascular risk optimization and low-dose aspirin use are often advised. Application of modern genetic tests and development of controlled therapeutic intervention trials are needed to advance current clinical practice.
Abstract 13369: Sympathovagal Imbalance Decades After Atrial Septal Defect Repair
Authors: Mathias Alstrup, Zarmiga Karunanithi, Vibeke Hjortdal
Journal: Circulation (2020)

Introduction: Heart rate variability (HRV), a measure of the autonomic nervous system activity, is a morbidity and mortality predictor. HRV is decreased in children with atrial septal defects (ASD) indicating parasympathetic withdrawal and sympathetic predominance, and increased right atrial end-diastolic pressure is believed to influence the sympathovagal balance. Despite the belief of a benign long-term outcome after closure, ASD patients have increased mortality rates after the age of 30 yrs. This may correlate to HRV, why we study HRV in adults after closure. Hypothesis: ASD patients have impaired HRV after closure when compared with controls. Methods: Surgically closed ASD patients (n=17, mean age 32±9 yrs., mean time since closure 19±8 yrs.), percutaneously closed ASD patients (n=18, mean age 28±7 yrs., mean time since closure 15±5 yrs.) and age- and gender-matched controls (n=15, mean age 30±9 yrs.) underwent a 48-hr Holter monitoring. Inclusion criteria were an age of minimum 2 yrs. at the time of diagnosis and minimum 3 yrs. must have passed since ASD closure. The following time-domain HRV measures were analyzed: SD of NN intervals (SDNN), SD of the average NN interval for each 5-minute segment, mean of the SDs of all NN intervals for each 5-minute (SDNNi), root mean square of successive RR interval differences (RMSSD), percentage of successive RR intervals that differ by &gt;50 ms (pNN50), and triangular index. Results: Surgically closed ASD patients have an impairment of all time-domain parameters, while transcatheter closed patients have an impairment of half the parameters. Conclusion: These novel findings demonstrate a cardiac sympathovagal imbalance in adult patients several yrs. after ASD closure and may potentially explain why we observe a long-term morbidity and mortality increase in ASD patients.
The Difference of Ventricular Fibrillation Cycle Length in Patients between with Symptomatic and Asymptomatic Brugada Syndrome
Authors: Hiratsuka Atsushi, Shimizu Akihiko, Ueyama Takeshi, Yoshiga Yasuhiro, Doi Masahiro, Yoshida Masaaki, Fukuda Masakazu, Katoh Takayoshi, Fumimoto Tomoko, Matsuzaki Masunori
Journal: Circulation (2012)
Abstract P020: Triglyceride-lowering Lipoprotein Lipase Gene Variants And Improvements In Lipids And Lipoprotein Subspecies Defined By Apolipoprotein C-iii: Pounds Lost Trial
Authors: Yoriko Heianza, Tao Zhou, Hua He, George Bray, Frank M Sacks, Lu Qi
Journal: Circulation (2021)

Introduction: Triglyceride-lowering variants in the lipoprotein lipase ( LPL ) gene have been associated with a lower risk of coronary heart disease. Lipoproteins are heterogeneous, and lipoprotein subspecies containing apolipoprotein C-III (ApoCIII) have adverse effects on cardiovascular disease (CVD) risk. Hypothesis: We examined associations of triglyceride-lowering LPL gene variants with long-term improvement in lipids and lipoprotein subspecies with ApoCIII in patients with obesity. We also investigated whether the LPL gene variants were significantly related to the improvement of the 10-year CVD risk estimated using the Framingham risk score in the participants of a weight-loss dietary intervention trial. Methods: This study included 382 overweight and obese adults of white European ancestry in a 2-year weight-loss dietary intervention, the POUNDS Lost trial. We evaluated changes in lipids (triglycerides and cholesterol) and lipoproteins (such as very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL)) subfractions defined by the presence or absence of ApoCIII from baseline to 2 years after the intervention. A genetic risk score of LPL (LPL-GRS) was calculated by summing triglyceride-lowering alleles of five independent single nucleotide polymorphisms (SNPs). We calculated the Framingham risk score and estimated changes in the 10-year CVD risk after the intervention. Results: At baseline, higher scores of triglyceride-lowering LPL-GRS were significantly associated with higher levels of HDL cholesterol (p= 0.0065) and lower levels of triglycerides (p= 0.017). Higher LPL-GRS was also associated with more decreases in total triglycerides (p= 0.028) and triglycerides in VLDL with ApoCIII (p=0.018) at 2 years. The LPL-GRS was also predictive of 2-year improvements in other atherogenic lipoprotein subtypes, such as cholesterol in VLDL with ApoCIII (p= 0.037) and cholesterol in LDL with ApoCIII (p= 0.027) after the intervention. Further, the LPL-GRS was significantly associated with a 2-year reduction of the estimated CVD risk, regardless of the initial risk status (p=0.034). Conclusion: The triglyceride-lowering LPL-GRS was significantly predictive of improvements in unfavorable lipid profiles, including lipoprotein subtypes containing ApoCIII after consuming a weight-loss diet in patients with obesity. The reduction of the estimated CVD risk after the dietary intervention was predicted by the LPL-GRS at the pre-intervention.
Enhanced differentiation of functional human T cells in NSGW41 mice with tissue-specific expression of human interleukin-7
Authors: Emilie Coppin, Bala Sai Sundarasetty, Susann Rahmig, Jonas Blume, Nikita A. Verheyden, Franz Bahlmann, Sarina Ravens, Undine Schubert, Janine Schmid, Stefan Ludwig, Katharina Geissler, Orlando Guntinas-Lichius, Constantin von Kaisenberg, Tanja Groten, Alexander Platz, Ronald Naumann, Barbara Ludwig, Immo Prinz, Claudia Waskow, Andreas Krueger
Journal: Leukemia (2021)

Abstract Humanized mouse models have become increasingly valuable tools to study human hematopoiesis and infectious diseases. However, human T-cell differentiation remains inefficient. We generated mice expressing human interleukin-7 (IL-7), a critical growth and survival factor for T cells, under the control of murine IL-7 regulatory elements. After transfer of human cord blood-derived hematopoietic stem and progenitor cells, transgenic mice on the NSGW41 background, termed NSGW41hIL7, showed elevated and prolonged human cellularity in the thymus while maintaining physiological ratios of thymocyte subsets. As a consequence, numbers of functional human T cells in the periphery were increased without evidence for pathological lymphoproliferation or aberrant expansion of effector or memory-like T cells. We conclude that the novel NSGW41hIL7 strain represents an optimized mouse model for humanization to better understand human T-cell differentiation in vivo and to generate a human immune system with a better approximation of human lymphocyte ratios.