bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients withPIK3CA-Mutant Cancers
Authors: Jhaveri Komal , Chang Matthew T. , Juric Dejan , Saura Cristina , Gambardella Valentina , Melnyk Anton , Patel Manish R. , Ribrag Vincent , Ma Cynthia X. , Aljumaily Raid , Bedard Philippe L. , Sachdev Jasgit C. , Dunn Lara , Won Helen , Bond John , Jones Surai , Savage Heidi M. , Scaltriti Maurizio , Wilson Timothy R. , Wei Michael C. , Hyman David M.
Published: November 2020

Purpose:

Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib.

Patients and Methods:

Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed.

Results:

A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index.

Conclusions:

Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.
Lactococcus lactis NZ9000 Prevents Asthmatic Airway Inflammation and Remodelling in Rats through the Improvement of Intestinal Barrier Function and Systemic TGF-β Production
Authors: Cervantes-García Daniel , Jiménez Mariela , Rivas-Santiago César E. , Gallegos-Alcalá Pamela , Hernández-Mercado Alicia , Santoyo-Payán Leslie S. , Loera-Arias María de Jesús , Saucedo-Cardenas Odila , Montes de Oca-Luna Roberto , Salinas Eva
Published: November 2020

Introduction: The use of probiotics has been broadly popularized due to positive effects in the attenuation of aberrant immune responses such as asthma. Allergic asthma is a chronic respiratory disease characterized by airway inflammation and remodelling. Objective: This study was aimed to evaluate the effect of oral administration of Lactococcus lactis NZ9000 on asthmatic airway inflammation and lung tissue remodelling in rats and its relation to the maintenance of an adequate intestinal barrier. Methods: Wistar rats were ovalbumin (OVA) sensitized and challenged and orally treated with L. lactis. Lung inflammatory infiltrates and cytokines were measured, and remodelling was evaluated. Serum OVA-specific immunoglobulin (Ig) E levels were assessed. We also evaluated changes on intestinal environment and on systemic immune response. Results: L. lactis diminished the infiltration of proinflammatory leucocytes, mainly eosinophils, in the bronchoalveolar compartment, decreased lung IL-4 and IL-5 expression, and reduced the level of serum allergen-specific IgE. Furthermore, L. lactis prevented eosinophil influx, collagen deposition, and goblet cell hyperplasia in lung tissue. In the intestine, L. lactis-treated asthmatic rats increased Peyer’s patch and goblet cell quantity and mRNA expression of IgA, MUC-2, and claudin. Additionally, intestinal morphological alterations were normalized by L. lactis administration. Splenocyte proliferative response to OVA was abolished, and serum levels of transforming growth factor (TGF)-β were increased by L. lactis treatment. Conclusions: These findings suggest that L. lactis is a potential candidate for asthma prevention, and the effect is mediated by the improvement of intestinal barrier function and systemic TGF-β production.
Use of Complementary Medicine in Competitive Sports: Results of a Cross-Sectional Study
Authors: Rotter Gabriele , Schollbach Lisa , Binting Sylvia , Dornquast Christina , Scherr Johannes , Pfab Florian , Brinkhaus Benno
Published: November 2020

Background: Although complementary medicine is frequently used in Germany, there is almost no information about complementary medicine use in competitive sports. The aim was to assess the use of complementary medicine among elite athletes in Germany. Patients and Methods: A cross-sectional study among athletes was performed between March 2012 and September 2013. Athletes of both sexes who visited a sports medical outpatient clinic in Munich, Bavaria were included. Data about the use of complementary medicine were collected by means of a standardized measurement instrument, the German version of the international complementary and alternative medicine questionnaire. Results: Of the 334 athletes (female 25%, mean age 20.2 ± 6.6 years) who completed all 4 sections of the questionnaire, 69% reported the use of at least one type of complementary medicine within the last 12 months. 505 athletes (female 26%, mean age 20.5 ± 7.0 years) completed at least one section of the questionnaire entirely. Within 12 months, the osteopath (11%), herbal medicine (17%), vitamins/minerals (32%), and relaxation techniques (15%) were the most frequently visited/used in relation to the respective sections of the questionnaire. Conclusion: Complementary medicine is frequently used by athletes in Germany. The efficacy, safety, and costs of complementary medicine should be investigated in clinical trials among athletes in the future.
Type mineralogy of Brazil: a book in progress
Authors:   Universidade de São Paulo. Instituto de Geociências, Atencio Daniel
Published: November 2020

This is a compilation of bibliographic (historical and descriptive) information for the minerals first described from Brazil; it includes both valid and invalid, discredited species, unnamed, unidentified, problematic minerals, and so on. This work brings together as much data as possible concerning type mineral species. It will save future researchers a lot of work because it contains data from many publications that are difficult to obtain.
A Legislative History of Nonhuman Animal Fighting in the U.S. and Its Territories
Authors: Pacelle Wayne , Pacelle Richard L.
Published: November 2020

Nonhuman animal fighting is an ancient form of exploitation, still attracting millions of followers. While 19th-century proscriptions imposed in the U.S. succeeded in stigmatizing it, animal fighters adapted to these cultural and legal taboos and continued to operate, often clandestinely. Cockfighting thrived, operating as a quasi-legal enterprise until an incremental policy-making campaign succeeded in passing a raft of local, state, and federal laws to outlaw it everywhere in the U.S. Between 1998 and 2018, legal cockfighting was banned in the final five states; more than 40 other states reformed their laws; and Congress passed multiple reforms to ban animal fighting, including in the U.S. territories. The process of outlawing animal fighting faced fierce resistance, but these practices are now the most widely and severely criminalized forms of animal mistreatment in the U.S. Adherence to the law and enforcement are continuing challenges.
Revenge Pornography in Nigeria: A Call for Legal Response and Cyber-Censorship of Content by Internet Service Providers
Authors: Nwafor Ifeoma E. , Nwafor Ndubuisi , Alozie Josiah
Published: November 2020

Revenge pornography is the online distribution of sexually uncensored images or videos of another person without consent and to cause embarrassment or torment. Victims of revenge pornography suffer significant harm, including losing jobs and, in extreme cases, committing suicide. The public blames the victim for the role they played. Rather than victim-blaming, victims deserve a takedown order and criminal liability for uploaders of such images. This study adopts a doctrinal approach; it examines key statutes and their interpretation by Nigerian courts while juxtaposing it with the law and practice in the United Kingdom. The United Kingdom was undertaken as a case study because it has a developed jurisprudence which can provide lessons for Nigeria. This study found that the current state of laws in Nigeria is ill-equipped to tackle the menace of revenge pornography. The objective of this study is to offer insights on the prevalence of revenge pornography in Nigeria and suggest legal solutions to address this phenomenon. It canvasses for a non-consensual pornography provision that would criminalise the act of revenge pornography in Nigeria. It also makes a case for cyber-censorship of contents by internet service providers and the need for third-party liability.
National Security, Property Rights, and Development in Nigeria: How Should the Leviathan Resolve Herder-Farmer Conflict?
Authors: Nwankwo Chidebe Matthew
Published: November 2020

The spate of violent clashes between nomadic pastoralists and agrarian communities in Nigeria raises a number of legal and policy questions that had been long overlooked. Issues arising from the phenomenon range from questions over constitutionally guaranteed rights such as the right to own property, to questions over the inadequacies of Nigeria’s security apparatus as well as calls for land use reforms. Additionally, due to the groups affected and the scale of casualties, the topic has become a political molten magma. The constant conflicts between nomadic pastoralists who are majorly from the Fulani ethnic group, and agrarian communities from other parts of the country have reached unprecedented levels leading to accusations of coordinated attempts at land grab, ethnic cleansing, jihad and insurgency, threatening the country’s security and stability in the process. Fiscally, the destruction of lives and property and the state of insecurity emanating from the clashes stood at $16 billion in potential revenue as at 2018. In no small measure have these clashes been precipitated by climate change and the consequent drought in the Sahara region. This paper analyses the role of the Nigerian state in balancing the interests of affected groups in the clashes and promoting development. At its core, it seeks to identify legal and policy gaps that require filling to put a definite end to the lingering crisis.
Tropical and Extratropical Cyclone Detection Using Deep Learning
Authors: Kumler-Bonfanti Christina , Stewart Jebb , Hall David , Govett Mark
Published: November 2020

Extracting valuable information from large sets of diverse meteorological data is a time-intensive process. Machine-learning methods can help to improve both speed and accuracy of this process. Specifically, deep-learning image-segmentation models using the U-Net structure perform faster and can identify areas that are missed by more restrictive approaches, such as expert hand-labeling and a priori heuristic methods. This paper discusses four different state-of-the-art U-Net models designed for detection of tropical and extratropical cyclone regions of interest (ROI) from two separate input sources: total precipitable water output from the Global Forecast System (GFS) model and water vapor radiance images from the Geostationary Operational Environmental Satellite (GOES). These models are referred to as International Best Track Archive for Climate Stewardship (IBTrACS)-GFS, Heuristic-GFS, IBTrACS-GOES, and Heuristic-GOES. All four U-Nets are fast information extraction tools and perform with an ROI detection accuracy ranging from 80% to 99%. These are additionally evaluated with the Dice and Tversky intersection-over-union (IoU) metrics, having Dice coefficient scores ranging from 0.51 to 0.76 and Tversky coefficients ranging from 0.56 to 0.74. The extratropical cyclone U-Net model performed 3 times as fast as the comparable heuristic model used to detect the same ROI. The U-Nets were specifically selected for their capabilities in detecting cyclone ROI beyond the scope of the training labels. These machine-learning models identified more ambiguous and active ROI missed by the heuristic model and hand-labeling methods that are commonly used in generating real-time weather alerts, having a potentially direct impact on public safety.
Identification and influence factors analysis of blade crack mistuning in hard-coated blisk based on modified component mode mistuning reduced-order model
Authors: Xu Kunpeng , Yan Xianfei , Du Dongxu , Sun Wei
Published: November 2020

Blade crack will cause severe mistuning of hard-coated blisks, which will lead to vibration localization. To identify crack mistuning and analyze influence factors, in this study, a mistuning identification method of blade cracks in hard-coated blisks is presented based on modified component mode mistuning reduced-order model, in which the hard-coated blisk with blade crack is decomposed into a substructure of tuned hard-coated blisk and a substructure of coated blade with cracks. Crack mistuning of each coated blade can be obtained by a single identification calculation. After verifying the rationality of this identification method, the influence factors of blade crack mistuning are analyzed. The influence factors include the crack location on the coated blade (cracks occurring only in coating or only in blade substrate or both in blade substrate and coating), crack length, crack position in the radial direction of the blisk, and modal data type of coated blisk used for mistuning identification calculation. The research results show that, with the increase of crack length, the mistuning of crack occurring only in the coating does not increase continuously but decreases firstly and then increases. For the first bending modes, the closer the blade crack is to the blade root, the larger the mistuning is. For the second bending modes, the blade crack located at the position of maximum modal displacement will produce large mistuning. For hard-coated blisk with blade crack, these crack mistuning variation rules are of great significance to the dynamic analysis and the determination of the crack location.
Acceptance of the disease and sexual functions of patients with heart failure
Authors: Wiśnicka Alicja , Uchmanowicz Izabella , Dyjakon Dorota , Cichoń Ewelina , Szczepanowski Remigiusz , Jankowska Ewa A
Published: November 2020

Background

Sexual activity is an important element of quality of life for many individuals suffering from heart failure.

Aims

The study investigated the influence of disease acceptance on sexual function in a population of male patients with chronic heart failure.

Methods

The study included 80 patients with chronic heart failure (mean age 63.3±9.2 years) who filled in the Mell–Krat Scale questionnaire to evaluate sexual needs and reactions. We also used the International Index of Erection Function (IIEF-5) inventory and the Acceptance of Illness Scale (AIS).

Results

The study showed that the acceptance of the illness was positively associated with all of the Mell–Krat components such as sexual need, F = (3.27), frequency of intercourse, F = (2.46), position and technique, F = (1.88). Also, according to the IIEF-5 questionnaire, 84.42% of respondents had erectile dysfunction. Taken together these indicated that psychological adjustments such as acceptance of disease increase quality of all aspects of sexual functions in heart failure patients, including their erectile functions.

Conclusions

Our findings suggest that psychological adjustments to feelings of loss associated with the onset of heart failure disease is the important determinant of quality of sexual life among male adults. Our research implicates that effects of AIS on sexual functioning give reasonable information to tailor sexual counselling for males suffering from heart failure.
Circulating microRNAs Is a Potential Prognostic Biomarker in Primary Central Nervous System Lymphoma
Authors: Ma Yan , Suolitiken Dina , Chen Bobin , Xu Xiaoping , Kang Hui , Zhiguang Lin
Published: November 2020

Backgrounds and purposes Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin's lymphoma. The prognosis of PCNSL is poor and heterogeneous. MicroRNA is associated with prognosis of various cancers. Our study is the first time to compare circulating microRNAs of PCNSL patients with different prognosis using miRNA microarray scanning and find novel microRNAs associated with prognosis of PCNSL by further large-scale validation.

Materials and methods From a retrospective cohort, we collected the clinical data of patients who were diagnosed as PCNSL in Huashan Hospital between January 2007 and June 2016. We collected clinical data and blood samples from residual blood routine test of PCNSLs. First, we compared circulating microRNAs between patients with different overall survival (OS) using miRNA microarray scanning. Second, PCR assay was used for miRNAs quantification in blood sample from 6 patients that had long overall survival and other 6 patients that had short overall survival. Further miRNA validation was made by PCR assay in blood sample from 94 patients to validate prognostic value of miRNAs in PCNSLs. The Kruskal-Wallis and Mann-Whitney U tests were used for quantitative parameters and the χ2 square test was used for non-quantitative parameters. Univariate analysis was performed using log-rank test, and survival distributions were analyzed by the Kaplan-Meier curve and log-rank test. Multivariate analysis was done by Cox regression model.

Results A total of 90 differentially expressed miRNAs were identified, including 24 up-regulated miRNAs and 66 down-regulated miRNAs using miRNA microarray scanning. Then PCR assay was used for 10 differentially expressed miRNAs quantification in blood sample from 6 patients that had long overall survival and 6 patients that had short overall survival. Mir-21, mir-129-5p, mir-144-5, mir-363-5p, mir-409-3p, mir-1246, mir-1299 and mir-1825 showed no differences between 2 groups, while the expression of mir-455-3P and mir-940 between 2 groups are significantly different (P<0.05). Further validation in 94 patients showed median OS in miR-940 overexpression group was 91 months and in miR-940 low-expression group was 28 months (P=0.0005), while median PFS in miR-940 overexpression group was 25 months and in miR-940 low-expression group was 16 months (P =0.0292). Multivariate analysis of COX model showed miR-940 was independent factors for OS and PFS.

Conclusion Circulating mir-940 had prognostic value in PCNSL and was an independent prognostic factor for PCNSL.

Figure 1

Disclosures

No relevant conflicts of interest to declare.
Mechanisms of Leukemia Stem Cell Plasticity Revealed By Single Cell Analysis
Authors: Rowe R. Grant , Daley George Q. , North Trista E. , Marion William , Pikman Yana , Harris Marian H. , Morris Vivian , Lummertz da rocha Edroaldo , Shalek Alex K. , Hughes Travis , Sensharma Prerana , Wang Dahai , Sousa Patricia , Ho Sui Shannan , Naumenko Sergey , Vinicius Da Silva Renan
Published: November 2020

Leukemia stem cells (LSCs) are the subset of leukemic cells that drive leukemia progression, resist therapy, and remain latent to spark disease relapse. LSCs are quantified by efficiency of xenografting immunodeficient mice, a measurement that is predictive of leukemia outcome. Although LSCs have been previously thought to be rare and phenotypically primitive, recent data indicate that LSCs may actually be heterogeneous. Here, we use single-cell transcriptomics combined with limiting dilution xenotransplantation to dissect the ontogeny of MLL-rearranged B-lymphoblastic leukemia (MLL-r B-ALL), an aggressive form of childhood leukemia. Compared to acute myeloid leukemia (AML), LSCs are abundant in MLL-r B-ALL. Recapitulating the unique clinical behavior of this form of leukemia, MLL-r B-ALL cells undergo a B-lymphoid to myeloid lineage switch under chemotherapy pressure consistent with primitive, multipotent transcriptional programs present in LSCs. Although we identify rare, chemotherapy-resistant, primitive LSCs, we also observe LSCs emerging from more differentiated populations. These facultative LSCs self-renew and possess the capability to replenish the full cellular diversity of MLL-r B-ALL. Using CITE-seq, we find that stem cell programs can be fully uncoupled from immunophenotype in MLL-r B-ALL. In mechanistic studies, we find that the phenotypically differentiated LSCs that drive bottom-up reconstitution of the leukemic cellular ontogeny bear signatures of MYC activation and oxidative phosphorylation. We confirm recruitment of these pathways in actively reconstituting, phenotypically differentiated LSCs, and define a pathway by which MYC rewires metabolism in MLL-r B-ALL LSCs. We find that MYC is required for LSC plasticity in vitro and in vivo. Targeting oxidative metabolism impairs LSC engraftment, identifying a potential therapeutic intervention. We conclude that the high LSC content and dual lineage and LSC plasticities of MLL-r B-ALL contribute to its chemotherapy resistance and persistently poor outcomes.

Disclosures

Shalek: Honeycomb Biotechnologies: Consultancy, Current equity holder in publicly-traded company; Cellarity: Consultancy, Current equity holder in publicly-traded company; Repertoire Immune Medicines: Consultancy, Current equity holder in publicly-traded company; Merck: Consultancy; Orche Bio: Consultancy, Current equity holder in publicly-traded company; Dahlia Biosciences: Consultancy, Current equity holder in publicly-traded company.
Frequency of Arterial Thromboemobolic Events in Patients with Cancer Associated Venous Thromboembolism
Authors: Attia Doaa , Jia Xuefei , Wilks Mailey L , Tripp Barbara , D'Andrea Christopher , McCrae Keith R , Khorana Alok A , Angelini Dana E
Published: November 2020

Background:Patients with cancer are at high risk of both venous thromboembolism (VTE) and arterial events, however, little is known about the association between venous and arterial thromboembolic events in patients with cancer. In this study, we evaluated the incidence and relative risk of subsequent arterial thromboembolism in patients with a confirmed diagnosis of acute cancer-associated VTE.

Methods:We conducted a retrospective cohort study at the Cleveland Clinic Taussig Cancer Institute of cancer patients with confirmed VTE who were referred to a centralized thrombosis clinic between January 2017-October 2019 with at least 6 months of follow-up. Arterial thrombotic events (ATE), including myocardial infarction, peripheral arterial thrombosis, and ischemic stroke, were identified by manual review of electronic medical records. The cumulative incidence rate of each ATE event was calculated.

Results:The study population comprised 294 patients with a median age of (63.5) years (range 27-90), and 49.7 % were male. The cumulative incidence rate of overall ATE during the 6-month, 1-year, and 2-year follow-up period was 3.07%, 3.42%, and 3.42%, respectively. A total of 10 patients who experienced arterial events of whom 7 had ischemic stroke, 2 had myocardial infarction, 2 had peripheral arterial thrombosis where one patient had two arterial events of myocardial infarction and peripheral arterial thrombosis(Table 1 shows the incidence rates of arterial events). Amongst patients with ATE, 30 % were active smokers (n=3), 90% had hypertension (n=9), 20% had diabetes mellitus (n=2), 50% had a family history of coronary artery disease (n=5), 40% were on statin and daily aspirin use (n=4), 40% were obese with BMI >30 (n=4). 40% of ATE patients(n=4) were on a therapeutic anticoagulant therapy at the time of arterial thrombotic event (3 on enoxaparin, 1 on apixaban)

Conclusion:Cancer patients with acute VTE have a substantial increased risk of subsequent arterial thromboembolism particularly in the first six months after VTE. Ischemic stroke was the most frequent arterial event and ATE events occured despite therapeutic anticoagulation in a large subset of our cohort. Further prospective studies are needed to better understand the risk of ATE in cancer patients, and further studies should be designed to mitigate the risk of arterial events in this patient population.

Disclosures

McCrae: Momenta Pharmaceuticals:Consultancy;Novartis:Honoraria;Rigel:Consultancy;Dova:Consultancy.Khorana:Pharmacyclics:Honoraria;Pharmacyte:Honoraria;Seattle Genetics:Honoraria;Leo Pharma:Honoraria;Medscape:Honoraria;Sanofi:Honoraria;Pfizer:Honoraria;Bayer:Honoraria;Janssen:Honoraria;Array:Other: Research funding (to institution);Merck:Research Funding;BMS:Honoraria, Research Funding;Leap:Research Funding.
Large Scale Ex Vivo Expansion of Γδ T Cells Using Artificial Antigen Presenting Cells for the Treatment of Acute Myeloid Leukemia
Authors: Boucher Justin C. , Yu Bin , Li Gongbo , Shrestha Bishwas , Lancet Jeffrey E. , Sallman David A. , Landin Ana Marie , Mailloux Adam William , Anasetti Claudio , Kelley Linda L. , Davila Marco L. , Bejanyan Nelli
Published: November 2020

Patients with relapsed or refractory acute myeloid leukemia (AML) are at increased risk of mortality. Higher γδ T cell count in a bone marrow or peripheral blood of patients with leukemia is associated with better survival. However, γδ T cells are rare in the blood and functionally impaired or exhausted in patients with malignancies. Promising results are reported on the treatment of various malignancies with in vivo expansion of autologous γδ T cells using zoledronic acid (zol) and IL-2. Here we demonstrated that zol and IL-2, in combination with a novel genetically engineered K562 CD3/CD137L/CD28/IL15RA quadruplet artificial antigen presenting cell (aAPC), efficiently expand allogeneic donor-derived γδ T cells using a GMP-compliant protocol sufficient to achieve cell doses for future clinical use. We achieved a 633-fold expansion of γδ T cells after day 10 of co-culture with aAPC, the majority of which exhibited central (47%) and effector (43%) memory phenotypes. Additionally, >90% of the expanded γδ T cells expressed NKG2D, while they have low cell surface expression of PD1 and LAG2 inhibitory checkpoint receptors. In vitro real-time cytotoxicity analysis showed that expanded, previously cryopreserved, γδ T cells were effective in killing target cells. Our results demonstrate that large scale ex vivo expansion of donor-derived γδ T cells can be achieved with the use of CD3/CD137L/CD28/IL15RA quadruplet aAPC and zol/IL-2 for clinical application as promising antineoplastic immunotherapy.

Figure 1

Disclosures

Lancet: Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.
Wtapblock Cell Differentiation of Hematopoietic Stem and Progenitor Cells
Authors: Liu Yuanyuan , Xiao Feifei , Yang Bijie , Chen Zhiwei , Chen Jieping , Hou Yu
Published: November 2020

Wilms' tumor 1-associating protein (WTAP) is a ubiquitously expressed nuclear protein has been associated with regulation of cell proliferation, apoptosis, embryonic development, cell cycle, RNA splicing and stabilization, N6-Methyladenosine RNA modification in various physiological processes. Recently,WTAPwas reported to promoter tumorigenicity in Glioblastoma and cholangiocarcinoma. Besides solid tumors,WTAPplays an important role in abnormal proliferation and arrested differentiation in acute myeloid leukemia (AML) cell, suggesting its oncogenic activity. For its promising novel therapeutic target in AML, a systematic investigation of the roles ofWTAPin normal hematopoiesis is warranted.To investigate the function ofWTAPin normal hematopoietic system, we firstly determined the mRNA level ofWTAPin different hematopoietic stem and progenitor cells (HSPCs) and several mature populations in C57/B6 mouse bone marrow (BM).WTAPwas ubiquitously expressed in different cell populations and especially elevated in HSPCs. For WTAP-null and heterozygous caused early embryonic lethality, we generated endothelial system conditional knockout (cKO) mice by crossing WTAP floxed mice with poly (I:C) induced Mx1-Cre transgenic mice. In poly (I:C) inducedWTAPfl/fl-Mx1-Cre, WTAP deficiency lead to approximately 2-fold increase in HSC and LSK pool size, and modest expansion of HPC, CLP and LMPP population. In competitive BM transplantation assay, lossWTAPshowed a significantly decreased repopulation capacity. WhileWTAPknockout did not significantly affect the proliferation, cell cycle and apoptosis of HSPCs tested by Brdu, Ki67 and Annexin-V straining assay. Mechanistically, deletion ofWTAPin HSC resulted in decreased transcription of myeloid cell and erythrocyte differentiation gene (including Jak3, Jun and Junb) and genes regulating pluripotency of stem cells (induding Akt2, Fzd1/9 and Mapk3).Collectively, we speculateWTAPplay important role in blocking cell differentiation of HSPCs. Currently, we are conducting a series of studies to reveal the underlying molecular mechanism(s) ofWTAPregulating normal hematopoiesis.

Disclosures

No relevant conflicts of interest to declare.
Fotemustine-Based in Combination with Rituximab As First-Line Induction Chemotherapy for Newly Diagnosed Primary Central Nervous System Lymphoma:a Prospective Phaseii Trial
Authors: Wu Jingjing , Gao Fenghua , Zhang Lei , Li Xin , Li Ling , Wang Xinhua , Zhu Linan , Zhang Xudong , Fu Xiaorui , Sun Zhenchang , Dong Meng , Ding Mengjie , Yu Hui , Nan Feifei , Yan Jiaqin , Chang Yu , Wu Xiaolong , Zhou Zhiyuan , Zhang Mingzhi , Young Ken H.
Published: November 2020

Objective:To evaluate the safety, efficacy, and feasibility of rituximab, fotemustine, pemetrexed and dexamethasone (R-FPD) regimen for primary central nervous system lymphoma (PCNSL) patients.

Methods:A prospective, single-center, single-arm, phase II clinical trial. Patients with newly diagnosed PCNSL diagnosed from the First Affiliated Hospital of Zhengzhou University from July 2018 to July 2020. R-FPD regimen consisted of rituximab (375 mg/m2 i.v. on D0), fotemustine (100mg/m2 i.v. on D1) ,pemetrexed (600mg/m2 i.v. on D1), and dexamethasone (40 mg i.v. on D1).(NCT04083066)

Results: 30 patients were included. After two cycles, the objective response rate(ORR) was 96.4%(27/28,26 PR,1 CR,0 SD,0 PD,2 Censored),the disease control rate(DCR) was 96.4%(27/28); After four cycles, the ORR was 71.4% (15/21, 5PR,10 CR,1SD,5PD,7NR,2 Censored),DCR was 76.2%(16/21). The median progression-free survival (PFS) was 20.3 months (95%CI:5.2--35.4),The median overall survival (OS) was 22.0 months (95%CI:16.1-27.9).The grade III-IV toxicities were mainly leukopenia(17.9%), thrombocypenia(25%) and anemia(10.7%).

Conclusion: Fotemustine-based in combination with Rituximab chemotherapy can improve outcomes with the progress free survival and the overall survival benefits, as well as with better tolerability for newly diagnosed PCNSL patients.

Keywords: rituximab; primary central nervous system lymphoma; pemetrexed; fotemustine; efficacy

Disclosures

No relevant conflicts of interest to declare.
Potential Usefulness of D-Dimers Assay in Treated Patients with FVIII Deficiency to Detect a Prothrombotic State
Authors: Hermans Cedric , Lambert Catherine
Published: November 2020

Introduction

The D-dimer (DD) assay represents a major biological test for the diagnosis and monitoring of thrombotic conditions. DD testing is usually not performed as part of the routine laboratory management of patients with hemophilia (PWH). There is an increasing concern about the risk of thrombotic complications in PWH, whether related to age, the presence of cardiovascular risk factors, invasive thrombogenic procedures, over-correction of FVIII or FIX, or the administration of new therapeutic agents in particular rebalancing agents such as TFPI-inhibiting molecules or Fitusiran. Arterial and venous thrombotic events have indeed recently been reported in PWH treated with these agents. It is therefore important to have simple, easily accessible biological tests available to detect and monitor the development of any prothrombotic condition in PWH with these agents and at increased risk of thrombosis. Baseline DD concentrations in PWH have not been extensively studied yet.

Patients and methods

We prospectively measured over a 18 months period the DD level in all consecutive PWH with hemophilia A (PWHA) in routine clinics outside bleeding episode, invasive procedure or acute medical or surgical problems. A total of 65 adult PWHA (17-76 yr) with severe (58) to moderate (n=7) disease without inhibitor on replacement therapy with FVIII were included. CRP, fibrinogen, FVIII and VWF levels were also measured at time of DD assay.

Results

Thirty-three patients had not measurable DD (< 250 ng/ml), 15 had levels below 500 ng/ml, 10 had levels between 500-1000 ng/ml and 7 > 1000 ng/ml. Age>70 (3), smoking (7), arterial vascular disease (2), liver cancer (2) could explain DD > 500 ng/ml in 15/17 patients.

Conclusions

Most PWHA on replacement therapy with FVIII had low or unmeasurable DD levels. The reasons for high DD level in PWHA do not differ from the general population. In most PWAH, the DD assay could be a useful tool to detect prothrombotic state, potentially related to hemophilia therapies.

Disclosures

Hermans: Bayer:Consultancy, Research Funding, Speakers Bureau;Pfizer:Consultancy, Research Funding, Speakers Bureau;Shire, a Takeda company:Consultancy, Research Funding, Speakers Bureau;Sobi:Consultancy, Research Funding, Speakers Bureau;Biogen:Consultancy, Speakers Bureau;CAF-DCF:Consultancy, Speakers Bureau;CSL Behring:Consultancy, Speakers Bureau;LFB:Consultancy, Speakers Bureau;Novo Nordisk:Consultancy, Speakers Bureau;Roche:Consultancy, Speakers Bureau;Octapharma:Consultancy, Speakers Bureau;Kedrion:Speakers Bureau;EAHAD:Other;WFH:Other.
Hottip-Mediated R-Loops Regulate CTCF TAD Boundary to Control WNT/b-Catenin Pathway in AML Genome
Authors: Luo Huacheng , Zhu Ganqian , Ma Xiaoyan , Claxton David F. , Qiu Yi , Xu Mingjiang , Huang Suming
Published: November 2020

lncRNA, transcribed from genomic DNA, can form a DNA: RNA hybridization structure to access regulatory elements. HOX loci associated long noncoding RNA (lncRNA), HOTTIP, acts as an epigenetic regulator to define oncogenic HOXA topologically associated domain (TAD) and drive HOXA associated leukemic transcription program. Activation of HOTTIP promoted AML pathogenesis by perturbing leukemic transcription program and hematopoietic/progenitor stem cells (HS/PCs) function. However, the mechanism by which HOTTIP accesses and regulates genomic DNA transcriptional output remains unknown.

Here, Combined RNA-seq, ChIP-seq, NG-Capture-C and Hi-C integrated analysis demonstrated that HOTTIP dependent stratification/formation of TADs at WNT/b-catenin loci is critical for b-catenin (CTNNB1) target gene transcription in AML cells. We further showed that HOTTIP specifically interacts with CTCF-occupied TAD boundary CTCF binding sites (CBSs) at b-catenin and its target loci (e.g. MYC and MECOM) by formation of R-loops. To test whether HOTTIP-mediated R-loops contribute to boundary maintanence and TAD stablization, we created CRISPR/dCas9-RNaseH-mediated disruption of R-loop structure In MOLM13 cells by which the Ribonuclease H (RNase H) was targeted to the HOTTIP/CTCF co-occupied CTNNB1 or MYC boundary CBSs to specifically target RNA: DNA hybridization region. Our DNA-RNA immunoprecipitation (DRIP)-qPCR data indicated that CRISPR/dCas9-RNaseH-mediated sgRNAs disrupted the R-loop structure in MYC and CTNNB1 defined TAD boundary regions. Furthermore, HOTTIP CHIRP-qPCR and CTCF CHIP-qPCR suggested that loss of R-loop structure in MYC or CTNNB1 TAD boundary CBSs decreased both CTCF and HOTTIP binding in these CBSs. Disruption of R-loops also affects the long-range interaction within CTNNB1 or MYC TADs that are important for WNT/b-catenin signaling network and AML leukemogenesis.

In conclusion, our finding demonstrated that HOTTIP forming DNA∙RNA hybridized R-loops mediate AML genome organization at specific gene loci and control leukemic transcription program. Thus, HOTTIP lncRNA mediated R-loop structure will be considered as a novel molecular mechanism in AML leukemogensis.

Disclosures

Claxton: Daiichi Sankyo Co: Research Funding; Astellas Pharma: Research Funding; Incyte Corporation: Research Funding; Cyclacel Pharmaceuticals, Inc.: Research Funding.
Bone Marrow-Derived Mesenchymal Stem Cells Inhibit CD8+ t Cell Immune Responses Via PD-1/PD-L1 Pathway in Multiple Myeloma
Authors: Liu Zhaoyun , Mi Fu , Han Mei , Tian Mengyue , Liu Hui , Fu Rong , Shao Zonghong
Published: November 2020

High expression of the inhibitory receptor programmed death ligand 1 (PD-L1) on tumor cells and tumor stromal cells have been found play a key role in tumor immune evasion in several human malignancies. However, the expression of PD-L1 on bone marrow mesenchymal stem cells (BMSCs) and whether the PD-1/PD-L1 signal pathway is involved in the BMSCs versus T cell immune response in Multiple Myeloma (MM) remain poorly defined. In this study, we explored the expression of PD-L1 on BMSCs from newly diagnosed MM (NDMM) patients and the role of PD-1/PD-L1 pathway in BMSCs-mediated regulation of CD8+T cells. The data showed that the expression of PD-L1 on BMSCs in NDMM patients was significantly increased than that in normal controls (NC) (18.81±1.61% vs. 2.78±0.70 %; P<0.001). Furthermore, the PD-1 expression on CD8+T cells with NDMM patients was significantly higher than that in normal controls (43.22±2.98% vs. 20.71±1.08%; P<0.001). However, there was no significant difference in PD-1 expression of CD4+ T cells and NK cells between NDMM group and NC group. Additionally, the co-culture assays revealed that BMSCs significantly promoted CD8+ T cells apoptosis and suppressed CD8+ T cells function. However, PD-L1 inhibitor effectively reversed BMSCs-mediated suppression in CD8+ T cells. We also found that the combination of PD-L1 inhibitor and pomalidomide can further enhance the killing effect of CD8+ T cells on MM cells. In summary, our findings demonstrated that BMSCs in patients with MM may induce apoptosis of CD8+T cells through the PD-1/PD-L1 axis and inhibit the release of perforin and granzyme B from CD8+ T cells so as to promote the immune escape of MM.

Disclosures

No relevant conflicts of interest to declare.
Dasatinib Promotes the Maturation of Healthy Donors and Chronic Myelogenous Leukemia Patients Derived Dendritic Cells
Authors: Cao Wangjun , He Lin , Zheng Hong , Huang Xiaobing , Yang Xi , WANG Xiaodong , Dai Jingying
Published: November 2020

Dasatinib has been discovered to obtain immunomodulatory effects in addition to the targeting effect towards BCR-ABL in chronic myelogenous leukemia (CML) patients. But the effect of dasatinib on dendritic cells (DCs) is still not fully understood. Objective To investigate the effect of dasatinib on the maturation of monocyte derived dendritic cells (moDCs) from healthy donors (HDs) and CML patients. Method Peripheral blood mononuclear cells (PBMCs) were isolated from HDs (n=14) and CML patients (n=14) who had got remission of MR4.5 with imatinib treatment. The generation of moDCs was completed after 7 days of incubation in DC I medium, and another 3 days of incubation in DC II medium with or without 25nM dasatinib. On the 10th day, the moDCs were harvested and analyzed for the expression of surface markers CD83, CD80, CD86, CD40 and HLA-DR to reflect the maturation of the moDCs by flow cytometry. Results When analyzing the moDCs from all the 14 HDs together, dasatinib significantly enhanced the expression levels of the surface marker CD83 (P=0.039), CD40 (P=0.002) and HLA-DR (P=0.000) on moDCs compared with the control group, but there was no statistically significant difference in CD80 (P=0.073) and CD86 (P=0.897). Differently, when analyzing the moDCs derived from all the 14 patients together, there was no statistically significant difference in the expression levels of CD80 (P=0.086), CD86 (P=0.166), CD83 (P=0.674), CD40 (P=0.574) and HLA-DR (P=0.561) on moDCs between the dasatinib group and the control group. However, moDCs derived from 3 of the 14 patients show the enhanced expression of all the five surface makers with dasatinib administration compared to the control group. Besides, the moDCs derived from 6 of the 14 patients show the enhanced expression of at least one of the five surface markers. Notably, compared with moDCs derived from HD group (n=14), moDCs from patient group (n=14) express lower levels of CD80 (P=0.340), CD86 (P=0.007), CD40 (P=0.010), CD83 (P=0.019) and HLA-DR (P=0.036). Conclusion Dasatinib at the concentration of 25nM can efficiently promote the maturation of HD-derived moDCs in vitro, whereas this effect only occurs in part of the CML patients. And the moDCs from patients generally show much lower levels of the maturation associated surface makers compared with moDCs from HDs. Dasatinib shows potential as a DC adjuvant to be applied in DC-based therapeutic strategies, such as DC vaccine and DC cell-therapy.

Disclosures

No relevant conflicts of interest to declare.
Cidofovir, a Choice for Salvage Treatment of CMV Infection in the Patients with Haploidentical Hematopoitic Stem Cell Transplantation
Authors: Yin Zhao , Xu Na , Jiang Ling , Shi Pengcheng , Fan Zhiping , Huang Fen , Liu Qifa , Sun Jing , Yu Guopan
Published: November 2020

Cidofovir (CDV) is a nucleotide analogue with broad antiviral activity and has been approved for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome. Data on the use of CDV for anti-CMV treatment in the patients with haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is rare. In this study, 31 (defined as CDV-second line treatment, ST group) out of 101 (conventional treatment, CT group) haplo-HSCT recipients with CMV infection being front-line treated with intravenous ganciclovir (GCV) or foscarnet (FSC) between the year 2017 and 2019, failed or intolerated to the preemptive antiviral therapy, and were switched to CDV therapy. Also, another 9 (CDV-front line treatment, FT group) patients with CMV infection were preemptively treated with CDV. CDV was used at a dose of 5 mg/kg per week until CMV-DNA negative twice with quantification polymerase chain reaction (qPCR) detection or disease progression.

23/28(82.1%) patients achieved treatment response with a median response time of 9(2-23) days and 20/28(71.8%) obtained complete response (CR) in CDV-ST group. While 6/8(75.0%) acquired CR with a median time of 6 (4-25) days in CDV-FT group. Higher response rate was seen in CDV treatment groups, though not significantly different, when being compared with those in CT groups (66/95(69.5%), 7 (2-34) days, 65(68.4%, respectively, all P-value >0.05). Also, there was not statistical difference in CMV-related mortality among the three groups (P-value >0.05). With a median follow-up of 10 (1-28) months, cumulatively 8/22(36.3%) patients experienced CMV reactivation in CDV-ST group, while 23/62(37.0%) happened in CT group, there was not significant difference (P>0.05). Whereas none with CMV recurrence was observed in the CDV-FT group. CDV-related toxicities were recorded in a total of 13/40 (32.5%) patients, shown as 7(17.5%) with I~II° gastrointestinal side effects, 6(15%) presenting reversible nephrotoxicity.

Taking together, salvage treatment with CDV shows no worse efficacy than ganciclovir or foscarnet does in the front line treatment of CMV infection in haplo-HSCT recipients. Also, CDV-related toxicity is tolerated.

Keywords: cidofovir, CMV infection, haplo-hematopoietic stem cell transplantation, efficacy, safety

Disclosures

No relevant conflicts of interest to declare.
A Systematic Review on Efficacy and Safety of Bortezomib Based Regimens for Treatment of Waldensterom Macroglobulinemia
Authors: Dar Abdul Jabbar , Khurshid Qasim , Ahmad Muhaddis Ejaz , Mirza Muhammad Ali , Khalid Farhan , Jaan Ali , Abdullah Syed Maaz , Farooqi Muhammad Saad , Khan Atif Irfan , Kashyap Richi , Khan Anam , Javed Saad , Qamar Fazeel , Anwer Faiz
Published: November 2020

Introduction:

Waldenström macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration and immunoglobulin M (IgM) monoclonal gammopathy. Various studies have shown that the proteasome inhibitor bortezomib (V) targets signaling pathways of relevance in WM. We reported published data on the efficacy profile of (V) for the patients of WM.

Methods:

We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after 2004, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library and Web of Science. Total 580 articles were identified initially and after detailed screening, we finalized 9 studies involving 375 patients with Waldenstrom Macroglobulinemia (WM) treated by combination of Bortezomib.

Results:

The total number of patients in the studies involving Bortezomib were 375 and dose of the drug used ranged between 1.3 mg/m2 to 1.6mg/m2. The Complete response (CR) ranged from 0-19% and the partial response (PR) ranged from 44-58%.

Bortezomib(V):

In the study Treonet et al., N=27, the highest major respose rate was 85% and minimal response rate was 37%. In the study Chen et al., N=27, the major response rate was 26% and the PR was 44%. Progression free survival (PFS) was 16.3 months for Chen et al.

Bortezomib(V), Rituximab(R), and Dexamethasone(D):

In the study Treon et al., N=23, the highest major response rate was 96%, CR was 13%, Very good partial response (VGPR) was 13%, and PR was 46%. Highest PR and was observed in Dimopolous et al., which was 58% and 42 months respectively.

Bortezomib(V), and Rituximab(R):

In the study Agathocleus et al., N=42, the highest CR was 14.2-19%. The highest PR was between 47.6-52.3%. In the study Ghobrial et al., N=37, the CR was 3% and PR was 46%. PFS was 15.6 months.

Bortezomib(V), Rituximab(R) and Everolimus(E):

In the study Ghobrial et al., N=46, the CR was 4%, PR was 46% and PFS was 18 months.

Conclusion:

Despite heterogenicity in WM patients and various regimens used in literature, Bortezomib containing regimens are a remarkably effective treatment. Combination regimens showed an overall response rate of 96%. The main side effects being anemia, leukopenia, thrombocytopenia, nausea and sensory neuropathies. Although we recommend future randomized prospective trials to better understand the efficacy and safety profile of Bortezomib for WM treatment.

Disclosures

Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.