bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.