bluuebunny/crossref_metadata_2025 huggingface dataset:
Models of Traumatic Brain Injury in Aged Animals: A Clinical Perspective
Authors: Iboaya Aiwane , Harris Janna L. , Arickx Alexandra Nielsen , Nudo Randolph J.
Published: November 2019

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the United States, with advanced age being one of the major predictors of poor prognosis. To replicate the mechanisms and multifaceted complexities of human TBI and develop prospective therapeutic treatments, various TBI animal models have been developed. These models have been essential in furthering our understanding of the pathophysiology and biochemical effects on brain mechanisms following TBI. Despite these advances, translating preclinical results to clinical application, particularly in elderly individuals, continues to be challenging. This review aims to provide a clinical perspective, identifying relevant variables currently not replicated in TBI animal models, to potentially improve translation to clinical practice, especially as it applies to elderly populations. As background for this clinical perspective, we reviewed articles indexed on PubMed from 1970 to 2019 that used aged animal models for studying TBI. These studies examined end points relevant for clinical translation, such as neurocognitive effects, sensorimotor behavior, physiological mechanisms, and efficacy of neuroprotective therapies. However, compared with the higher incidence of TBI in older individuals, animal studies on the basic science of aging and TBI remain remarkably scarce. Moreover, a fundamental disconnect remains between experiments in animal models of TBI and successful translation of findings for treating the older TBI population. In this article, we aim to provide a clinical perspective on the unique attributes of TBI in older individuals and a critical appraisal of the research to date on TBI in aged animal models as well as recommendations for future studies.
Unfavourable early outcomes of total trapeziectomy with RegJoint™ interposition: a report of 38 osteoarthritic hands in 34 patients
Authors: Mattila Simo , Haapamäki Ville , Waris Eero
Published: November 2019

This retrospective study analysed the results of total trapeziectomy with RegJoint™ interposition in 38 osteoarthritic hands in 34 patients. Patients were evaluated preoperatively, at follow-up visits, and at a mean final follow-up of 33 months (range 20–53) with plain radiographs, computed tomography, as well as with subjective and objective evaluations. Pain decreased and subjective outcomes and function improved significantly. Computed tomography 18 months after operation showed osteolysis in 24 cases. Three patients developed wrist pain 12–18 months after operation with MRI findings of a foreign-body reaction in each case. One of these patients was scheduled for revision surgery. Although the clinical results were satisfactory, the risk of foreign-body reaction and osteolysis is noteworthy. We conclude that the use of RegJoint™ should be reconsidered since the implant probably offers no benefit in the treatment of trapeziometacarpal osteoarthritis.

Level of evidence: IV
A modified Terrono classification for Type 1 thumb deformity in rheumatoid arthritis: a cross-sectional analysis
Authors: Toyama Shogo , Oda Ryo , Asada Maki , Nakamura Satoru , Ohara Masato , Tokunaga Daisaku , Mikami Yasuo
Published: November 2019

The most common thumb deformity in rheumatoid arthritis is Nalebuff Type 1 deformity (boutonniere deformity). Type 1 deformity severely impairs hand function, and this impairment is evaluated by the Terrono classification. In some cases, the Terrono classification incorrectly categorizes advanced thumb deformity into earlier stages. We modified the Terrono classification by assessing the active range of motion of the interphalangeal joint prior to assessing the passive range of movement of the metacarpophalangeal joint. An active range of movement of the interphalangeal joint was strongly correlated with hand function. In 55 hands that we treated between 2004 and 2015, we compared the modified classification with the original Terrono classification. Our modified classification could detect advanced deformity earlier, and was more strongly correlated with hand function. Additionally, correlation analysis showed that advanced Type 1 deformity should be treated first, even in cases with severe ulnar drift. Our results suggest that the modified classification may benefit the treatment of Type 1 deformity, including joint-preserving surgery.

Level of evidence: III
Prognosis of combined pulmonary fibrosis and emphysema: comparison with idiopathic pulmonary fibrosis alone
Authors: Jiang Chun-guo , Fu Qiang , Zheng Chun-ming
Published: November 2019

Background:

Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome characterized by the coexistence of upper lobe emphysema and lower lobe fibrosis. However, whether CPFE has a higher or lower mortality than idiopathic pulmonary fibrosis (IPF) alone is still not clear. In this study we conducted a meta-analysis to assess the survival rate (SR) of CPFE versus IPF alone in clinical trials.

Methods:

We performed a systematic search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials for trials published prior to 31 March 2018. Extracts from the literature were analyzed with Review Manager version 5.3.

Results:

Thirteen eligible trials were included in this analysis (involving 1710 participants). Overall, the pooled results revealed that no statistically significant difference was detected in the 1-year [relative risk (RR) = 0.98, 95% confidence interval (CI): 0.94–1.03, p = 0.47], 3-year (RR = 0.83, 95% CI: 0.68–1.01, p = 0.06), and 5-year (RR = 0.80, 95% CI: 0.59–1.07, p = 0.14) SRs of CPFE versus IPF alone.

Conclusions:

CPFE exhibits a very poor prognosis, similar to IPF alone. Additional studies are needed to provide more convincing data to investigate the natural history and outcome of patients with CPFE in comparison to IPF. The reviews of this paper are available via the supplemental material section.
Of Caring Nurses and Assertive Police Officers: Social Role Information Overrides Gender Stereotypes in Linguistic Behavior
Authors: Gustafsson Sendén Marie , Eagly Alice , Sczesny Sabine
Published: November 2019

Three studies demonstrated the expression of gender stereotypes in linguistic behavior. In Study 1, participants composed sentences describing a person by freely choosing from female- or male-dominated occupations, female or male pronouns, and communal or agentic traits. In Study 2a, participants chose traits to describe a person identified by a female- or male-dominated occupation and in Study 2b by a female or male pronoun and noun. In Study 3, participants chose traits for a person identified by both a female- or male-dominated occupation and a female or male pronoun. In general, participants chose more communal and fewer agentic traits for sentences containing a female- (vs. male-) dominated occupation and a female (vs. male) pronoun or noun. However, participants described women and men in the same occupation as similarly agentic or communal, demonstrating the primacy of role over sex information as predicted by social role theory.
Middle cerebral artery infarction following common carotid compression due to a multiloculated parapharyngeal abscess
Authors: Raja Shariff Raja Ezman Faridz bin , Sapuan Sapiah
Published: November 2019

Deep neck space infections (DNSIs) include retropharyngeal and parapharyngeal abscesses. We report a rare complication of left-sided middle cerebral artery infarction precipitated by left common carotid artery compression secondary to a multiloculated parapharyngeal abscess. A 59-year-old woman with poorly controlled diabetes was admitted following a loss of consciousness. Examination demonstrated unilateral right-sided hemiparesis and computed tomography (CT) of the brain revealed an acute left-sided frontoparietal infarct. The patient had been complaining of a fever, left-sided ear redness and pain six days prior. Unfortunately, despite antibiotics in the community, her ear pain worsened to involve her left jaw. Closer examination revealed a swelling in her left submandibular region and a CT of her neck was performed, revealing a multiloculated left parapharyngeal abscess with evidence of left common carotid compression. A naso-pharyngo-laryngoscopy (NPLS) was performed to confirm the presence of an abscess. Owing to the size and complex location of the abscess, management via a prolonged antibiotic treatment was opted for over surgical intervention. After completion there was improvement in medical state and resolution on repeat NPLS. Vascular-related complications are rare following DNSI. Carotid artery compression has been reported, although current literature suggests it to be a benign phenomenon. Our case is the first reported instance of a parapharyngeal abscess with severe neurological complications, reminding physicians that such complications following a DNSI remain possible. Although rare, in the event of a cerebrovascular accident and sepsis, DNSI remains a possible cause to be considered.
Evaluating the effectiveness of China’s nation branding with data from social media
Authors: He Lan , Wang Rongdang , Jiang Mingshan
Published: November 2019

In the past few decades, the rise of China has become the theme of heated debates, the central question of which is whether China will rise peacefully or as a “threat.” Faced with various speculations and predictions about China’s possible future course of action, Chinese political leaders and eminent scholars began engaging in the making and projecting of China’s soft power as well as a series of nation-branding campaigns. In order to study and evaluate the effectiveness of China’s nation-branding campaigns as well as how well the general public receives them, we looked into the perspectives and attitudes of the populace to find out their attitudes toward China’s national image. In this article, we intend to scrutinize the public opinions toward China as reflected by the questions and answers on social media ( quora.com in this case), using content analysis. As the findings show, the ranking of effectiveness of the different aspects of China’s nation branding is as follows: (1) history, (2) place, (3) language, (4) political and economic systems, (5) culture, (6) people, (7) infrastructure, and (8) social institution. Based on the results of the study, a model for evaluating the success or effectiveness of nation-branding campaigns was proposed.
Empowering Farmers of Madhya Pradesh: An Initiative of Madhya Bharat Consortium of Farmers Producer Company Limited
Authors: Kumar Sunil , Verma Ashutosh
Published: November 2019

Madhya Bharat Consortium of Farmers Producer Company Limited is a federation of producer companies that aims to empower the farmers to overcome various challenges from farm to market. It has made multiple interventions that have benefitted the farmers. The company plans to expand its outreach to one million farmers but is facing a few dilemmas related to its operations. It has incurred significant losses in its vegetable business and has to decide whether to continue it or not. The company markets quality seeds but due to emerging competitive scenario needs to relook at its value chain. The main bottleneck in its supply chain is lack of infrastructure. It has to decide whether to outsource or build its own facilities.

The present case is aimed for discussion in the operations management or supply chain management courses. The learning objective of this case is to understand the value chain of agricultural products operationalized through farmer producer companies which are a new form of business organization in India. It further highlights the challenges faced by the farmers and validates the fact that the change in the value chain of agricultural products empowers the farmers.
Mammalian target of rapamycin is activated in the kidneys of patients with scleroderma renal crisis
Authors: Salituri Jessica , Patey Natalie , Takano Tomoko , Fiset Pierre , Del Rincon Sonia , Berkson Laeora , Baron Murray , Hudson Marie , Baron M. , Hudson M. , Gyger G. , Pope J. , Larché M. , Khalidi N. , Masetto A. , Sutton E. , Robinson D. , Rodriguez-Reyna T.S. , Smith D. , Thorne C. , Fortin P.R. , Fritzler M.
Published: November 2019

Objectives:

Scleroderma renal crisis is a rare but serious complication affecting 2%–15% of patients with systemic sclerosis. Despite treatment with angiotensin-converting enzyme inhibitors, outcomes for scleroderma renal crisis patients are still poor. The cellular signaling mechanisms in scleroderma renal crisis are not yet known. Mammalian target of rapamycin, comprised of the subunits mTORC1 and mTORC2, has been shown to be activated in vascular lesions of renal transplant patients with anti-phospholipid antibody syndrome. Given the similarities between the pathophysiology of scleroderma renal crisis and anti-phospholipid antibody syndrome, we hypothesized that the mammalian target of rapamycin pathway would also be activated in the renal vasculature of patients with scleroderma renal crisis.

Methods:

We retrospectively analyzed renal biopsies of five patients with scleroderma renal crisis in the Canadian Scleroderma Research Group cohort. Immunostaining was performed using anti-P-S6RP antibodies to evaluate the phosphorylation of mTORC1, and anti-Rictor and anti-S473 to determine activation of mTORC2.

Results:

Four of the five patients showed mTORC1 activation in arteriolar endothelial cells, and three of the five patients showed mTORC1 activation in the arterial endothelial cells. Two of four samples showed Rictor expression in the arteriolar and arterial endothelial cells, showing mTORC2 activation. There was no expression of mTORC1 or mTORC2 in samples from two healthy controls.

Conclusion:

We demonstrate that both mTORC1 and mTORC2 are activated in renal biopsies with typical histologic features of scleroderma renal crisis. Dual mammalian target of rapamycin inhibitors are currently available and in development. These findings could inform further research into novel treatment targets for scleroderma renal crisis.
Advanced Pericentral Hydroxychloroquine Retinopathy in an Asian Woman
Authors: Sheth Neil , Schaab Tara , Mirza Rukhsana G.
Published: November 2019

Purpose:

This case report describes the unique clinical attributes of pericentral retinopathy associated with hydroxychloroquine (Plaquenil) use in patients of Asian ancestry.

Methods:

A complete ophthalmologic examination including optical coherence tomography, fundus autofluorescence, and Humphrey visual fields was performed. Serial images were obtained at subsequent follow-up appointments.

Results:

A dilated fundus examination demonstrated extensive bilateral parafoveal and perifoveal atrophy extending past the superior and inferior arcades as well as central macular preservation. Fundus autofluorescence exhibited prominent pericentral hypoautofluorescence.

Conclusions:

The distinct variant of pericentral hydroxychloroquine retinopathy has become increasingly recognized in patients of Asian origin. It is important for ophthalmologists to distinguish this pattern and consider modifying screening methods.
Territory, sustainability, and beyond: Latin American urbanization through a political ecology
Authors: Quimbayo Ruiz Germán A
Published: November 2019

In this article, I identify how territory is a useful concept to explore the political ecologies of urbanization. In the Latin America region, territory is a key concept to explore urban and rural connections between (neo)extractivism, violence, and dispossession, with socio-ecological transformations in the configuration of urban spatialities. Following recent calls to re-locate both urban theory and political ecology beyond the Anglophone debate, the article proposes a dialogue between the Latin American theorization on territory and the political ecology of urbanization. Based on an empirical analysis of urbanization in Bogotá, Colombia, the article also discusses implications for urban justice with respect to territory and sustainability. Finally, the article offers some remarks to further the research agenda on the political ecology of urbanization with a focus on territory.
How Do I Know What My Theory Predicts?
Authors: Dienes Zoltan
Published: November 2019

To get evidence for or against a theory relative to the null hypothesis, one needs to know what the theory predicts. The amount of evidence can then be quantified by a Bayes factor. Specifying the sizes of the effect one’s theory predicts may not come naturally, but I show some ways of thinking about the problem, some simple heuristics that are often useful when one has little relevant prior information. These heuristics include the room-to-move heuristic (for comparing mean differences), the ratio-of-scales heuristic (for regression slopes), the ratio-of-means heuristic (for regression slopes), the basic-effect heuristic (for analysis of variance effects), and the total-effect heuristic (for mediation analysis).
Low-frequency facial hemodynamic oscillations distinguish migraineurs from non-headache controls
Authors: Cortez Melissa M , Theriot Jeremy J , Rea Natalie A , Gowen Forrest E , Brennan KC
Published: November 2019

Background:

Surface imaging is a promising, noninvasive approach to assess regional perfusion in craniovascular disorders such as migraine.

Methods:

We used optical imaging to examine differences in facial blood volume at baseline and in response to ammonia inhalation (a noxious stimulus), as well as standardized measures of cardiovascular autonomic function, in healthy, non-headache controls ( n = 43) and in interictal migraine subjects ( n = 22).

Results:

Resting facial cutaneous oscillation (FCO) frequency was significantly different in migraine compared to healthy controls. Following ammonia inhalation, healthy controls showed a significant increase in resting FCO frequency, whereas this response was not significant in the migraine group. Standardized autonomic reflex parameters did not differ significantly between study groups, and facial cutaneous activity did not correlate with standardized cardiovascular autonomic reflex parameters, suggesting potentially different regulation.

Conclusions:

This approach to the assessment of craniofacial hemodynamic function appears to exhibit differing mechanisms from previously available techniques, and represents a promising new physiological biomarker for the study of craniofacial vascular function in migraine and potentially other craniovascular disorders.
TP53 Action and the Consequences of TP53 Mutation in Acute Myeloid Leukemia
Authors: Lowe Scott W.
Published: November 2019

p53 action and the consequences of p53 mutation in acute myeloid leukemia

TP53 mutations are common in treatment associated myeloid neoplasia (tMN) and complex karyotype acute myeloid leukemia (CK-AML), where they are associated with chemoresistance and one of the worst prognoses of any leukemia genotype. To understand the impact of TP53 mutations on AML biology, we are performing arge scale genomic analyses of p53 mutant AML and have produced a series of animal models that appear to faithfully reflect molecular and biological features of the human disease. We have gone on to explore the biology of particular TP53 mutational configurations drive AML initiation and maintenance, and to identify and understanding the events that cooperate with p53 mutations during leukemogenesis.

Disclosures

Lowe: Blueprint Medicines: Consultancy, Equity Ownership; ORIC pharmaceuticals: Consultancy, Equity Ownership; Mirimus: Consultancy, Equity Ownership; Constellation Pharma: Consultancy, Equity Ownership; Petra Pharmaceuticals: Consultancy, Equity Ownership; PMV Pharmaceuticals: Consultancy, Equity Ownership; Faeth Therapeutics: Consultancy, Equity Ownership.
The Effect of Anticoagulant Choice on Venous Thromboembolism Recurrence and Bleeding in Sickle Cell Disease
Authors: Gupta Vishal K , Lawrence Romy Carmen , Khan Sarah L. , Strykowski Rachel , Scarpato Brittany , Cohen Robyn T. , Sloan John Mark , Klings Elizabeth S
Published: November 2019

Patients with sickle cell disease (SCD) experience accelerated morbidity and mortality. Venous thromboembolism (VTE), a risk factor for early mortality in SCD, occurs in 11-12% of patients with SCD by the age of 40. While indefinite anticoagulation is indicated in the SCD population, there is limited understanding of comparative efficacy and hemorrhagic risk of individual anticoagulation agents in this population. We reviewed the use of anticoagulation for treatment of VTE in patients with SCD at our institution to begin to address these questions.

A retrospective chart review of all patients with SCD 18 years of age and older (currently alive or deceased) who received care at Boston Medical Center/Boston University between 2003 and 2018 was performed. VTE was defined as deep venous thrombosis (DVT) diagnosed by duplex ultrasound or pulmonary embolism (PE) diagnosed by either ventilation-perfusion scanning or computed tomography angiography. The primary efficacy outcome was the number of VTE events which occurred while the patient was receiving anticoagulation. The primary safety outcome was major bleeding as defined by the International Society on Thrombosis and Hemostasis 2005 guidelines.

The medical records of 233 patients with SCD were reviewed; VTE was identified in 55 (23.6%) patients. Sixty-five percent were female. In these 55 patients, a total of 94 VTE events occurred. Fifteen (16.0%) were catheter-associated upper extremity DVTs. For the first event, initial outpatient treatment consisted of warfarin in 56%, low-molecular-weight heparin (LMWH) in 18.2%, rivaroxaban in 9.1%, apixaban in 5.5%, and fondaparinux in 3.6%. The median length of treatment was 7.3 (median: 6, IQR: 3-12) months. Recurrent VTEs occurred in 27 (49%) patients with a total of 39 recurrent events. Among the recurrent events, thirteen (33.0%) were treatment failures occurring during anticoagulation therapy (see Table 1): 7 of 37 (18.9%) on warfarin, 2 of 20 (10.0%) on LMWH, and 4 of 15 (26.7%) on rivaroxaban. Death from recurrent VTE occurred in two patients; one occurred while a patient was therapeutic on warfarin. Major bleeding occurred in two patients (3.6%); in both cases, this was intracranial hemorrhage while on warfarin.

In this retrospective study, there was a high rate of VTE recurrence despite anticoagulation in patients with SCD. Treatment failure was highest with warfarin and rivaroxaban, although adherence was difficult to assess. Risk of hemorrhage and death appears higher in those prescribed warfarin. These data affirm the need for long-term anticoagulation in most patients with SCD with a VTE and support the use of direct oral anticoagulants as a first-line agent.

Disclosures

Sloan: Abbvie: Other: Endpoint Review Committee; Stemline: Consultancy; Merck: Other: endpoint review commitee.
Single Cell Transcriptomics Predicts Relapse in Infants with Acute Lymphoblastic Leukemia
Authors: Candelli Tito , Schneider Pauline , Garrido Castro Patricia , Jones Luke A , Pieters Rob , Margaritis Thanasis , Stam Ronald W. , Holstege Frank C.P.
Published: November 2019

Care of infants (<1 year of age) diagnosed with MLL (KMT2A)-rearranged acute lymphoblastic leukemia (MLLr-iALL) suffers from two major drawbacks. First, a poor survival rate due to a high rates of early relapse and chemo-resistance. Additionally, the approximately 30-50% of patients that do survive, suffer from life-long, debilitating side-effects of current treatment. While almost all MLLr-iALL patients show an initial promising response to treatment, two-third of the patients relapse, typically within the first year from diagnosis and while still on treatment. Accurate relapse prediction would allow implementation of treatment strategies that take relapse risk into account, with great potential benefit for all patients. Here, we show that Single-cell RNA sequencing (scRNA-seq) can be valuable for risk stratification and that the abundance of chemo-resistant cells within the diagnosis sample might be a powerful indicator of the likelihood of relapse.

We have used scRNA-seq to analyze the response to treatment of leukemic cells in bone marrow biopsies of seven MLLr-iALL patients, expressing either the oncogenic MLL-AF4 or MLL-ENL fusion gene, at the time of initial diagnosis. Three of these patients successfully underwent treatment and remained disease-free during 7 years of follow-up, while in the remaining four cases the disease returned within a year from diagnosis. All samples were subjected to scRNA-seq by FACS index sorting with the aim of identifying differences between early relapsers and long-term survivors.

Quantification of the proportion of cells classified by single cell transcriptomics, categorized as either chemo-resistant or chemo-sensitive, accurately predicts the occurrence of future relapse in individual patients. Strikingly, the single cell-based classification is even consistent with the order of relapse timing. Additionally, leukemic cells associated with high relapse risk are typified by a small phenotype, which coincides with an apparent quiescent gene expression pattern.

This study clearly and, to the best of our knowledge, for the first time shows how disease classification and treatment management can directly benefit from single cell genomics. It demonstrates how classification based on a pivotal functional characteristic of single cells can be performed, despite individual patient variation. Our results shed light on the subpopulation from which leukemic relapse originates, and opens up opportunities for strong, risk-based strategies for future MLLr-iALL treatment regimens.

Disclosures

Pieters: medac: Consultancy; jazz farmaceuticals: Consultancy.
Apatinib Exhibits Cytotoxicity to Acute Myeloid Leukemia Cell Via Targeting VEGFR2-Mediated Pro-Survival Signaling and Angiogenesis
Authors: Yu Lian , Deng Manman , Li Zhifeng , Fang Zhihong , Dai Yun , Xu Bing
Published: November 2019

Objective:Vascular permeability contributes to disease progression and drug resistance in acute myeloid leukemia (AML). Thus, targeting angiogenetic signaling is a promising strategy for the treatment of AML, especially for relapsed and resistant diseases. The aim of the present study was to evaluate the potential efficacy of Apatinib, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2, in AML treatment.

Method: CCK8 and Annexin V/PI assay were separately utilized to determine the IC50 value and apoptosis of AML cell lines. The cytotoxic efficacy of Apatinib against primary AML cells from 57 adult patients and 11 normal counterparts were then evaluated by analysis of apoptosis. Using JC-1 kit to detect the mitochondrial membrane potential, and western bolting and mass cytometry assay as well as immunohistochemistry to explore the underlying mechanism. Finally, the anti-leukemia activity was further evaluated in in vivo xenograft models.

Results: Our findings demonstrated apatinib markedly inhibited proliferation and promoted apoptosis in AML cell lines. Similarly, apatinib showed cytotoxicity against primary AML cells while harmless to normal hematopoiesis. Its effect was correlated with several clinical features such as NPM1 mutation, extramedullary infiltration, relapse/refractory disease and FAB subtypes. Additionally, apatinib suppressed AML cells growth and attenuated angiogenesis in xenograft model. Mechanistically, apatinib-induced cytotoxicity was closely associated with the inhibition of VEGFR2-meidated Src/STAT3 and AKT/mTOR pathway and the induction of mitochondrial-mediated apoptosis.

Conclusion: In summary, apatinib exerts anti-leukemia function via targeting VEGFR2-triggered pro-survival signaling and angiogenesis, providing a rationale for clinical trials of apatinib in the treatment of AML.

Disclosures

No relevant conflicts of interest to declare.
IVIG-Induced Abrupt Hemolysis in Neurological Conditions
Authors: Chadha Juskaran , Levine Randy L. , Ilyas Omer
Published: November 2019

Background

Immunoglobulin (IVIG) is used to treat autoimmune conditions, but there are reports of brisk hemolysis within 48 hours (hrs) of treatment due to anti-A isohemogglutinins(1). Despite these reports, hemolysis remains an unrecognized side effect of IVIG.

Methods

We presented a series of 3 cases of IVIG-induced hemolysis in patients with autoimmune neurological disorders. In the investigative phase, we traced the cases to a common IVIG lot number. The sample was tested to determine the anti-A titer levels.

Case Studies (See Table 1)

Case 1

75-year-old man presented with SOB and dysarthria from myasthenia gravis (MG). He received IVIG for 4 days. He developed a hemolytic anemia with 3 g drop in hemoglobin (Hb) 48 hours later. He needed a pRBC transfusion and folic acid.

Case 2

59-year-old female with history of MG treated with IVIG at another hospital until 3 months earlier in crisis, with SOB and dysphagia. She received IVIG for 5 days and rituximab. She improved and was discharged, but returned to the ER 7 days later with SOB. Her Hb fell to 8.0 g/dL from 13 g/dL on last admission. She required a pRBC transfusion, folic acid, and vitamin B12 with improvement of SOB.

Case 3

20-year-old female admitted for lower extremity weakness, diagnosed with presumed syndrome (GBS). She received IVIG for 4 days. On the 5th day, her Hb fell from 15 g/dL to 9 g/dL. She began prednisone, folic acid, and vitamin B12 with improvement in her Hb.

Conclusions

Although acute hemolysis is well described in the literature, it is under recognized, as exemplified by the first two cases. Their initial SOB was due to MG, so when SOB recurred, they were misdiagnosed with recurrent MG. A hemolytic anemia was later suspected, and a work up revealed a positive DAT. The initial eluate was negative against type O panel cells, suggesting a drug related hemolysis. It was only when the eluate was tested against type A cells that the etiology became clear. The third patient's hemolytic reaction was then rapidly identified. These cases remind us to consider IVIG induced anti-A hemolysis in patients who are blood type A and AB, and to evaluate the eluate against the appropriate reagent cells. These patients should receive specific IVIG that is low in anti-A isohemagglutinins. Since the second patient did not hemolyze from earlier exposure to IVIG, she likely received a low titer product.

Disclosures

No relevant conflicts of interest to declare.
Challenges in Management of Severe Hemophilia with Acute Hematologic Malignancies
Authors: Jain Akshat , Meyer Mary
Published: November 2019

Childhood Leukemia treatment is one of the most common malignancies seen across the globe in the pediatric age group. Severe Hemophilia A is still considered a rare bleeding disorder. Only 13 patients with hemophilia A or B have been reported in literature to also be

diagnosed with acute leukemia in childhood .

This rarity appeared again in a 13 year boy with severe hemophilia A who presented with worsening bone pain and joint swelling, weight loss and

leukocytosis. Morphology and molecular diagnostics confirmed Acute Pre B Lymphoblastic Leukemia . The patient happens to be the first case of Acute Lymphoblastic Leukemia in a patient with severe Hemophilia with Inhibitors.

Severe hemophilia with inhibitors pose challenge in clinical management given their propensity of bleeding and poor response to traditional therapies due to a neutralizing antibody as is. Treatment of acute lymphoblastic leukemia requires an intensive treatment with systemic and intrathecal chemotherapy. Medications are commonly administered through a central line, in many cases an implantable catheter.

Coexistence of both these life threatening disorders posed a unique practical challenge in providing standard care and our discussion aims at highlighting strategies in management of Severe Hemophilia in challenging clinical scenarios.

Disclosures

No relevant conflicts of interest to declare.
Sleep Disturbance Among Patients with Myelodysplastic Syndromes and Acute Leukemia
Authors: Luskin Marlise , Zhou Eric , Zhang Zilu , DeAngelo Daniel J. , Stone Richard , Wadleigh Martha , Garcia Jacqueline S , Winer Eric S. , Recklitis Christopher , O'Day Kelsey , Lapiana Victoria , Osborn Ryan , Steensma David P. , Abel Gregory A.
Published: November 2019

BACKGROUND: Most patients with myelodysplastic syndromes (MDS) describe difficulty sleeping (Luskin et al Br J Haem 2017) and sleep disturbance is a likely contributor to the fatigue experienced by patients with MDS and acute leukemia. Data are sparse regarding the sleep of this patient population as formally assessed with sleep-focused survey instruments.

METHODS: We surveyed consecutive adult patients with MDS, AML or ALL at the Dana-Farber Leukemia clinic. With permission from the treating oncologist, patients with a physician-assessed life expectancy ≥ 12 weeks were mailed a questionnaire packet assessing insomnia symptom severity (Insomnia Severity Index; ISI), sleep quality (Pittsburgh Sleep Quality Index; PSQI), obstructive sleep apnea risk (STOP-Bang), and depressive symptoms (Patient Health Questionnaire-9; PHQ-9). Respondents underwent concomitant medical record review.

RESULTS: Of 332 eligible patients contacted, 158 (47.6%) responded. Responders were 56% male with a median age of 67 years. Overall, 42% of patients reported insomnia symptoms (ISI ≥10) with the prevalence of such symptoms similar among patients with MDS and acute leukemia (48% vs 38%, p=0.23). OSA risk was high (58%), particularly in patients with MDS (67% vs 52% p=0.10). Those with high OSA risk were more likely to have clinical insomnia as defined by ISI ≥10 (OR 2.6, p=0.01). Depression was uncommon: only 7% had PHQ-measured moderately severe or severe depression. Median sleep duration for the entire cohort was 6.9 hours (range 3-12) indicating that over half of respondents slept less than the 7 hours per night recommended by the National Sleep Foundation for healthy adults. Poor sleep quality (PSQI "Bad Sleep") was seen in 79% of the overall cohort.

CONCLUSION: When measured with validated tools, disturbed sleep is common among patients with MDS and acute leukemia. OSA risk is also prevalent but does not likely explain all of the poor sleep quality seen. These data suggest that strategies are needed to improve both quantity and quality of sleep in this population.

Table

Disclosures

DeAngelo: Abbvie: Research Funding; GlycoMimetics: Research Funding; Blueprint: Consultancy, Research Funding; Amgen: Consultancy; Celgene: Consultancy; Shire: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Pfizer: Consultancy. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Winer:Jazz Pharmaceuticals, Pfizer: Consultancy. Steensma:Aprea: Research Funding; Arrowhead: Equity Ownership; Pfizer: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.; Astex: Consultancy; Onconova: Consultancy; Stemline: Consultancy; Summer Road: Consultancy.
Hematological Profile in the Saudi Population: Reference Intervals By Gender, Age and Regions
Authors: Alaskar Ahmed , Rehan Hina , Mendoza May Anne , Alsahan Aljowhara , Immanuel Anita , Alhejazi Ayman , Abuelgasim Khadega , Salama Hind , Damlaj Moussab , Gmati Giamal , Alzahrani Mohsen , Rather Mushtaq , Alahmari Bader , Al Mugairi Areej , Ahmed Anwar
Published: November 2019

Background: Although the prevalence of genetic hematological disorders varies widely between geographical regions, region-specific hematological reference ranges have not been defined in Saudi Arabian adults. Methods: A multicenter retrospective cross-sectional study was conducted with 1127 participants who completed their pre-employment screening and recruitment process between January 2013 and December 2016. Data related to the demographic and hematological indices were extracted. Results: The mean age was 28.0±5.2 years (range 19.4-72.8 years) and gender was distributed equally (47.5% female vs. 52.5% male). The WBC reference range was 3.3-11.4 ×109/L; hemoglobin 111-174 gm/l; platelet 163-412 ×109/L; MCV 80-95.7 fl, and neutrophils 1.2-8.8 ×109/L. A robust regression model was used to evaluate the effect of the participant's characteristics on the hematological indices. Except for WBC, the rest of the hematological indices were significantly influenced by gender, region, and age. The 2.5 percentile hemoglobin values were 135 gm/L in males and 104 gm/L in females, while platelet values were 173 x109/L in females and 159 x109/L in males. Conclusion: The study defined local hematological reference ranges, which were mostly lower than reported in international studies used in our center. Hematological values were mainly influenced by gender and region. A community nationwide screening study is required to create reference ranges specifically for the Saudi population.

Disclosures

No relevant conflicts of interest to declare.
Activation of JAK2/STAT5 Pathway Reduces Expression Level of DNMT3a in MPN Cell Line
Authors: Zhou Jie , Liang Aibin , Li Shaoguang , Zhang Wenjun , FU Jianfei
Published: November 2019

Introduction: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by overproduction of mature blood cells and increased risk of transformation to acute myeloid leukemia (AML), and JAK2V167F is the most frequent MPN driving mutation detected in >95% of PV and 50-60% ET and PMF. DNMT3A is a de novo DNA methyltransferase that catalyzes the addition of methyl groups into active chromatin in CpG-rich regions leading to gene inactivation. Dnmt3a-/- HSC have enhanced self-renewal and a block in differentiation in vivo. Previous study showed that JAK2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation, while whether JAK2V617F regulates DNMT3a still remains unclear. AZ960 is a potent and selective ATP competitive inhibitor of the JAK2 kinase, and previous studies reported that AZ960 possessed the activity selectively against JAK2. LY2784544 has been identified as a selective inhibitor of JAK2V617F and has undergone clinical trials for the treatment of several myeloproliferative disorders.

Methods: Empty vector (control) and mutant JAK2V617F were transduced into BaF3 cells using a lentivirus system. JAK2V617F-expressing BaF3 cells grow IL-3 independent and were selected by fluorescence-activated cell sorting (FACS) for GFP expression. The protein expression levels of p-STAT5 and DNMT3a were detected by western blotting. JAK2V617F-expressing and control BaF3 cells were incubated with gradient concentration of LY2784544 or AZ960 to inhibit JAK2/STAT5 pathway.

Results: The expression levels of p-STAT5 were obviously up-regulated in the JAK2V617F-expressing BaF3 cells, and DNMT3a was down-regulated. After 1-hour incubation in the serial diluted LY2784544, p-STAT5 were reduced in JAK2V617F-expressing BaF3 cells, with expression of DNMT3a elevated. To further confirm the correlation between JAK2/STAT5 pathway and expression of DNMT3a, another JAK2 inhibitor AZ960 was tested similar to LY2784544. With p-STAT5 expression suppressed, protein level of DNMT3a showed significantly promotion.

Conclusion: We observed that JAK2V167F mutation suppresses protein expression levels of DNMT3a in MPN cell lines. JAK2 inhibition by AZ960 and LY2784544 significantly improved expression levels of DNMT3a. The activation of JAK2/STAT5 pathway reduces expression level of DNMT3a in MPN cell line, and the specific mechanism still needs to be explored.

Figure

Disclosures

No relevant conflicts of interest to declare.
Deformability Based Sorting of Stored Red Blood Cells Reveals Donor-Dependent Aging Curves
Authors: Islamzada Emel , Matthews Kerryn , Guo Quan , Santoso Aline , Scott Mark D. , Ma Hongshen
Published: November 2019

A fundamental challenge in the transfusion of red blood cells (RBCs) is that not all donated RBC units will confer the same benefit to the recipient. While some RBC units will remain in circulation for long periods after transfusion maintaining homeostasis, some will be cleared rapidly, leading to the need of an increased number of transfusions. This variability stems, in part, from the inherent ability of donor RBCs to withstand the physical and chemical insults of cold storage, which ultimately dictate their survival in circulation. The loss of RBC deformability during cold storage is well-established and has been identified as a potential biomarker for the quality of donated RBCs. Previous methods for characterizing RBC deformability have been limited in their sensitivity and consistency. As a result, these methods have only been able to characterize pathological and chemically degraded RBCs, but have not been able to distinguish differences between healthy donors.

Recently, we developed a microfluidic device to sort RBCs based on deformability using a matrix of asymmetrical tapered constrictions that form microfluidic ratchets. Due to the geometric asymmetry of the taper, the force required to deform cells through the constriction along the direction of taper is less than against the direction of taper. Coupling this deformation asymmetry with an oscillatory flow creates a ratcheting effect that selectively transports cells based on their ability to squeeze through each microscopic constriction. Importantly, this oscillatory flow also minimizes the contact between cells and the filter microstructure to prevent clogging and fouling to ensure that a consistent filtration force is applied to each cell.

We measured the deformability profiles of eight healthy donors using the microfluidic ratchet device. We found the deformability profile to be consistent for each donor over multiple donations. We also found significant variability across different donors. We then cold stored donated RBCs in SAGM media in plastic test tubes for 14 days to accelerate cold storage related damage. We find that the aging curve of RBC deformability varies significantly across donors, but is also consistent for each donor over multiple donations. Specifically, certain donors seem capable of providing RBCs that maintain their deformability during two weeks of accelerated aging.

This study illustrates a potential route to identify high-quality donors, or super-donors, that can provide RBCs that maintain their integrity during cold storage. Being able to identify these donors will enable blood bankers to reserve high-quality RBC units for chronic transfusion recipients, which will reduce the total number of transfusions for these patients and increase the overall blood supply.

Disclosures

Ma: Patent (US 9880084): Other: Inventor.
The Role of Protein Tyrosine Phosphatase PTP4A3 in T-Cell Acute Lymphoblastic Leukemia Progression
Authors: Wei Min , Blackburn Jessica
Published: November 2019

The tyrosine protein tyrosine phosphatase PTP4A3 has been extensively reported to play a causative role in numerous cancers, including several types of acute leukemia. We found PTP4A3 to be highly expressed in T-cell Acute Lymphoblastic Leukemia samples, and show that PTP4A3 accelerates T-ALL onset and increases the invasive ability of T-ALL cells in a zebrafish model, and is required for T-ALL engraftment and progression in mouse xenograft. Our in vitro studies showed that PTP43A3 enhances T-ALL migration, in part via modulation of SRC signaling. However, whether SRC is a direct substrate of PTP4A3, and whether the phosphatase activity of PTP4A3 actually plays a role in T-ALL or other types of leukemia progression is unknown and remains a major question in the field.

We used a BioID-based proximity labeling approach combined with PTP4A3 substrate trapping mutant pull down assay to capture the PTP4A3 substrates candidates. BioID, a biotin ligase, was fused to PTP4A3 to generate a Biotin-PTP4A3 (BP) fusion protein. The overexpression of BP in T-ALL cell lines led to biotin modification of 288 PTP4A3 proximal proteins, including the potential direct PTP4A3 substrates. PANTHER pathway analysis showed that PTP4A3 interacting proteins are largely clustered in the T-cell activation, PDGF signaling, and angiogenesis. We are in process of validating potential substrates using immunoprecipitation and phosphoenrichement assays.

Finally, we are using a novel zebrafish Myc+PTP4A3 induced T-ALL model to assess the function of PTP4A3 in leukemia progression. We have created several PTP4A3 protein mutants, including a phosphatase-dead mutant, a mutant unable to bind magnesium transporter, and a prenylation deficient mutant, and are in process of assessing the effects of these mutants in T-ALL onset and progression in our in vivo model. In total, these studies will allow us to better understand function of PTP4A3 in T-ALL progression, and may provide a strong rationale for the development of PTP4A3 inhibitors for use in leukemia.

Disclosures

No relevant conflicts of interest to declare.
A Refractory B-ALL Patient Relapsed with Leukemia Cells Expressing CD19 and Anti-CD19 CAR Gene 14 Days after CR from Anti-CD19 CAR T-Cell Therapy
Authors: Meijing Liu , Cui Rui , Mu Juan , Yuan Ji-jun , Mou Nan , Yang Zhen-xing , Yan-yu Jiang , Juanxia Meng , Deng QI
Published: November 2019

Purpose: To investigate the immunophenotypic characteristics of CD19 CAR transfected into leukemia cells with CD19 expression during CAR-T cell preparation.

Patient and Methods: Here we reported a TP53 positive refractory B-ALL patient relapsed 14 days after Complete response (CR) from the CD19 CAR-T therapy. But her leukemia cells expressed CD19 and expressed aberrantly the anti-CD19 CAR gene at the same time. We transfected CD19 CAR gene into Nalm-6 cells to detect the expression of CD19 CAR Nalm-6 cells and the sensitivity to anti-CD19 CAR T-cell and anti-CD22 CAR T-cell. The binding of CD19 antigen on the surface of CD19 CAR Nalm-6 cells and Nalm-6 cells to CD19 CAR in CD19 CAR Nalm-6 cells was observed by confocal microscopy. The proportion of Nalm-6 cells in the transfection system was increased gradually to observe the change of CD19 expression on CD19 CAR Nalm-6 cells.

Results: The patient received a CD22 CAR-T therapy followed by a haploid hematopoietic stem cell transplantation and achieved CR with vanishment of TP53 mutation. To date, she had leukemia-free survival (LFS) and complete donor chimerism for 8 months. We found that there had 1.41% leukemic cells in the peripheral blood mononuclear cells (PBMC) during anti-CD19 CAR T-cell preparation, which may contribute to the relapse of the first CD19 CAR-T therapy. The CD19 expression was only 1.19% in CD19 CAR Nalm-6 cell culture system with a transfection rate of 46.5±3.78%, while the proportion of CD19 expression increased gradually when we increased the proportion of Nalm-6 cells in the transfection system. CD19 CAR of CD19 CAR Nalm-6 cells occupied the CD19 expression site of the cells themselves, meanwhile occupied the CD19 expression site of Nalm-6 cells. We found that the CD19 CAR Nalm-6 cells were sensitive to anti-CD22 CAR T-cell, althought they were resistant to anti-CD19 CAR T-cell.

Conclusions: There had a presence that CD19 CAR gene was transferred into leukemia cells during T cell manufacturing. The immunophenotype of leukemia cells of these refractory B-ALL patients who relapsed after CR from anti-CD19 CAR T-cell therapy were CD19+ or CD19-. It was determined by the proportion of CD19 CAR leukemia cells and leukemia cells. Anti-CD22 CAR T-cell therapy could be as a salvage measure to such patients.

Figure

Disclosures

No relevant conflicts of interest to declare.