bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tet2 Deficiency Rejuvenates Hematopoietic Stem and Progenitor Cells during Ageing
Authors: Hong Tingting , Li Shengli , Fang Shaohai , Guzman Anna , Han Wei , Zhou Yubin , Han Leng , Goodell Margaret , Huang Yun 
Published: February 2021

Ageing is accompanied by a significant reduction of hematopoietic competence driven by various causes including epigenetic alternations [1-4]. Ten-eleven translocation 2 (TET2) has been well delineated as a critical epigenetic regulator that affects hematopoietic progenitor and stem cells (HSPCs) function. Tet2 deficiency confers advantages in clonal expansion of HSPCs and skews myeloid lineage differentiation, giving rise to increased risk of hematological malignancy transformation [5-8]. TET2 loss-of-function mutations are frequently detected in aged HSPCs [10-11], thereby raising the question of how Tet2 deficiency affects HSPCs self-renewal and lineage specification during ageing.
To address this question, we harvested HSPCs from wild-type (WT) or Tet2KO young and aged donor mice, followed by competitive bone marrow transplantations to monitor age-dependent functional alterations. Despite the enlargement of the HSC pool size (the number of cells with regenerative potential) in aged mice, the aged WT HSPCs exhibited lower self-renewal capability and displayed impaired hematopoietic differentiation when competed against young stem cells. However, we found that both aged and young Tet2-deficient HSPCs shared comparable peripheral blood reconstitution, indicating no engraftment defects were caused by age for Tet2-deficient HSPCs. In parallel, scRNA-seq analysis revealed that Tet2 deficiency and age promoted the expansion of HSC compartment in a synergistic manner, leading to the largely augmented pool size of Tet2-deficient aged HSCs. But unlike aged WT stem cells, these expanded aged Tet2-null stem cells retained high self-renewal potential and possessed a competitive advantage of lineage outputs both in vitro and in vivo. Overall, through conducting repopulation assays and single-cell transcriptomes analysis, we have demonstrated that Tet2 ablation alters age-dependent HSC functional decline, revealing a disparate ageing process in the Tet2-deficient haemopoietic system.

Disclosures
No relevant conflicts of interest to declare.
Preliminary Exploration of Ibrutinib Combined with Methotrexate, Ifosfamide, Liposomal Doxorubicin and Methylprednisolone in the Treatment of Relapsed/Refractory Primary CNS Lymphoma
Authors: Yuedan Chen , Sun Xuefei , Bai Xueyan , Cui Qu , Xing Ruixian , Liu Yuanbo 
Published: February 2021

Background Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma with an aggressive clinical course and poor outcomes. Although high-dose methotrexate (HD-MTX) based regimen significantly improves the outcome of the patients, approximately 10-35% of PCNSL patients are treatment refractory and 35-60% of patients eventually relapse. There is great unmet need in improving the prognosis of patients with relapsed/refractory PCNSL. In this study, we describe our institutional experience with I-MIDD regimen(ibrutinib combined with methotrexate, ifosfamide, liposomal doxorubicin and methylprednisolone) for patients with relapse/refractory PCNSL. Methods The clinical data of 18 relapse/refractory PCNSL patients treated from September 2017 to December 2019 were analyzed retrospectively. The doses and administration schedule were as follows: ibrutinib 560 mg/d for 21 consecutive days, methotrexate 3.5 g/m2 on day 1, ifosfamide 1.5 g/m2 on day 2, liposomal doxorubicin 25 mg/m2 on day 3 and methylprednisolone 80 mg/d from day 1 to day 3. Every 21 days were as a course of treatment, and they were treated for 1-6 courses. The primary endpoint was complete response (CR) rate, and secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs). Results The median follow-up time of 18 patients was 13 (3-27) months, 10 patients achieved complete remission, 5 achieved partial remission, 1 had stable disease and 2 had progression of disease. The ORR was 83.3%(5/18). The median PFS was 6 (1-27) months, the OS ranged from 3 to 27 months and the median OS was not achieved. The 1-year PFS and OS were 42.8% and 87.4% respectively. The AEs of chemotherapy were mainly bone marrow suppression. 17/69(24.6%) events was grade 3 to 4 leukopenia, neutropenia and thrombocytopenia in the course of the disease and was all manageable. No grade 4 non-hematologic AEs were observed. The only grade 3 non-hematologic toxicity was infectious disease which occurred in 2 cases, and one patient experienced fungal pneumonia with a favorable outcome. Conclusion I-MIDD regimen is a feasible and active combination for patients with relapse/refractory primary central nervous system lymphoma.

Disclosures
No relevant conflicts of interest to declare.
Defining Quality Though a Collaborative Process for Multiple Myeloma Care
Authors: Babar Arslan , Behera Tapas Ranjan , Abdullah Syed Maaz , Waris Imtisaal , Amin Saher Nasir , Masood Adeel , Anwer Faiz 
Published: February 2021

Background:
With the increase in life expectancy, prevalence, early diagnosis of plasma cell disorders, advances in effective therapies and improved overall survival (OS) in multiple (MM); improvements in the quality standards and delivery of quality of care remain a challenge. Currently there are no standardized quality metrics and many studies have highlighted the disparities in treatment and supportive care in MM. We propose a quality model based on Donabedian's triadof structure, process and outcomes to further improve outcomes in MM. We aim to share a team process at Cleveland Clinic for defining components of quality measure for MM treatment.
Structure:
Multidisciplinary clinics (MDCs) have become popular over the recent years and have proven to improve patient outcomes for many malignancies. Our MDC has healthcare team composed of MM physicians, palliative care physicians, nurse coordinators, clinical pharmacists, pathologists, clinical research team, basic science laboratory collaboration, and psycho-social workers. To improve efficiency, team focus is on prompt diagnosis, easy accessibility, tissue banking, efficient EMR, access to transplant /cellular therapy /immunotherapy and efficient infusion suites with focus to reduce time to treatment in the same building.
Process:
With the rapid advancements in the treatment of MM, our process is focused on the comprehensive diagnosis based on tissue analysis, comprehensive staging, risk defining genetic factor testing, and evidence based treatment selection for MM based on literature, clinical practice guidelines (CPGs) like specialty society guidelines
Recent studies have suggested that delays in treatment from diagnosis can result in negative patient outcomes, similarly studies have suggested that patients with MM can experience significant treatment delays. We focus on reduced time to treatment; recommend patients should undergo treatment within ten days of diagnosis. Patients should undergo evaluation for toxicity management, undergo supportive treatment based on CPGs. These should include: Risk estimation for DVT and score driven prophylaxis, bone modulation therapy, infection prophylaxis, management of anemia, frailty assessment and front line transplant eligibility assessment.
Outcomes:
Clinical and patient reported outcomes should be recorded, analyzed and reported. A dedicated quality improvement process should streamline data collection and select quality improvement QI projects with the aim to improve recurring issues.
Figure

Disclosures
Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
Impact of Pharmaceutical Prescription Assistance Programs on the Care of Patients with Chronic Myeloid Leukemia in a Safety Net Hospital
Authors: Sadeghi Navid , Kainthla Radhika , Li Hsiao Ching , Hong Aaron 
Published: February 2021

Introduction:
The ever-rising cost of the oncology prescription drugs not only impacts the global cost of cancer care, but also affects the individual patient's financial toxicity, compliance, and outcomes. In safety-net setting, where the quality and quantity of care can be limited by the institution's budget, Prescription Assistance Programs (PAPs) are critical to patient care. Navigating the application process for these programs can be challenging for patients, especially for minorities and those with low health literacy. We looked at a pharmacy-run service for PAP enrollment at our safety-net hospital for patients diagnosed with chronic myeloid leukemia (CML).
Methods:
A total of 113 patients with CML who were receiving care at Parkland Health and Hospital System in Dallas, Texas, between January 2018 and December of 2019 were identified. Our pharmacy-run PAP service utilizes medication access technicians to complete PAP application packets for oncology patients. Patient records were reviewed to identify the payor mix, the choice of tyrosine kinase inhibitor (TKI), and number of prescriptions filled during the study period. Cost estimates are based on best advertised price for the individual drugs. For imatinib, cost estimate was based on the generic form.
Results:
Of the 113 CML patients, 78 did not have insurance. The majority of patients were Hispanic (61%); 19% were Black. In 62 patients (55%), English was not the primary language. TKIs used in first-line (insured vs uninsured) were: imatinib (49% vs 46%), dasatinib (31% vs 49%) and nilotinib (11% vs 5%). All uninsured patients were enrolled in Prescription Assistance Programs (PAP). The average time from diagnosis to application approval by the pharmaceutical companies was 23 days. Patients on average received the drug shipment 7 days after application approval. Uninsured patients received a total of 623 months' supply of their TKIs during the study period. Of these, only 7 were covered by the institution, most commonly to allow timely initiation of treatment while the PAP application was being processed. The estimated medication cost for the uninsured patients over the study period was $5.4m, of which $93k (2%) was covered by the institution.
Conclusion:
Our pharmacy-run PAP service allowed for rapid enrollment of all uninsured patients in pharmaceutical free drug programs and significantly reduced the cost of CML care for the institution. An expansion of this service to allow better utilization of copay assistance programs for insured patients can impact the financial toxicity associated with TKIs and is currently being planned.

Disclosures
No relevant conflicts of interest to declare.
Unexpected redundancy of Gpr56 and Gpr97 during hematopoietic cell development and differentiation
Authors: Maglitto Antonio , Mariani Samanta A. , de Pater Emma , Rodriguez-Seoane Carmen , Vink Chris S. , Piao Xianhua , Lukke Mari-Liis , Dzierzak Elaine 
Published: February 2021

Abstract
Integrated molecular signals regulate cell fate decisions in the embryonic aortic endothelium to drive hematopoietic stem cell (HSC) generation during development. The G-protein–coupled receptor 56 (Gpr56, also called Adgrg1) is the most highly upregulated receptor gene in cells that take on hematopoietic fate and is expressed by adult bone marrow HSCs. Despite the requirement for Gpr56 in hematopoietic stem/progenitor cell (HS/PC) generation in zebrafish embryos and the highly upregulated expression of GPR56 in treatment-resistant leukemic patients, its function in normal mammalian hematopoiesis remains unclear. Here, we examine the role of Gpr56 in HS/PC development in Gpr56 conditional knockout (cKO) mouse embryos and Gpr knockout (KO) embryonic stem cell (ESC) hematopoietic differentiation cultures. Our results show a bias toward myeloid differentiation of Gpr56 cKO fetal liver HSCs and an increased definitive myeloid progenitor cell frequency in Gpr56KO ESC differentiation cultures. Surprisingly, we find that mouse Gpr97 can rescue Gpr56 morphant zebrafish hematopoietic generation, and that Gpr97 expression is upregulated in mouse Gpr56 deletion models. When both Gpr56 and Gpr97 are deleted in ESCs, no or few hematopoietic PCs (HPCs) are generated upon ESC differentiation. Together, our results reveal novel and redundant functions for these 2 G-protein coupled receptors in normal mammalian hematopoietic cell development and differentiation.
Investigating the effect of outer layer of magnetic particles on cervical cancer cells HeLa by magnetic fluid hyperthermia
Authors: Bhardwaj Anand , Jain Neeraj , Parekh Kinnari 
Published: February 2021

Abstract
Background
Magnetic fluid hyperthermia (MFH) is a successful nanotechnology application in recent decade where a biocompatible magnetic fluid is used to kill cancer cells in a controlled heating using AC magnetic field. In the present study, two ferrite-based magnetic fluids, with and without surfactant coating, were synthesized to study the effect of the outer layer of magnetic nanoparticles on cervical cancer cells. The magnetic fluid without surfactant coating (MFWI) was made stable by providing negative charge on the surface of each particle. On the other hand, lauric acid was used as a surfactant to have a stable dispersion of particles in aqueous media (MFWL).

Methods
The structural, magnetic properties and induction heating response of both the fluids were investigated using XRD, VSM, DLS, TGA, FTIR, and a high-frequency induction heater. The in vitro cytotoxicity of the synthesized fluids was observed on HeLa cells by performing MTT assay, and the effect of magnetic fluid hyperthermia was examined using Trypan blue assay.

Results
The crystallite size of surfactant stabilized particles was higher (11.0 ± 0.5 nm) compared to the charge stabilized particles (8.3 ± 0.5 nm). Induction heating experiments showed that the specific absorption rate of the surfactant-coated particles was almost double compared to ionic particle fluid. Magnetic fluid hyperthermia up to 1 hour at a concentration of 0.25 mg/mL of surfactant-coated magnetic fluid and 0.2 mg/mL concentration of charged fluid resulted in approximately 66 and 80% cell death, respectively, compared to untreated control cells.

Conclusion
The preliminary analysis of this study shows significant cell death due to hyperthermia, wherein MFWI revealed higher cytotoxicity compared to MFWL. Additional analysis into the role of the outer stabilizing layer on nanoparticle’s surface, concentration of nanoparticles, and hyperthermic duration is desirable to utilize MFH as a futuristic anti-cancer therapeutic tool.
Identification of QTL regions and candidate genes for growth and feed efficiency in broilers
Authors: Li Wei , Zheng Maiqing , Zhao Guiping , Wang Jie , Liu Jie , Wang Shunli , Feng Furong , Liu Dawei , Zhu Dan , Li Qinghe , Guo Liping , Guo Yuming , Liu Ranran , Wen Jie 
Published: February 2021

AbstractBackgroundFeed accounts for about 70% of the total cost of poultry meat production. Residual feed intake (RFI) has become the preferred measure of feed efficiency because it is phenotypically independent of growth rate and body weight. In this study, our aim was to estimate genetic parameters and identify quantitative trait loci (QTL) for feed efficiency in 3314 purebred broilers using a genome-wide association study. Broilers were genotyped using a custom 55 K single nucleotide polymorphism (SNP) array.ResultsEstimates of genomic heritability for seven growth and feed efficiency traits, including body weight at 28 days of age (BW28), BW42, average daily feed intake (ADFI), RFI, and RFI adjusted for weight of abdominal fat (RFIa), ranged from 0.12 to 0.26. Eleven genome-wide significant SNPs and 15 suggestively significant SNPs were detected, of which 19 clustered around two genomic regions. A region on chromosome 16 (2.34–2.66 Mb) was associated with both BW28 and BW42, and the most significant SNP in this region, AX_101003762, accounted for 7.6% of the genetic variance of BW28. The other region, on chromosome 1 (91.27–92.43 Mb) was associated with RFI and ADFI, and contains theNSUN3andEPHA6as candidate genes. The most significant SNP in this region, AX_172588157, accounted for 4.4% of the genetic variance of RFI. In addition, a genomic region containing the geneAGKon chromosome 1 was found to be associated with RFIa. TheNSUN3andAGKgenes were found to be differentially expressed in breast muscle, thigh muscle, and abdominal fat between male broilers with high and low RFI.ConclusionsWe identified QTL regions for BW28 and BW42 (spanning 0.32 Mb) and RFI (spanning 1.16 Mb). TheNSUN3,EPHA6, andAGKwere identified as the most likely candidate genes for these QTL. These genes are involved in mitochondrial function and behavioral regulation. These results contribute to the identification of candidate genes and variants for growth and feed efficiency in poultry.
Multi-omics analysis reveals the glycolipid metabolism response mechanism in the liver of genetically improved farmed Tilapia (GIFT, Oreochromis niloticus) under hypoxia stress
Authors: Ma Jun-Lei , Qiang Jun , Tao Yi-Fan , Bao Jing-Wen , Zhu Hao-Jun , Li Lian-Ge , Xu Pao 
Published: February 2021

AbstractBackgroundDissolved oxygen (DO) in the water is a vital abiotic factor in aquatic animal farming. A hypoxic environment affects the growth, metabolism, and immune system of fish. Glycolipid metabolism is a vital energy pathway under acute hypoxic stress, and it plays a significant role in the adaptation of fish to stressful environments. In this study, we used multi-omics integrative analyses to explore the mechanisms of hypoxia adaptation in Genetically Improved Farmed Tilapia (GIFT,Oreochromis niloticus).ResultsThe 96 h median lethal hypoxia (96 h-LH50) for GIFT was determined by linear interpolation. We established control (DO: 5.00 mg/L) groups (CG) and hypoxic stress (96 h-LH50: 0.55 mg/L) groups (HG) and extracted liver tissues for high-throughput transcriptome and metabolome sequencing. A total of 581 differentially expressed (DE) genes and 93 DE metabolites were detected between the CG and the HG. Combined analyses of the transcriptome and metabolome revealed that glycolysis/gluconeogenesis and the insulin signaling pathway were down-regulated, the pentose phosphate pathway was activated, and the biosynthesis of unsaturated fatty acids and fatty acid metabolism were up-regulated in GIFT under hypoxia stress.ConclusionsThe results show that lipid metabolism became the primary pathway in GIFT under acute hypoxia stress. Our findings reveal the changes in metabolites and gene expression that occur under hypoxia stress, and shed light on the regulatory pathways that function under such conditions. Ultimately, this information will be useful to devise strategies to decrease the damage caused by hypoxia stress in farmed fish.
Genome-wide analysis of the apple CaCA superfamily reveals that MdCAX proteins are involved in the abiotic stress response as calcium transporters
Authors: Mao Ke , Yang Jie , Wang Min , Liu Huayu , Guo Xin , Zhao Shuang , Dong Qinglong , Ma Fengwang 
Published: February 2021

Abstract
Background
Calcium (Ca2+) plays an important role in plant growth and development, and the maintenance of calcium homeostasis is necessary for the survival of all plant species. Ca2+/H+ exchangers (CAXs) are a subgroup of the CaCA (Ca2+/cation antiporter) superfamily. In general, CAX proteins mediate cytosolic Ca2+ entry into vacuoles to prevent excessive accumulation of Ca2+ in the cytosol. The CaCA superfamily has been identified and characterised in many plant species; however, characterisation of the CaCA superfamily and functional study of apple CAX proteins have yet to be conducted in apple (Malus × domestica Borkh.).

Results
Here, we identified 21 CaCA family proteins in apple for the first time. Phylogenetic and gene structure analysis, as well as prediction of conserved motifs, suggested that these proteins could be classified into four groups: CAX, CCX, NCL, and MHX. Expression analysis showed that the 10 MdCAX genes we cloned strongly responded to calcium and abiotic stress treatments. Collinearity analysis and characterisation of calcium transport capacity resulted in the identification of a pair of segmental duplication genes: MdCAX3L-1 and MdCAX3L-2; MdCAX3L-2 showed strong calcium transport capacity, whereas MdCAX3L-1 showed no calcium transport capacity. Yeast two-hybrid (Y2H) assays showed that these two proteins could interact with each other. The high sequence similarity (94.6%) makes them a good model for studying the crucial residues and structural basis of the calcium transport of CAX proteins. Prediction of the protein interaction network revealed several proteins that may interact with CAX proteins and play important roles in plant stress responses, such as SOS2, CXIP1, MHX, NRAMP3, and MTP8.

Conclusions
Our analysis indicated that MdCAX proteins have strong calcium transport capacity and are involved in the abiotic stress response in apple. These findings provide new insight and rich resources for future studies of MdCAX proteins in apple.
Prevalence, correlates, and mortality impacts of ventricular arrhythmia among older men and women: a population-based cohort study in Moscow
Authors: Shkolnikova Maria A. , Ildarova Rukijat A. , Jdanov Dmitri A. , Shalnova Svetlana A. , Shkolnikov Vladimir M. 
Published: February 2021

Abstract
Background
In Russia, cardiovascular disease (CVD) mortality is high and the mortality gap between men and women is large. Conventional risk factors cannot explain these phenomena. Ventricular arrhythmia (VA) is an important contributor to the death toll in community-based populations. The study examines the prevalence and the mortality impacts of VA in men and women and the role of VA in the male mortality excess at older ages.

Methods
This is a secondary analysis of data from the Stress, Aging, and Health in Russia (SAHR) study that was fielded in 2007–9 in Moscow (1800 individuals, mean age 68.8 years), with mean mortality follow-up of 7.4 years (416 deaths, 248 CVD deaths). Indicators reflecting the frequency and the complexity of VA were derived from 24-h ambulatory ECG recordings. Other covariates were: socio-demographic characteristics, conventional risk factors, markers of inflammation, reported myocardial infarction, and stroke. The impacts of VA and other variables on CVD and all-cause mortality among men and women were estimated with the proportional hazard models. We assessed the contributions of VAs to the male–female mortality gap using hazard models that do and do not include groups of the predictors. Logistic models were used to assess the associations between VA and other biomarkers.

Results
VAs were about twice as prevalent among men as among women. In both sexes, they were significantly associated with CVD and all-cause mortality independently of conventional risk factors. The highest hazard ratios (HRs) for CVD death were found for the runs of ventricular premature complexes (VPCs) HR = 2.45, 95% CI 1.63–3.68 for men and 2.75, 95% CI 1.18–6.40 for women. The mortality impacts of the polymorphic VPCs were significant among men only (HR = 1.50, 95% CI 1.08–2.07). VA indicators can potentially explain 12.3% and 9.1% of the male–female gaps in mortality from CVD and all causes, respectively. VAs were associated with ECG-registered ischemic problems and reported MI, particularly among men.

Conclusions
VA indicators predicted mortality in older Muscovites independently of other risk factors, and have the potential to explain a non-trivial share of the excess male mortality. The latter may be related to more severe coronary problems in men compared to women.