bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimal Residual Disease Assessment Is an Independent Prognostic Factor in Splenic Marginal Zone Lymphoma
Authors: Lv Ryu , Wang Yi , Wang Tingyu , Wenjie Xiong , Wang Huijun , Yan Yuting , Wang Qi , Liu Wei , An Gang , Huang Wenyang , Sui Weiwei , Xu Yan , Yu Zhen , Zou Dehui , Wang Jianxiang , Qiu Lugui , Yi Shuhua
Published: February 2021

Purpose: Splenic marginal lymphoma (SMZL) is a rare indolent B-cell lymphoma with long survival. The minimal residual disease (MRD) detection in indolent B-cell lymphomas has shown power in predicting survival and even in guiding treatment duration in chronic lymphocytic leukemia. As almost all SMZL patients have bone marrow involvement (BMI) at diagnosis, we prospectively designed the MRD detection during treatment to study its prognostic value in SMZL.

Methods: SMZL patients who needed chemotherapy would regularly monitor the MRD status until undetectable MRD by multiparameter flow cytometry (MFC). Patients with MRD under 0.01% were defined as uMRD. Other clinical factors were also analysed as prognostic factors.

Results: In total, 71 patients with frontline therapy were enrolled in this study. There were 284 evaluable BM MRD samples. At end of treatment, 55 patients (77.4%) got uMRD, 10 patients had a MRD level of 0.01-1%, and 6 patients had a MRD level of ≥ 1%. The uMRD rate increased at the end of treatment. With a median follow-up of 50 (24-157) months, uMRD patients showed superior outcomes compared with MRD-positive patients. Patients with uMRD had a significant better progression free survival (PFS) compared to those with MRD. PR with positive-MRD after induction therapy was a significantly poor predictor for PFS and overall survival (OS). Multivariate prognostic analysis showed it was a powerful independent prognostic factor for PFS [HR=0.357 (95%CI 0.131-0.972), P=0.044].

Conclusion: uMRD in BM was an independent prognostic factor in SMZL patients, especially for the patients only achieving PR at the end of therapy.

Figure

Disclosures

No relevant conflicts of interest to declare.
Long-Term Follow-up of a Randomized Trial of Two Dose Levels of Antithymocyte Globulin in Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Wang Yu , Lin Ren , Xu Lan-Ping , Liu Kai-Yan , Zhang Xiao-Hui , Liu Qi-Fa , Huang Xiao-Jun
Published: February 2021

Background The optimal dose of antithymocyte globulin (ATG) with respect to the prevention of graft-versus-host disease (GVHD) following haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is under investigation. In our previous single-center randomized study, as compared with 6 mg/kg ATG, 10 mg/kg ATG was found to be associated with better GVHD prevention and superior GRFS, but an increase in infection-related deaths. Later on, in our multi-center randomized trial, 7.5 mg/kg ATG for GVHD prophylaxis was associated with reduced EBV and CMV infections without increased incidence of GVHD in comparison with 10.0 mg/kg ATG in haplo-HSCT.

Methods We reanalyzed and updated the prospective, randomized trial (clinicaltrials.gov, NCT01883180) identifying the influence of 7.5mg/kg versus 10.0 mg/kg of ATG on clinical outcomes in haplo-HSCT with extended follow-up (N=145. Seventy-six patients received 7.5 mg/kg ATG (ATG-7.5), whereas the remaining patients received 10 mg/kg ATG (ATG-10).

Results The median follow-up period was 1702 days (range, 23-2036 days). The rate of infection-related deaths in ATG-10 arm was double that of the ATG-7.5 arm (20.0% vs 11.8%; P=0.024). The 5 year cumulative incidence of relapse was not significantly different between the ATG-7.5 and ATG-10 groups (16.8% vs. 5.7%, P = 0.053). The 5 year cumulative incidence of non-relapse mortality was comparable between the ATG-7.5 and ATG-10 groups (27.6% vs. 28.7%, P = 0.938). The 5 year cumulative incidence of chronic GVHD (46.7% vs. 48.3%, P = 0.913), moderate-to-severe chronic GVHD (32.8% vs. 25.3%, P = 0.248), and severe chronic GVHD (17.1% vs. 13.3%, P = 0.505) were comparable between the ATG-7.5 and ATG-10 groups. The 5 year probabilities of disease-free survival (DFS) in the ATG-7.5 and ATG-10 groups were 55.6% and 65.7%, respectively (P = 0.281). The 5 year probability of GVHD-free/relapse-free survival (GRFS) in the ATG-10 group was significantly higher than that in the ATG-7.5 group (48.1% vs. 29.5%, P = 0.020). The 5 year cumulative incidence of late effects of grades 1-5 (67.2% vs. 71.2%, P = 0.695) and multiple late effects (26.2% vs. 25.4%, P = 0.920) were comparable between the ATG-7.5 and ATG-10 groups. In multivariate analysis, ATG-7.5 was associated with a significantly lower GRFS compared to ATG-10 (hazard ratio, 1.819; 95% confidence interval, 1.106-2.994; p=0.019).

Conclusion it appears that 10 mg/kg ATG was found to be associated with superior GRFS and comparable GVHD and late effects, but an increase in infection-related deaths as compared with 7.5 mg/kg ATG for haplo-HSCT.

Figure

Disclosures

No relevant conflicts of interest to declare.
Interleukin-2 Receptor Alpha Chain, Also Called CD25, Is a Potential Target in Acute Lymphoblastic Leukemia
Authors: Carrà Giovanna , Cartellà Antonio , Maffeo Beatrice , Circosta Paola , Cignetti Alessandro , Pautasso Marisa , Familiari Ubaldo , Volante Marco , Dragani Matteo Emidio Emidio , Rege Cambrin Giovanna , Saglio Giuseppe , Morotti Alessandro
Published: February 2021

Background: Acute lymphoblastic leukemia (ALL) is a molecularly heterogeneous disease originating from clonal proliferation of precursor B-lineage cells. In adults, ALL diagnosis is still associated with a dismal prognosis due to the lack of specific targeted therapies. This study was designed to investigate the expression of interleukin-2 receptor alpha chain CD25 in B-ALL and its biological significance, especially following the availability of specific CD25 targeting compounds.

Methods:The expression of IL2RA (CD25 gene) was detected by flow cytometry (FC), immunohistochemistry and Western blot analysis, in 25 newly diagnosed ALL patients, both Philadelphia positive (12 patients) and Philadelphia negative (13 patients). Similarly, CD25 expression was assessed in four B-ALL commercially available cell lines. Infection with shRNA specifically directed against CD25 was used to evaluate apoptosis induction and cell cycle arrest in primary B-ALL cells established from two patients.

Results:Our data suggest that ALL, and in particular Ph-positive ALL, aberrantly expresses the interleukin-2 receptor alpha chain, CD25. Whereas normal B cells display low amounts of CD25, primary ALL cells and ALL cell lines (over)-express CD25. While the high frequency of CD25 on the surface of many different hematological tumor cells has been established and confirmed in our study, there is little investigation focusing on the significance of CD25 expression. Indeed, CD25 may be present on ALL cells and enable oncogenic signaling pathways. In such respect, we observed that CD25 silencing in primary cells promotes cell cycle arrest and apoptosis induction. While these data support the rational to target CD25, ALL cells did not appear to be in-vitro sensitive to basiliximab, an antibody able to target the Il2RA, but in-vivo investigations are needed to better assess the effects of this therapeutic approach in ALL context.

Conclusions:We concluded that CD25 expression is elevated in patients with B-ALL. Our results also demonstrate that CD25 silencing induces cell cycle arrest and apoptosis. The latter result has important implications from a therapeutic point of view. Targeting CD25 receptor with anti-CD25 antibodies or peptide mimetics could be an effective strategy for targeting leukemic cells. Additionally, high CD25 expression could be exploited for the development of CAR-T therapy

Disclosures

Saglio: Roche:Research Funding;Pfizer:Research Funding;Incyte:Research Funding;Novartis:Research Funding;Ariad:Research Funding;Bristol-Myers Squibb:Research Funding.
Overexpression of hTLX3 in Association with Mutant IL7Rα Is Sufficient to Generate T-ALL In Vivo and to Transform Thymocytes in
Vitro
Authors: Rodrigues Gisele Olinto Libanio , Hixon Julie , Winer Hila , Matich Erica , Andrews Caroline , Cramer Sarah , Li Wenqing , Durum Scott
Published: February 2021

Mutations of the IL-7Rα chain occur in approximately 10% of pediatric T-cell acute lymphoblastic leukemia cases. While we have shown that mutant IL7Ra is sufficient to transform an immortalized thymocyte cell line, mutation of IL7Ra alone was insufficient to cause transformation of primary T cells, suggesting that additional genetic lesions may be present contributing to initiate leukemia. Studies addressing the combinations of mutant IL7Ra plus TLX3 overexpression indicates in vitro growth advantage, suggesting this gene as potential collaborative candidate. Furthermore, patients with mutated IL7R were more likely to have TLX3 or HOXA subgroup leukemia. We sought to determine whether combination of mutant hIL7Ra plus TLX3 overexpression is sufficient to generate T-cell leukemia in vivo. Double negative thymocytes were isolated from C57BL/6J mice and transduced with retroviral vectors containing mutant hIL7R plus hTLX3, or the genes alone. The combination mutant hIL7R wild type and hTLX3 was also tested. Transduced thymocytes were cultured on the OP9-DL4 bone marrow stromal cell line for 5-13 days and accessed for expression of transduced constructs and then injected into sublethally irradiated Rag-/- mice. Mice were euthanized at onset of clinical signs, and cells were immunophenotyped by flow cytometry. Thymocytes transduced with muthIL-7R-hTLX3 transformed to cytokine-independent growth and expanded over 30 days in the absence of all cytokines. Mice injected with muthIL7R-hTLX3 cells, but not the controls (wthIL7R-hTLX3or mutIL7R alone) developed leukemia approximately 3 weeks post injection, characterized by GFP expressing T-cells in blood, spleen, liver, lymph nodes and bone marrow. Furthermore, leukemic mice had increased white blood cell counts and presented with splenomegaly. Phenotypic analysis revealed a higher CD4-CD8- T cell population in the blood, bone marrow, liver and spleen compared in the mutant hIL7R + hTLX3 mice compared with mice injected with mutant IL7R alone indicating that the resulting leukemia from the combination mutant hIL7R plus hTLX3 shows early arrest in T-cell development. Taken together, these data show that oncogenic IL7R activation is sufficient for cooperation with hTLX3 in ex vivo thymocyte cell transformation, and that cells expressing the combination muthIL7R-hTLX3 is sufficient to trigger T-cell leukemia in vivo.

Figure

Disclosures

No relevant conflicts of interest to declare.
Comparative Transcriptomics of Alpha-Beta Subcutaneous Panniculitis-like T-Cell Lymphoma and Primary Cutaneous Gamma Delta T-Cell Lymphoma
Authors: Li Xing , Severson Kevin J , Patel Meera H , Brumfiel Caitlin M , Hughes Alysia , DiCaudo David , Comfere Nneka , Sluzevich Jason , Rosenthal Allison C. , Torres-Cabala Carlos A , Pittelkow Mark R , Mangold Aaron R
Published: February 2021

Background: Subcutaneous lymphomas are a heterogeneous group of diseases with variable clinical behavior that ranges from a lymphoproliferative disorder to an aggressive cytotoxic lymphoma. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon, often indolent cutaneous lymphoma that localizes to the subcutaneous adipose tissue. These tumors exhibit an alpha/beta phenotype (abSPTCL). Primary cutaneous gamma-delta T-cell lymphoma (PCgdTCL) is a rare, highly aggressive lymphoma that frequently involves the subcutaneous adipose tissue. The goal of this study is to identify key inflammatory and oncogenic pathways in SPTCL and PCgdTCL to determine which mutational or expression patterns differentiate abSPTCL and PCgdTCL. A comprehensive catalog of cancer gene expression profiles generated via RNA sequencing on patient samples is essential to understand tumorigenesis and to develop effective therapies.

Methods: We performed transcriptomic profiling analysis using RNA sequencing in lesional skin biopsies from patients of abSPTCL (n=10), PCgdTCL (n=9), and controls (n=5). Differential analyses were performed on the entire transcriptomic profiles among the 3 groups.

Results: Although the transcriptomic profiles of abSPTCL and PCgdTCL samples had similarities, there were notable differences between these groups that may elucidate unique pathways that propagate each disease. In contrast to abSPTCL, PCgdTCL samples demonstrated upregulation of cell motility and proliferation, and downregulation of pathways involving apoptosis and tumor necrosis factor production. The most significantly upregulated gene pathways in both abSPTCL and PCgdTCL samples were those involving immune and inflammatory response, viral defense, type I interferon signaling, interferon-gamma-mediated signaling, and positive regulation of T cell proliferation. The most significantly downregulated gene pathways in the two groups were those involving cell adhesion, rRNA processing and translation, and extracellular matrix organization. The top 5 upregulated immune response and downregulated cell adhesion hub genes for abSPTCL highlighted by gene interaction network analysis included: TNF, CTLA4, CD86, IL10, CCR5 & ITGB5, ITGA8, VWF, APP, CDH5, respectively.

Conclusion: Our transcriptomic profiling pinpoints disease-related enrichment pathways and gene functions in abSPTCL and PCgdTCL patients, which may shed light on molecular mechanisms that drive disease activity. Hub genes in abSPTCL represent potential drug targets for further development of novel therapies.

Disclosures

Mangold: Kirin:Membership on an entity's Board of Directors or advisory committees;Elorac:Research Funding;Sun Pharma:Research Funding;MiRagen:Research Funding;Solagenix:Research Funding.
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

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

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

Background

Feed 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.

Results

Estimates 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.

Conclusions

We 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

Background

Dissolved 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).

Results

The 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.

Conclusions

The 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

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

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.
Clinical characteristics of inpatients with coronavirus disease 2019 (COVID-19) in Sichuan province
Authors: Wang Wen , Chen Lei , He Qiao , Wang Mingqi , Liu Mei , Deng Taibing , Deng Xiaoju , Yang Jianrong , Jiang Ou , Li Rongmei , Long Bo , Mai Gang , Huan Wenhui , Li Wenquan , Jiang Xin , Wen Zeqiang , Chen Yongjun , Fu Wanzhi , Long Zhiling , Zeng Fanxin , Chen Yan , Du Yihua , Tang Juan , Sun Xin , Li Weimin
Published: February 2021

Background

The outbreak of COVID-19 has resulted in serious concerns in China and abroad. To investigate clinical features of confirmed and suspected patients with COVID-19 in west China, and to examine differences between severe versus non-severe patients.

Methods

Patients admitted for COVID-19 between January 21 and February 11 from fifteen hospitals in Sichuan Province, China were included. Experienced clinicians trained with methods abstracted data from medical records using pre-defined, pilot-tested forms. Clinical characteristics between severe and non-severe patients were compared.

Results

Of the 169 patients included, 147 were laboratory-confirmed, 22 were suspected. For confirmed cases, the most common symptoms from onset to admission were cough (70·7%), fever (70·5%) and sputum (33·3%), and the most common chest CT patterns were patchy or stripes shadowing (78·0%); throughout the course of disease, 19·0% had no fever, and 12·4% had no radiologic abnormality; twelve (8·2%) received mechanical ventilation, four (2·7%) were transferred to ICU, and no death occurred. Compared to non-severe cases, severe ones were more likely to have underlying comorbidities (62·5% vs 26·2%, P = 0·001), to present with cough (92·0% vs 66·4%, P = 0·02), sputum (60·0% vs 27·9%, P = 0·004) and shortness of breath (40·0% vs 8·2%, P <  0·0001), and to have more frequent lymphopenia (79·2% vs 43·7%, P = 0·003) and eosinopenia (84·2% vs 57·0%, P = 0·046).

Conclusions

The symptoms of patients in west China were relatively mild, and an appreciable proportion of infected cases had no fever, warranting special attention.
Broad range detection of viral and bacterial pathogens in bronchoalveolar lavage fluid of children to identify the cause of lower respiratory tract infections
Authors: Wang Heping , Gu Jiali , Li Xiaonan , van der Gaast-de Jongh Christa E. , Wang Wenjian , He Xuehui , Xu Zhi , Yang Yonghong , de Groot Ronald , de Jonge Marien I. , Zheng Yuejie
Published: February 2021

Background

Knowledge on the etiology of LRTIs is essential for improvement of the clinical diagnosis and accurate treatment. Molecular detection methods were applied to identify a broad range of bacterial and viral pathogens in a large set of bronchial alveolar lavage (BAL) fluid samples. The patterns of detected pathogens were correlated to the clinical symptoms.

Methods

BAL fluid samples and clinical data were collected from 573 hospitalized children between 1 month and 14 years of age with LRTIs, enrolled from January to December 2018. Pathogens were detected using standardized clinical diagnostics, with a sensitive, high-throughput GeXP-based multiplex PCR and with multiplex qPCR. Data were analyzed to describe the correlation between the severity of respiratory tract disease and the pathogens identified.

Results

The pathogen detection rate with GeXP-based PCR and multiplex qPCR was significantly higher than by clinical routine diagnostics (76.09% VS 36.13%,χ2 = 8.191, P = 0.004). The most frequently detected pathogens in the BAL fluid were human adenovirus (HADV)(21.82%), Mycoplasma pneumoniae (20.24%), human rhinovirus (13.96%), Streptococcus pneumoniae (8.90%) and Haemophilus influenzae (8.90%). In 16.4% of the cases co-detection with two or three different pathogens was found. Viral detection rates declined with age, while atypical pathogen detection rates increased with age. Oxygen supply in the HADV and Influenza H1N1 infected patients was more frequent (49.43%) than in patients infected with other pathogens.

Conclusion

Broad range detection of viral and bacterial pathogens using molecular methods is a promising and implementable approach to improve clinical diagnosis and accurate treatment of LRTI in children.
A case report of streptococcal toxic shock syndrome caused by Streptococcus mitis in a healthy adult
Authors: Chen Xiang , Gong Ying Ying , Zhang Li
Published: February 2021

Background

Streptococcal toxic shock syndrome (STSS) is an acute, multisystem and toxin-mediated disease that usually causes shock and multiple organ failure in the early stages of its clinical course. It is associated with a substantial increase in mortality rate. The disease has been associated with invasive group A Streptococcus and is rarely caused by Streptococcus mitis (S. mitis). In healthy adults, S. mitis is closely related to endocarditis but rarely related to STSS.

Case presentation

We report a case of STSS caused by S. mitis in a healthy 45-year-old woman. She presented with fever 14 h after surgery and with hypotension 24 h later, and she subsequently suffered from septic shock, low albumin, dysfunction of coagulation, acute kidney dysfunction, respiratory alkalosis and metabolic acidosis, acute respiratory distress syndrome and cellulitis of the incision. The diagnosis was obtained through clinical manifestation and blood culture examination. The patient was treated with aggressive fluid resuscitation, adequate antibiotics for a total of 4 weeks, respiratory support, and surgical debridement and drainage of the incision. She was discharged after her vital signs returned to normal and the incision healed on day 40 after surgery.

Conclusions

The diagnosis of STSS is often delayed or missed, which leads to a high mortality rate. It is possible to cure patients if the disease can be identified early and treated with aggressive fluid resuscitation, adequate antibiotics and control of the source of infection. Clinicians should consider the disease in the differential diagnosis of septic shock to prevent death.
Assessing the predictive value of common gait measure for predicting falls in patients presenting with suspected normal pressure hydrocephalus
Authors: Davis Alexander , Luciano Mark , Moghekar Abhay , Yasar Sevil
Published: February 2021

Objective

To assess the predictive value of common measures validated to predict falls in other geriatric populations in patients presenting with suspected Normal Pressure Hydrocephalus (NPH).

Methods

One hundred ninety-five patients over the age of 60 who received the Fall Risk Questionnaire were retrospectively recruited from the CSF Disorders clinic within the departments of Neurosurgery and Neurology. Multiple logistic regression was used to create a model to predict falls for patients with suspected NPH using common measures: Timed Up & Go, Dual Timed Up & Go, 10 Meter Walk, MiniBESTest, 6-Minute Walk, Lower Extremity Function (Mobility), Fall Risk Questionnaire, and Functional Activities Questionnaire.

Results

The Fall Risk Questionnaire and age were shown to be the best predictors of falls. The model was 95.92% (Positive predictive value: 83.93%) sensitive and 47.92% specific (Negative predictive value: 77.78%).

Conclusion

Patients presenting with suspected NPH are at an increased fall risk, 75% of the total patients and 89% of patients who responded to a temporary drain of CSF had at least one fall in the past 6 months. The Fall Risk Questionnaire and age were shown to be predictive of falls for patients with suspected NPH. The preliminary evidence indicates measures that have been validated to assess fall risk in other populations may not be valid for patients presenting with suspected NPH.
Effectiveness of mechanical thrombectomy in cancer-related stroke and associated factors with unfavorable outcome
Authors: Lee Eung-Joon , Bae Jeonghoon , Jeong Hae-Bong , Lee Eun Ji , Jeong Han-Yeong , Yoon Byung-Woo
Published: February 2021

Background

The effectiveness of mechanical thrombectomy (MT) in cancer-related stroke (CRS) is largely unknown. This study aims to investigate the clinical and radiological outcomes of MT in CRS patients. We also explored the factors that independently affect functional outcomes of patients with CRS after MT.

Methods

We retrospectively reviewed 341 patients who underwent MT after acute ischemic stroke onset between May 2014 and May 2020. We classified the patients into CRS (n = 34) and control (n = 307) groups and compared their clinical details. Among CRS patients, we analyzed the groups with and without good outcomes (3-months modified Rankin scale [mRS] score 0, 1, 2). Multivariate analysis was performed to investigate the independent predictors of unfavorable outcomes in patients with CRS after MT.

Results

A total of 341 acute ischemic stroke patients received MT, of whom 34 (9.9%) had CRS. Although the baseline National institute of health stroke scale (NIHSS) score and the rate of successful recanalization was not significantly different between CRS patients and control group, CRS patients showed more any cerebral hemorrhage after MT (41.2% vs. controls 23.8%,p = 0.037) and unfavorable functional outcome at 3 months (CRS patients median 3-month mRS score 4, interquartile range [IQR] 2 to 5.25 vs. controls median 3-month mRS score 3, IQR 1 to 4, [p = 0.026]). In the patients with CRS, elevated serum D-dimer level and higher baseline NIHSS score were independently associated with unfavorable functional outcome at 3 months (adjusted odds ratio [aOR]: 1.524, 95% confidence interval [CI]: 1.043–2.226; aOR: 1.264, 95% CI: 1.010–1.582, respectively).

Conclusions

MT is an appropriate therapeutic treatment for revascularization in CRS patients. However, elevated serum D-dimer levels and higher baseline NIHSS scores were independent predictors of unfavorable outcome. Further research is warranted to evaluate the significance of these predictors.