bluuebunny/crossref_metadata_2025 huggingface dataset:
Identità, narrativa bilingue e canone letterario (trans)nazionale: Jhumpa Lahiri
Authors: Sica Paola
Published: November 2019

Un esame delle opere di Jhumpa Lahiri induce a chiedersi come possano essere rappresentate varie forme di identità diasporica tramite la narrativa, e quello che tali forme significhino se rapportate a culture diverse, create tramite lingue diverse, oppure recepite da lettori di comunità diverse. Qui, certe opere come Interpreter of Maladies (1999), scritta originariamente in inglese, e In altre parole (2015) e Dove mi trovo (2018), scritte originariamente in italiano, sono studiate come dettagli che prefigurano un disegno più ampio. Incorporando elementi di più culture, esse sono concepite come un indice rivelatore di tendenze sociologiche e letterarie che, sviluppandosi, inducono a criticare modelli universalisti di autorità culturale e a ripensare le dinamiche che sottendono la formazione di molteplici canoni letterari. La prospettiva adottata in questa analisi è sia interna che esterna. Attraverso la prospettiva interna si può risalire al funzionamento testuale, al modo in cui si creano vari modelli di identità, al loro rapportarsi a più memorie culturali, categorie sociologiche e lingue. Attraverso la prospettiva esterna, invece, si può analizzare la ricezione. Si possono valutare ad esempio le risposte di certe comunità ermeneutiche anglofone e italofone, il modo in cui esse includono entro un canone l'opera di Lahiri, oppure la escludono, e perché.
Speech Workload Estimation for Human-Machine Interaction
Authors: Heard Jamison , Fortune Julian , Adams Julie A.
Published: November 2019

Performing tasks quickly and accurately in dynamic and intense environments is critical, such as supervising a remotely piloted aircraft; however, these environments contain periods of low and high workload, which can decrease task performance. A system capable of intelligently adapting its interaction modality based on the human’s workload state may mitigate these undesirable workload states: underload and overload. Such a system requires mechanisms to determine accurately the human’s overall workload state and each workload component state (i.e., cognitive, physical, visual, speech, and auditory) in order to understand the current workload state’s underlying cause effectively. Existing work estimates multiple workload components, but no method estimates speech workload. This manuscript presents an algorithm for accurately estimating a human’s speech workload level using methods suitable for real-time workload assessment. The algorithm is an essential component to future adaptive human-machine interfaces.
An Application of Machine Learning for Police Mobile Computer Terminal Usability Evaluation
Authors: Zahabi Maryam , McCollum Emily
Published: November 2019

Police in-vehicle technologies especially mobile computer terminals (MCTs) are the major cause of motor vehicle crashes for law enforcement officers. Previous studies have found several usability issues with the design of MCT interfaces. The objective of this study was to develop an algorithm for classification of MCT interface usability based on a combination of officer performance, visual attention allocation, and subjective measures. It was found that speed deviation, secondary task completion time, off-road fixation frequency and glance duration are informative features that associate with MCT usability. The developed algorithm has the potential to be used in MCT design and development process to ensure efficient interaction in multi-tasking situations of driving and using the MCT.
Visualization Design for Human-Collective Teams
Authors: Roundtree Karina A. , Cody Jason R. , Leaf Jennifer , Onan Demirel H. , Adams Julie A.
Published: November 2019

Robotic collectives (i.e., colonies and swarms) are applicable to a wide range of applications, including environmental monitoring, search and rescue, as well as infrastructure monitoring. The presented evaluation focuses on how two visualization designs impact human-collective team performance during a best-of- n sequential decision making task with colonies of 200 agents. Traditional visualizations present all the individual robots that encompass the entirety of the collective, which may cause the human operator to suffer from information overload which hinders understanding the collective’s current state, the reasoning behind actions, and associated predictive future outcomes. Interface designs that abstract the individual collective member details and present the collective’s state are needed to alleviate high workload and mitigate human error. The evaluation determined that an abstract visualization of the collective’s state produced better overall performance than the visualization that showed all the individual agents.
Identifying and Quantifying Personnel Skill Gaps
Authors: McKenney Martin J. , Handley Holly A.
Published: November 2019

One of the issues organizations face is identifying the required skills needed for a position and then evaluating if their personnel have these skills or if there is a “skills gap”. A “skills gap” is the distance between the position requirements and the skills currently possessed by the person in that position. At issue is the lack of a framework to clearly identify the required skills. A composite skills gap model has been developed that can be adapted to any occupation and give quantitative results to help determine worker-to-job fit and help identify gaps. By applying the model to identify position requirements and worker qualifications, organizations can move personnel to better suited positions or utilize needed training in the specific areas identified. This type of model addresses the shortcomings identified in previous models by getting the worker and position information into the same language for comparisons. With technology moving towards automation, robotics and artificial intelligence, this type of model can identify what skills are necessary for “re-tooling” the workforce to meet the needs to support these systems. Additionally, the framework provides a theoretical foundation for skills gap analyses that allows for more analytical research in this area.
A Model of Indian Drivers’ Ratings of In-Vehicle Alerts to Pedestrian Encounters on Roads in India
Authors: Kip Smith Issaquah , Källhammer Jan-Erik , Veoneer Sweden AB
Published: November 2019

At previous HFES meetings, we have presented the evolution of a quantitative model with two factors - pedestrian location and motion – that predicts how Swedish drivers rate the desirability of receiving alerts to pedestrian encounters recorded by an in-vehicle pedestrian-detection system. In this paper we extend the model to the Indian subcontinent and identify two additional factors – vehicle lane and the lateral distance to the pedestrian - that, when added to the ‘Swedish model’, predict the ratings provided by Indian drivers to pedestrian encounters in India.
A Tradespace Framework for Evaluating Crewing Configurations for Future Vertical Lift
Authors: Sushereba Christen E. , Diiulio Julie B. , Militello Laura G. , Roth Emilie
Published: November 2019

This paper presents a tradespace framework designed to analyze tradeoffs associated with different crewing configuration options. It was created in support of the United States Army’s Future Vertical Lift (FVL) program whose goal is to develop future Army rotorcraft that incorporate advanced automation and can be flexibly crewed depending on mission context. The tradespace framework provides an analytic tool that can help Army decision makers evaluate the tradeoffs associated with different crewing configurations and compare crewing options for different mission contexts. While the framework was developed to assess crew configurations for military rotorcraft, the use of tradeoffs as an organizing framework to analyze crewing alternatives can be applied to a variety of domains.
Evaluation of a Virtual Reality Environment for Cockpit Design
Authors: Joyce Richard , Robinson Stephen K.
Published: November 2019

The use of virtual reality (VR) to provide a higher fidelity simulation environment earlier in the design cycle of a new cockpit has benefits in development cost and time, but practitioners may have concerns that use of virtual environments may change feedback. In this work, we aimed to test our VR environment against a non-VR simulator in a mock design study to evaluate if and how subject feedback and performance changed. Two separate groups of subjects evaluated the same two designs, one group using VR and the other a touchscreen desktop simulator. The results indicate that both groups provided similar qualitative feedback on the two designs. Some quantitative performance measures changed between groups, but conclusions made from comparing designs within groups was consistent. We describe our findings on which quantitative measures are best for evaluation in a virtual environment.
Heuristic Evaluation of A Tesla Model 3 Interface
Authors: Parkhurst Eva L. , Conner Lindsay B. , Ferraro James C. , Navarro Mar E. , Mouloua Mustapha
Published: November 2019

Usability research is important in our age of developing technology as it has significant implications for how technology is perceived by users. In 2017 Tesla released the Model 3, their most affordable electric-only vehicle to date. The vehicle is unique in its simplistic inner controls, composed of a single centralized touchscreen and instrumentation on the steering wheel. A heuristic analysis was conducted on the interface system of a Model 3 and several heuristic violations were identified.

Suggestions to remedy the usability issues were provided along with considerations for future design of such interfaces.
Blood Flow Velocity of the Middle Cerebral Arteries: A Real-Time Measure of Attentional Load in the Laparoscopic Surgery Environment?
Authors: Klein Martina I. , Foster Eleanor K. , Greenlee Eric T.
Published: November 2019

Laparoscope (camera) rotations in laparoscopic surgery, and the resulting perceptual-motor distortions, increases the workload (attentional load) of surgeons. When attentional load is high, risks of surgical errors and patient injury increase. Blood flow velocity (BFV) changes of the middle cerebral arteries (MCAs) may serve as a real-time measure of attentional load in this environment. Seventeen undergraduates performed a laparoscopic training task (peg-transfer task) in a laparoscopic simulator at a non-rotated camera angle (0° condition−camera directly in front of the participant) and a rotated condition (camera was rotated 135° to the side). Performance (transfer speed) was superior in the 0° condition and performance in both camera conditions improved over time. Further, BFV was greater at the 135° rotation and declined over time in both conditions. The decline in BFV co-occurred with improved peg-transfer performance that occurred in both camera conditions. The results suggest that BFV changes of the MCAs are a sensitive indicator of attentional load induced by the perceptual-motor distortions inherent in laparoscopy. Thus, it may be possible to use BFV changes of the MCAs, a non-invasive measure, to assess real-time attentional load and attentional resource utilization in the surgical environment
Reflecting Abstraction Hierarchy of a Chemical Processing System on Standard Operating Procedures
Authors: Son Changwon , Peres S. Camille , Ade Nilesh , Neville Timothy J.
Published: November 2019

Standard operating procedures (SOPs) are an integral part of everyday operations in oil & gas and petrochemical industries. Also, a majority of incidents in these processing operations are ascribed to issues associated with SOPs. Although there have been continuous efforts to improve quality of SOPs and ensure accurate perception of information in the SOPs, designing SOPs that allow for workers to adapt to changing or unexpected conditions while still adhering to the procedure remains a persistent gap. As one way to address such gap, this study employs an ecological approach to understand the nature of the system domain and its relations to SOPs. First, this study models a 3-phase separation system, a common oil-water separation process, using an abstraction-decomposition space (ADS) as a functional structure of the system. Next, we apply abstraction hierarchy (AH), one of two dimensions of ADS, to the steps of the SOPs used in the 3-phase separation system. Results show that a majority of steps correspond to physical levels of the AH. Based on the results, several implications for the design and implementation of SOPs from the current study are discussed.
Neural Correlates of Trust During an Automated System Monitoring Task: Preliminary Results of an Effective Connectivity Study
Authors: Sanders Nathan , Choo Sanghyun , Kim Nayoung , Nam Chang S. , Fitts Edward P.
Published: November 2019

As autonomous systems become more prevalent and their inner workings become more opaque, we increasingly rely on trust to guide our interactions with them especially in complex or rapidly evolving situations. When our expectations of what automation is capable of do not match reality, the consequences can be sub-optimal to say the least. The degree to which our trust reflects actual capability is known as trust calibration. One of the approaches to studying this is neuroergonomics. By understanding the neural mechanisms involved in human-machine trust, we can design systems which promote trust calibration and possibly measure trust in real time. Our study used the Multi Attribute Task Battery to investigate neural correlates of trust in automation. We used EEG to record brain activity of participants as they watched four algorithms of varying reliability perform the SYSMON subtask on the MATB. Subjects reported their subjective trust level after each round. We subsequently conducted an effective connectivity analysis and identified the cingulate cortex as a node, and its asymmetry ratio and incoming information flow as possible indices of trust calibration. We hope our study will inform future work involving decision-making and real-time cognitive state detection.
The Classification of Representational Forms
Authors: Gilbert Stephen B. , Richards Whitman
Published: November 2019

Knowledge access and ease of problem-solving, using technology or not, depends upon our choice of representation. Because of our unique facility with language and pictures, these two descriptions are often used to characterize most representational forms, or their combinations, such as flow charts, tables, trees, graphs, or lists. Such a characterization suggests that language and pictures are the principal underlying cognitive dimensions for representational forms. However, we show that when similarity-based scaling methods (multidimensional scaling, hierarchical clustering, and trajectory mapping) are used to relate user tasks that are supported by different representations, then a new categorization appears, namely, tables, trees, and procedures. This new arrangement of knowledge representations may aid interface designers in choosing an appropriate representation for their users' tasks.
The Distribution of Advanced Practice Nurses Within the Psychiatric Workforce
Authors: Beck Angela J. , Page Cory , Buche Jessica , Gaiser Maria
Published: November 2019

OBJECTIVE: To examine the size and distribution of the advanced practice psychiatric nurse workforce relative to the total psychiatry workforce to determine whether nurses are predominantly working in areas with higher or lower levels of behavioral health specialists. METHODS: State-level data for psychiatric nurses were obtained from the American Nurses Credentialing Center, and included mental health psychiatric nurse practitioners, adult psychiatric nurse practitioners, child psychiatric clinical nurse specialists, and adult psychiatric clinical nurse specialists. Supply estimates of the full psychiatry workforce were calculated for comparison purposes. State population estimates were obtained from U.S. Census Bureau data. State workforce estimates were converted to a 1:100,000 provider-to-population ratio to analyze the density of providers across states. RESULTS: In 2018, the psychiatric workforce supply was estimated to be composed of 66,740 providers, including psychiatrists ( n = 47,046; 71%), psychiatric nurses ( n = 17,534; 26%), physician assistants ( n = 1,164; 2%), and psychiatric pharmacists ( n = 966; 1%). Overall, psychiatric providers appeared to be most densely concentrated in the northeast region of the United States. A dearth of providers was most pronounced within areas in the 12-state Midwest region, southern states, California, and Nevada. The average concentration of psychiatric workers was 22.61 per 100,000 population. CONCLUSIONS: The findings of this study find inconsistent pattern of how psychiatric nurses are distributed relative to the rest of the workforce, but reinforce the idea that they are essential in addressing care needs in areas with low concentrations of psychiatry specialists—especially if they are authorized to work to the full extent of their training/education.
Browsing for Cunzaigan on WeChat: Young People’s Social Media Presence in Accelerated Urban China
Authors: Fu Jun , Cook Julia
Published: November 2019

This article examines how young Chinese adults living in urban areas experience cunzaigan (a Chinese word that translates to ‘sense of existence’) through sharing mundane life moments on the social media platform—WeChat. We draw on the theories of social acceleration and social presence to interpret this practice and, in so doing, find that for our participants, cunzaigan signifies a subjective experience, testifying that they are here, providing a counterpoint to their mobile and fast-paced urban lives. Drawing on their experience of temporal social presence on WeChat, we contend that technological developments, which have been identified as a key motor of social acceleration, can also be harnessed as a resource to serve ontological and social purposes in an accelerated social context. In so doing, we address the role that everyday engagements with social media play in shaping the temporal nature of young people’s lives.
Stronger than your voices: A cognitive behavioral therapy for youth suffering from auditory verbal hallucinations
Authors: Maijer Kim , Staring Tonnie , Bartels-Velthuis Agna A , Palmen Saskia JMC , Sommer Iris EC
Published: November 2019

Objective:

Auditory verbal hallucinations (AVHs) are a common feature in youth and mostly transient. Nevertheless, while present, AVH can cause considerable distress. Children and adolescents seeking help for distressing AVH represent a heterogeneous group in terms of underlying factors, yet they consistently suffer from their AVH. Until now, a youth-specific psychotherapeutic intervention for AVH was lacking. Experts in the field of treating AVH in both adults and youngsters collaborated with service users to develop the cognitive behavioral therapy (CBT) “Stronger Than Your Voices” (STYV). We investigated feasibility and clinical outcomes of the STYV therapy.

Methods:

Patients were derived from children and adolescents seeking help for AVH at the UMC Utrecht outpatient clinic with an indication for STYV therapy. Therapists preferably originated from referring health care facilities and were required to have sufficient general knowledge and experience with CBT. They received a short individual training to apply STYV. After, patients and their therapists could participate this naturalistic pilot study, assessing feasibility, tolerability, and clinical change when applying the STYV therapy.

Results:

Six participants (10–16 years old), all suffering from comorbid psychopathology, provided pre and post measures, all completing STYV therapy without experiencing an aggravation of symptoms. AVH total impact decreased 40% with Cohen’s d within-group effect size (1.28) also suggesting clinically meaningful change. Therapists were positive about STYV therapy and manual.

Conclusion:

The STYV therapy is feasible for youth with distressing AVH. First results indicate that STYV may be clinically effective. A trial to further test effectiveness in a larger sample is needed.
The influence of technology on entrepreneurial self-efficacy development for online business start-up in developing nations
Authors: van der Westhuizen Thea , Goyayi Marialauda Joel
Published: November 2019

Business start-ups are usually volatile and risky. They require rapid response and adaptability, calling for entrepreneurial self-confidence among young entrepreneurs. As there is a presumption that technology can alleviate these challenges, this study assessed transformation in entrepreneurial self-efficacy (ESE) among young South Africans in relation to an online business start-up. The article’s contribution centres on the advancement of knowledge on youth entrepreneurship development by understanding/exploring the impact of technology in boosting entrepreneurial confidence and thus stimulating entrepreneurial activities. Using an action learning approach, a business tech start-up process was simulated with a group of 109 randomly recruited participants. Their ESE moving through the start-up cycle was captured and analysed. Likert-scale data were collected on their perceptions before and after the simulation in relation to tolerance self-efficacy, relationship self-efficacy, managerial self-efficacy and opportunity identification self-efficacy. Findings showed significant change in ESE for business start-up after exposure to the potentials and opportunities of technology-related businesses. Participants showed increased confidence and enthusiasm on prospects of success in establishing tech businesses. Effect on the development of ESE was also more pronounced in male participants than female participants.
Mothers’ Experience of Intimate Partner Violence and Subsequent Offspring Attachment Security Ages 1–5 Years: A Meta-Analysis
Authors: McIntosh Jennifer E. , Tan Evelyn S. , Levendosky Alytia A. , Holtzworth-Munroe Amy
Published: November 2019

Attachment status in early childhood is a key yet modifiable contributor to the development of social–emotional competence. The security and organization of the infant–mother attachment bond is particularly susceptible to stressors in the caregiving environment. While the impacts of normative interparental conflict on infant attachment are increasingly understood, the potentially unique place of intimate partner violence (IPV) in this pathway has been under-researched. This study surveyed all empirical work in this area, including unpublished literature ( k = 6, N = 3,394), to examine meta-analytic associations between maternal experiences of IPV and offspring attachment security (ages 1–5 years) measured at least 6 months post-IPV exposure. Mothers’ reports of IPV from pregnancy onward were inversely associated with offspring attachment security, r = −.23, CI [−0.42, −0.04], p = .02. Sample risk characteristics (e.g., clinical vs. community) moderated this association; child’s age at attachment measurement and method of assessing child attachment (e.g., observational, representational, parent report) also moderated at a trend level. Implications for early screening, intervention, and future research are discussed.
Treatment-naive CLL: lessons from phase 2 and phase 3 clinical trials
Authors: Woyach Jennifer A.
Published: November 2019

This article provides a comprehensive review of the first-line therapy in the rapidly evolving field of chronic lymphocytic leukemia (CLL).
Common variable immune deficiency: case studies
Authors: Cunningham-Rundles Charlotte
Published: November 2019

In this review, the authors describe 3 patients with common variable immunodeficiency (CVID), noting the disease manifestations most relevant to the practicing hematologist, especially autoimmune cytopenias, benign lymphoproliferation, granulomatous disease, and lymphomas such as common noninfectious complications of CVID.
Treatment of High Risk Diffuse Large B-Cell Lymphomas (DLBCL) with Ntensive Induction Chemotherapy, Rituximab and Autologous Stem Cell Transplant.
Authors: Pytlik Robert , Trneny Marek , Belada David , Pirnos Jan , Kubackova Katerina , Jankovska Milada , Vasova Ingrid , Kozak Tomas , Pukyova Jana , Pribylova Jana , Siffnerova Hana , Zak Pavel , Hamouzova Michaela , Klener Pavel
Published: November 2019

Background. Aggressive lymphomas with high-intermediate to high risk according to IPI or age-adjusted IPI (aaIPI) have approximately 50% probability of disease progression in two years. Previous studies of CLSG have shown that intensive induction chemotherapy combined with high-dose chemotherapy and autologous stem cell transplant (ASCT) might be benefitial in these patients (Trneny, Blood98(11) 682a, 2001). In current study, we have explored the efficacy and tolerability of this regimen in combination with antiCD20 antibody rituximab (R) for DLBCL with 2 or 3 risk factors according to aaIPI.

Methods. DLBCL patients of age 18–65 years and aaIPI 2 or 3 were eligible for the study. Treatment protocol consisted of three cycles of high-dose CHOP (MegaCHOP, cytoxan 3 g/m2, doxorubicin 75 mg/m2, vincristin 2 mg, and prednison 300 mg/m2 every 21 days with G-CSF support), followed by three cycles of ESHAP and BEAM with ASCT. Peripheral progenitor cells were collected after first cycle of ESHAP. Four to six doses of R 375 mg/m2 were given on day 1 of induction chemotherapy. As four treatment-related deaths occured in first twenty patients, prephase consisting of AOP (MegaCHOP without cytoxan) was incorporated into the treatment regimen from mid-2003.

Results were analysed with intend-to treat approach. Kaplan-Meier curves were constructed for survival analyses. Results. 57 patients were treated from 2002–2004. Median age was 42 years (range, 21–64), and 34 patients were males (60%). 39 patients (67%) had aaIPI 2 and 18 patients (33%) had aaIPI 3. 17 patients had mediastinal variant of DLBCL (30%), and 40 patients (70%) had DLBCL-other. Of 54 evaluable patients, 47 achieved CR or CRu (87%), 5 achieved PR (9%) and two progressed less than three months after treatment completion (4%). Six patients died due to treatment related toxicity (11%), four of them treated without prephase. Three other patients have life-threathening complications (6%). Only one patient (2%) progressed more than one year after study entry. Both 2-year actuarial overall survival (OS) and 2-year event-free survival (EFS) are 79% after median follow-up of 13 months and are not different for aaIPI 2 or 3 patients.

Conclusion. Intensive induction chemotherapy combined with rituximab and ASCT is an effective strategy for treatment of young and high risk patients with CD20 positive DLBCLs. The two-year survival rates are higher than expected especially for aaIPI 3 patients. However, the toxicity is quite severe and the advantage of this regimen is to be proven in randomized trials.
Megakaryocytes Package and Deliver Golgi-Associated Glycosyltransferases into Platelets and to Platelet Surfaces Using Dense Granules.
Authors: Wandall Hans H. , Sørensen Anne Louise , Patel Sunita , Richardson Jennifer , Italiano Joseph E. , Rumjantseva Victoria , Bennett Eric P. , Clausen Henrik , Stossel Thomas P. , Hartwig John H.
Published: November 2019

We recently presented evidence for the presence of a β4 galactosyl transferase (β4GalT) on the surface of platelets that catalyzes the coupling of galactose in a β1,4 linkage to exposed N-acetylglucosamine residues on the N-linked glycans of GP1ba and that this reaction improved the circulation of chilled murine platelets. Since an externally-disposed glycosyltransferase activity contradicts the dogma that such enzymes reside solely within the Golgi apparatus, we verified it by demonstrating that intact platelets glycosylate 2.8 μm beads coated with the acceptor substrate GlcNAc-β-R. We then explored the origin of this enzyme in megakaryocytes and its mechanism of delivery to platelets. We report that Golgi marker GM130 as well as a YFP tagged Golgi marker construct based on the polypeptide transferase GalNAc-T2 expressed in cultured mouse megakaryocytes transports from the cell body of to nascent platelets in discrete packets. In immature megakaryocytes, the Golgi organizes, as expected, into perinuclear arrays. However, once proplatelet extension begins, the perinuclear apparatus disassembles, and Golgi-associated proteins transport through the proplatelets in vesicular/granular structures. Labeling with granule markers reveals correspondence of Golgi markers only with dense granules. These findings suggest that Golgi membrane becomes packaged into dense granules, which deliver Golgi-associated glycosyltransferases into the nascent platelets and from there to the platelet surface.
Studies on Analogues of L-Cysteine and L-Cystine
Authors: WEISBERGER AUSTIN S. , SUHRLAND LEIF G. , SEIFTER JOSEPH
Published: November 2019

The amino acids L-cysteine and L-cystine appear to have an important role in the metabolism of leukocytes. Decreased availability of these amino acids may therefore have important effects on leukocytes.

The possibility of decreasing the influx of radioactive L-cystine into leukemic leukocytes was investigated by exposing the leukocytes to various analogues of cysteine (cystine) prior to incubation with S35 L-cystine. It was found that a highly specific structural and spatial configuration is required to decrease the influx of S35 L-cystine. Thus unlabeled L-cysteine is effective in decreasing the incorporation of radioactive L-cystine. However, analogues of cystine in which there is modification or substitution of the sulfhydryl, amino or carboxyl group do not decrease the influx of S35 L-cystine. Furthermore, any alteration in the spatial relationship of the sulfhydryl and amino groups of L-cysteine also results in a loss of the ability of an analogue to decrease the incorporation of S35 L-cystine.

Of the compounds studied and in the concentrations employed, only unlabeled L-cysteine, selenium cystine and phenyl selenium cysteine were effective. Selenium cystine is identical with cystine except that selenium replaces the sulfur in the molecule. Phenyl selenium cysteine is also closely related structurally to cysteine.

The mechanism of action of selenium cystine and phenyl selenium cysteine in decreasing the influx of S35 L-cystine is not known. Other selenium compounds tested were ineffective. These compounds may exert their inhibitory effect by (a) competitive combination with specific intracellular receptors for L-cysteine (L-cystine), (b) inactivation of enzymes or compounds essential for normal cellular function, (c) alteration in membrane permeability or (d) a toxic effect of selenium.

Since selenium cystine and phenyl selenium cystine are inhibitory in low concentrations in vitro, these compounds may have important effects on leukemic leukocytes in vivo.
The Plasma Clearance and Urinary Excretion of Parenterally Administered 58Co B12
Authors: MOLLIN D. L. , PITNEY W. R. , BAKER S. J. , BRADLEY J. E.
Published: November 2019

Intravenous injections of 1.5 µg. of 58Co B12 were given to subjects with normal serum B12 concentrations, to patients with vitamin B12 deficiency and to patients with chronic myelocytic leukemia.

The rate of plasma clearance of radioactivity after this dose was slowest in patients with chronic myelocytic leukemia and patients with pernicious anemia in severe relapse.

In patients with vitamin B12 deficiency, serum B12 concentrations were estimated microbiologically at frequent intervals after the injection. There was a good correlation between the results obtained by microbiological assay and as calculated from plasma radioactivity.

Significant differences were not observed between the urinary excretion of radioactivity by normal subjects and patients with B12 deficiency.
Incidence of the Common Forms of Human Leukemia
Authors: MACMAHON BRIAN , CLARK DUNCAN
Published: November 2019

From hospital records and from death certificates, an attempt was made to assemble data on all residents of the Borough of Brooklyn diagnosed as having leukemia in the period 1943-52. A total of 1792 abstracts of hospital records and 1830 death certificates gave information on 1709 patients. The mean Brooklyn population over the same period is used to express incidences of the various forms of leukemia in relation to color, sex and age.

The incidence of leukemia in white males and females was 71.3 and 57.7 per million per annum respectively. Corresponding rates for Negroes were 46.5 and 30.6. The white-Negro difference was decreased but not eliminated by standardization to allow for differences in the age distributions of the two populations.

Sex ratios were lower for the acute forms of the disease than for the chronic forms, and, in both acute and chronic forms, for myeloid than for lymphatic cell types. No relationship of sex ratio with age at diagnosis or initial white cell count was found.

Each pathologic variety of leukemia has its own distinct age incidence curve. The lymphatic forms appear to be more sharply associated with the extremes of life than do the myeloid varieties. That is, acute lymphatic leukemia appears at a younger age than does acute myeloid leukemia and the chronic lymphatic form appears at an older average age than the chronic myeloid variety.
Mortality in Relation to Histologic Type in Hodgkin’s Disease
Authors: SMETANA HANS F. , COHEN BERNARD M.
Published: November 2019

1. A study of the trends of mortality in Hodgkin’s disease of diverse histologic type was undertaken with 437 cases at the AFIP Lymphatic Tumor Registry. These represent the records and pathologic material in the Registry of all white males in whom the disease was diagnosed during service in the Army in the World War II period (1941-1946).

2. Follow-up through June 30, 1953 by means of service, Veterans Administration and other records was carried out by established methods which have been demonstrated to result in virtually complete tracing.

3. On histologic analysis of the cases, 388 were confirmed as Hodgkin’s disease and these were differentiated by histologic type as Hodgkin’s granuloma (308 cases, 79 pet cent), Hodgkin’s paragranuloma (35 cases, 9 per cent) and an unspecified group (40 cases, 10 per cent) in which a decision as to type could not be made and as sarcoma (5 cases, 1 per cent). A further analysis of the 308 cases of Hodgkin’s granuloma showed secondary histologic characteristics of sclerosis in 57 instances (18.5 per cent), and of sarcoid in 13 cases (4.2 per cent).

4. The mortality at seven years after diagnosis was 77.1 per cent for the entire group of cases of confirmed Hodgkin’s disease; 28.6 per cent for Hodgkin’s paragranuloma; and 82.8 per cent for Hodgkin’s granuloma. The difference in mortality between these types is significant.

5. The seven year mortality rate for granuloma without qualifying histologic characteristics was 85.7 per cent; for cases with a sarcoid component, 81.8 per cent. The difference in mortality between nonsclerosing and sclerosing Hodgkin’s granuloma (87.5 per cent as against 74.5 per cent) was significant although the significance is borderline.

6. On re-evaluation of the 15 instances diagnosed as Hodgkin’s paragranuloma and terminating fatally, it appeared from the original biopsy material that the diagnosis probably should have been Hodgkin’s granuloma in five instances, and "malignant lymphoma, type uncertain (Hodgkin’s disease not ruled out)" in one case. In the remaining nine instances the histologic diagnosis of the original biopsy material of paragranuloma was confirmed. Autopsy material was available in three of the fifteen cases; two of these showed widespread Hodgkin’s granuloma and one presented a generalized malignant neoplasm, possibly of the Hodgkin’s sarcoma type.

7. For 95 per cent of the deaths among the histologically confirmed cases of Hodgkin’s disease the reported cause of death as found in hospital records or on death certificates was Hodgkin’s disease. It is not known for many of these whether the stated cause of death was verified by autopsy.

8. From the available evidence the question of transformation from paragranuloma to granuloma, or to sarcoma, or to any other form of lymphoma cannot be answered.

9. The correct diagnosis of the types of Hodgkin’s disease and the differentiation of secondary histologic characteristics are of importance in the evaluation of the prognosis, and for the choice of treatment.
Negative Regulation of Cell Cycle Kinetics of Human Hematopoietic Cells by the Transcription Factor Dmtf1.
Authors: Kobayashi Michihiro , Srour Edward F.
Published: November 2019

Hematopoietic stem cells (HSCs) are predominantly quiescent with only a small number entering active phases of cell cycle at any time point. With such tightly regulated cell cycle kinetics, HSCs ensure preservation of the stem cell pool. Many cell cycle-related proteins, mainly tumor suppressor genes, are involved in maintenance of HSCs quiescence. Dmtf1 (Cyclin D-binding Myb-like Protein1) is a transcription factor that negatively regulates cell cycle by inducing Arf expression, and its deletion has been reported in some leukemias (Bodner SM et al, 1999). As there is no information regarding the role of Dmtf1 in hematopoiesis, we examined the impact of Dmtf1 on regulating cell cycle kinetics of hematopoietic progenitor cells. Dmtf1 mRNA was expressed in human granulocytes, lymphocytes, CD34+ cells, and in murine Sca1+lin-CD117+ (KSL) cells. Using retroviral vectors (MIEG3/IRES-GFP), we first investigated cell cycle progression in 293 cells transduced with four different constructs; GFP only control vector (−), wild type Dmtf1 (WT), and two dominant negative mutants expressing a point mutation (K319E) or a deleted myb-like repeat box (dMHR). A total of 36.0% of sorted and cultured GFP+ control (−) cells were in S/G2+M 24hr after initiation of culture. Whereas 30.8% of cells expressing (WT) were in S/G2+M at the same time point, expression of the two dominant negative mutants K319E and dMHR induced 46.6% and 45.5% of the cells into S/G2+M, respectively suggesting that loss of Dmtf1 activity results in rapid cell proliferation. Interestingly, a 2.5-fold increase in the ecxpression of Arf and p21 mesured by qPCR was detected in cells transduced with WT only whereas other transduced cells did not show any change in expression of both Arf and p21. The impact of these constructs was then evaluated in cord blood cells using CFU assays. Cord blood CD34+ cells were transduced with the four vectors mentioned above and GFP+ cells were subsequently sorted and cultured. Both K319E and dMHR induced a 25% increase in the number of clonogenic progenitors relative to (−) while a modest decrease of 10% in colony numbers was detected in the WT group. Cells cycle analysis of these cells is currently under investigation. These results demonstrate that Dmtf1 acts as a negative regulator of cell cycle control in hematopoietic cells and suggests that it may play a role in the maintenance of HSC quiescence.
Low Serum Folate Levels as a Risk Factor for Non-Hodgkin’s Lymphoma.
Authors: Kim HeeNam , Shin Min-Ho , Kim Yeo-Kyeoung , Lee Il-Kwon , Yang Deok-Hwan , Lee Je-Jung , Park Kyeong-Soo , Choi Jin-Su , Kim Hyeoung Joon
Published: November 2019

Folate plays an essential role in cell division by participating in DNA synthesis and regenerating S-adenosylmethionine, a universal methyl donor in methylation. Folate deficiency may be involved in carcinogenesis of several type cancers through impaired synthesis and repair of DNA, or by causing global hypomethylation of DNA. So far, there is no prior report on epidemiologic data concerning the relationship between folate intake or serum folate levels and non-Hodgkin’s lymphoma (NHL) risk. We performed a case-control study (432 cases and 1,700 controls) to examine the association between serum folate levels and risk of NHL. This is, to the best of our knowledge, the first study to show that serum folate levels and risk of NHL. We also investigate whether genetic polymorphisms in folate-metabolizing enzymes interact with serum folate levels in modifying NHL risk. Serum folate was measured by ion capture assay on an AxSYM Analyzer (Abbott Diagnostics, AbbottPark, IL). The geometric mean in cases was lower than in controls (e.g., 18.9 vs 22.1 nmol/L, P < 0.001). We found a statistically significant association between serum folate level and risk of NHL, with 3.35 of odds ratios (OR) (95% confidence interval (CI), 2.27–4.95) for individuals in the lowest serum folate level category (<11.3 nmol/L [5 ng/mL]) compared with the highest category (>22.7 nmol/L [10 ng/mL]) There was a significant thymidylate synthase (TS)-folate interaction in T-cell lymphoma subtype, but we did not observe any significant gene-folate interactions in NHL and DLBCL subtype. Among subjects with low serum folate concentration (<7.5 ng/ml), the OR of T-cell lymphoma for the 3R/3R or 2R/3R genotype were 2.80 (95% CI = 1.36–5.77) and 0.78(95% CI = 0.29–2.12) for 2R/2R genotype (P = 0.045, test for homogeneity). These results provide support for the important role of folate deficiency in the risk of NHL and folate-gene interaction in the etiology of T-cell lymphoma.
Bortezomib Is Synergistic with Rituximab and Cyclophosphamide in Inducing Apoptosis of Mantle Cell Lymphoma Cells In Vitro and In Vivo.
Authors: Zhang Liang , Shi Yuankai , Han Xiaohong , Yang Jing , Qian Jianfei , Kwak Larry W. , Romaguera Jorge , Yi Qing , Wang Michael
Published: November 2019

Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor clinical outcome. Although frontline therapy induces a high rate of complete remission, relapse is inevitable and new regimens are needed for relapsed MCL. The proteasome inhibitor bortezomib (BTZ) induces apoptosis and sensitizes MCL cells to chemotherapy in relapsed MCL, but as a single agent, response rate is low, duration of response is short and side effects are severe. Here we evaluated whether BTZ is additive or synergistic with cyclophosphamide (CTX) and rituximab (RTX).

Material and Methods: Four human MCL cell lines SP53, MINO, Grant 519, and Jeko-1 and freshly isolated primary tumor cells from three MCL patients were treated with BTZ, CTX, RTX individually or in combination of RTX and CTX (RC), or BTZ plus RTX and CTX (BRC regimen). Cell proliferation and apoptosis were evaluated to determine if there was additive or synergistic effect of the BRC regimen. Western blot analysis was used to elucidate the molecular mechanism by which BTZ, RTX, CTX, RC and BRC induces apoptosis in MCL cells. In addition, in vivo experiments using severe combined immunodeficiency mice with human mantle cell lymphoma xenografts were performed to examine the in vivo efficacy of the regimen to control the growth of and eradicate MCL cells.

Results: BTZ and CTX as single agents inhibited the growth of MCL cell lines in a dose-dependent manner (P < 0.01). The IC50 (inhibitory concentration at 50%) for BTZ and for CTX were between 10 and 20 nM and between 5 and 20 mM, respectively. Increasing doses of BTZ with a fixed dose of RTX (10 μg/mL) and CTX (10 mM) resulted in markedly synergistic growth inhibition of MCL cells (P < 0.01). The BRC regimen induced apoptosis in about 69.7% of MCL cell lines and 92.6% of primary tumor cells (P < 0.05 and P < 0.01, compared with those induced by BTZ, RTX, CTX or RC). Furthermore, western blotting analysis showed that BRC induced apoptosis earlier via activation and cleavage of caspases-8, -9, and -3, and PARP as compared with BTZ, RTX, CTX or RC. The pan-caspase inhibitor z-VAD-FMK completely blocked apoptosis induced by BRC. In vivo studies demonstrated that BRC regimen eradicated subcutaneous tumors in MCL-bearing SCID mice and significantly prolonged the long-term event-free survival up to 10 weeks in 70% of the mice, whereas all tumor-bearing mice receiving BTZ, RTX, CTX or RC or PBS (control) died of aggressive MCL within 6 weeks.

Conclusion: Cytoreductive chemotherapy with both BTZ and anti-CD20 antibody effectively inhibited the growth and induced apoptosis of MCL cells in vitro and in vivo. Bortezomib-rituximab-cyclophosphamide (BRC) regimen may offer a better therapeutic modality for MCL patients. Thus, our data lay the basis for a clinical trial in relapsed MCL using the BRC combination treatment.
Treatment of Idiopathic Myelofibrosis Employing siRNA for Heat Shock Protein 47 (siRNA/HSP47) Encapsulated in Liposomes.
Authors: Watanabe Junichi , Matsunaga Takuya , Murase Kazuyuki , Sato Yasushi , Nagaya Taiko , Ishiwatari Hirotoshi , Takahashi Sho , Takada Koichi , Kobune Masayoshi , Shimoda Kazuya , Harada Mine , Niitsu Yoshiro
Published: November 2019

Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by bone marrow (BM) fibrosis, splenomegaly, extramedurally hematopoiesis and anemia. At present, there is no curative treatment available for this disease except allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the high therapy-related mortality of allo-HSCT, even in reduced-intensity transplantation, could not be ignored. We report a novel approach for the treatment of IMF, utilizing siRNA for a collagen specific chaperon, heat shock protein 47 (HSP47) encapsulated in liposomes (lip-siRNA/HSP47). We first confirmed suppression of HSP47 in NIH3T3 murine fibroblast cell line and primary murine BM fibroblasts, and collagen secretion from these cells by siRNA/HSP47. We next treated thrombopoietin (TPO) transgenic mice exhibiting IMF like feature (Shimoda K, Harada M et al. Leuk Res29, 761–769, 2005; Am J Hematol82, 802–806, 2007). In these mice, treatment by intravenous injection of lip-siRNA/HSP47 resulted in histological resolution of myelofibrosis associated with apoptotic death of BM fibroblasts, and improvement of anemia and splenomegaly. Thus, lip-siRNA/HSP47 therapy may be a promising treatment for IMF.
Decreased MHC-II Expression and Immune Dysfunction by Mesenchymal Stem Cells in the Bone Marrow of Patients with Myeloproliferative Disorders.
Authors: Castillo Marianne D. , Rameshwar Pranela
Published: November 2019

The etiology of hematological disorders has been studied at the cellular and molecular levels. These studies have led to an understanding of the effects by the bone marrow microenvironment on the pathophysiology of myeloproliferative disorders. The overarching hypothesis states that resident bone marrow Mesenchymal Stem Cells (MSCs) are important in the development of myeloproliferative disorders and are also involved in the development of fibrosis. The specific hypothesis is that MHC-II expression is decreased in patients MSCs. This makes them unable to act as antigen presenting cells and to suppress immune mediated mechanisms that lead to the development of some myeloproliferative disorders. MSCs were expanded from bone marrow aspirates of patients with AML (n=10), CML (n=10), and MDS (n=10). Flow cytometric analysis showed decreased MHC-II expression in MSCs from all patients as compared to MSCs from patients without hematological malignancy. The flow cytometry results were verified in functional studies using the MSCs as stimulators in a one way mixed lymphocyte reaction. Compared to MSCs from non-hematological malignancy patients, MSCs from study subjects showed reduced ability to elicit allogeneic responses. Retrospective analyses of bone marrow biopsies using immunohistochemistry showed an increase in the amount of MSCs in myelofibrosis patients, compared to patients without evidence of fibrosis, alluding to their role in the development of this condition. These results suggest that MSCs may be dysfunctional in patients with hematological disorders. Variations in the immune properties and the increased amount of MSCs in these patients open an avenue for a lingering question on the etiology of the development of some hematological disorders. Do dysfunctions of MSCs precede myeloproliferative disorders and leukemia or does the opposite occur? In summary, we provide insight into the immune-mediated mechanisms related to the pathophysiology of these disorders, which may have clinical implications for future therapies of bone marrow related disease.