bluuebunny/crossref_metadata_2025 huggingface dataset:
Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication
Authors: Bellet Meritxell , Ahmad Faten , Villanueva Rafael , Valdivia Carolina , Palomino-Doza Julián , Ruiz Ada , Gonzàlez Xavier , Adrover Encarna , Azaro Analía , Valls-Margarit Maria , Parra Josep Lluís , Aguilar Juan , Vidal Maria , Martín Anastasi , Gavilá Joaquín , Escrivá-de-Romaní Santiago , Perelló Antonia , Hernando Cristina , Lahuerta Ainhara , Zamora Pilar , Reyes Victoria , Alcalde María , Masanas Helena , Céliz Pamela , Ruíz Isabel , Gil Miguel , Seguí Miguel Àngel , de la Peña Lorena
Published: May 2019

Drug–drug interactions are of significant concern in clinical practice in oncology, particularly in patients receiving Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are typically exposed to long-term regimens. This article presents the highlights from the ‘First Workshop on Pharmacology and Management of CDK4/6 Inhibitors: Consensus about Concomitant Medications’. The article is structured into two modules. The educational module includes background information regarding drug metabolism, corrected QT (QTc) interval abnormalities, management of psychotropic drugs and a comprehensive review of selected adverse effects of palbociclib and ribociclib. The collaborative module presents the conclusions of the five working groups, each of which comprised five experts from different fields. From these conclusions positive lists of drugs for treating common comorbid conditions that can be safely administered concomitantly with palbociclib and/or ribociclib were developed.
Diagnostic and therapeutic potential of the gut microbiota in patients with early hepatocellular carcinoma
Authors: Ponziani Francesca Romana , Nicoletti Alberto , Gasbarrini Antonio , Pompili Maurizio
Published: May 2019

The gut microbiota is involved in the maintenance of the homeostasis of the human body and its alterations are associated with the development of different pathological conditions. The liver is the organ most exposed to the influence of the gut microbiota, and recently important connections between the intestinal flora and hepatocellular carcinoma (HCC) have been described. In fact, HCC is commonly associated with liver cirrhosis and develops in a microenvironment where inflammation, immunological alterations, and cellular aberrations are dramatically evident. Prevention and diagnosis in the earliest stages are still the most effective weapons in fighting this tumor. Animal models show that the gut microbiota can be involved in the promotion and progression of HCC directly or through different pathogenic mechanisms. Recent data in humans have confirmed these preclinical findings, shedding new light on HCC pathogenesis. Limitations due to the different experimental design, the ethnic and hepatological setting make it difficult to compare the results and draw definitive conclusions, but these studies lay the foundations for a pathogenetic redefinition of HCC. Therefore, it is evident that the characterization of the gut microbiota and its modulation can have an enormous diagnostic, preventive, and therapeutic potential, especially in patients with early stage HCC.
Europe must deliver at the level closest to the citizens Subsidiarity: Past, present and future
Authors: Schneider Michael
Published: May 2019

Subsidiarity is a core value of the European People’s Party. It has been incorporated in the EU treaties to ensure that decisions are taken as closely as possible to the citizens. At a time when citizens are increasingly putting Europe’s democratic legitimacy into question, it is essential to place this principle at the heart of discourse on the EU. The Task Force on Subsidiarity, Proportionality and Doing Less More Efficiently, which was set up by European Commission President Jean-Claude Juncker in November 2018, has identified a ‘new way of working’. It gives local, regional and national authorities a stronger voice in EU policymaking, with the aim of improving the quality and effectiveness of legislation. If implemented by the different institutions, it will both ensure that EU legislation adds value and lead to the member states and their regions and cities taking greater ownership of EU decisions. And these developments, in turn, will help reconnect Europe with its citizens.
Subsidiarity in the service of regional policy: The perspective from Poland’s West Pomerania region
Authors: Geblewicz Olgierd
Published: May 2019

Poland’s local governments, introduced into the public administration system in two stages in 1989 and 1999, have become important actors in the development policy conducted at the national and local levels. Setting up voivodeships—the third-level units of local government—was particularly significant for building strong foundations for a comprehensive regional policy in Poland. Voivodeships create the conditions needed for the long-term economic and social development of their territories. That is why voivodeships should be governed by visionaries rather than administrators. The direct responsibility for regional development planning and programming positions their leaders as the coordinators of development activities in the region and the wise investors of EU funds. Their role must be reflected in the appropriate coordination of development activities at the local level and the ability to offer territorially sensitive financial tools to local communities.
Production and Antifungal Activity of Cordytropolone and (-)-Leptosphaerone A From the Fungus Polycephalomyces nipponicus
Authors: Surapong Nilawan , Sangdee Aphidech , Chainok Kittipong , Pyne Stephen G , Seephonkai Prapairat
Published: May 2019

Cordytropolone (1) and (−)-leptosphaerone A (2) were isolated from the culture broth of the fungus Polycephalomyces nipponicus. The structures of these two compounds were elucidated by spectroscopic methods and from a comparison of the spectroscopic data with those reported previously. The structure of 1 was confirmed by X-ray crystallography for the first time while the leptosphaerone class (compound 2) was first isolated as its (+)-antipode from the fungus Polycephalomyces ( Cordyceps). The fermentation process was monitored weekly by High performance liquid chromatography analysis for 10 weeks. The predominant compound (1) was produced at ~0.65 mg/mg of dry extract at week 9. Compound 1 exhibited modest antipathogenic fungal activity against Collectrichum musae, Colletotrichum capsici, Colletotrichum gloeosporioides, Fusarium spp. TFPK301, F. spp. FOC1708, and Pestalotia spp. with percentage of mycelial growth inhibition values of 3.74 ± 0.70%, 12.86 ± 1.43%, 0.91 ± 0.56%, 5.46 ± 0.56%, 7.93 ± 0.61%, and 18.75 ± 5.24%, respectively, at 25 μg/mL.
Effects of Viscosupplementation on Quality of Knee Joint Arthrokinematic Motion Analyzed by Vibroarthrography
Authors: Bączkowicz Dawid , Skiba Grzegorz , Szmajda Mirosław , Vařeka Ivan , Falkowski Krzysztof , Laudner Kevin
Published: May 2019

Objective

To evaluate the influence of viscosupplementation on osteoarthritic knee arthrokinematics analyzed by VAG. It is considered that intra-articular hyaluronic acid injection may improve the function of synovial joints by recovery of friction-reducing properties of articular environment.

Design

Thirty-five patients with knee osteoarthritis (grade II according to the Kellgren-Lawrence system) and 50 asymptomatic subjects were enrolled in the study. Patients were analyzed at 3 time points: 1 day before and 2 weeks and 4 weeks after single injection of 1.5% cross-linked hyaluronate. Control subjects were tested once. The vibroarthrographic signals were collected during knee flexion/extension motion using an accelerator and described by variation of mean square (VMS), mean range (R5), and power spectral density for frequency of 50 to 250 Hz (P1), and 250 to 450 Hz (P2).

Results

Patients before viscosupplementation were characterized by about 2-fold higher values of vibroarthrographic parameters than controls. Two weeks after the procedure, the values of R5, P1, and P2 significantly decreased, in comparison to pre-injection. At 4 weeks post-injection, we noted a significant increase in R5, P1, and P2 values, when compared to 2 weeks post-injection. Finally, at 4 weeks post-injection, the level of VMS, R5, and P2 parameters did not differ from values obtained at pre-injection.

Conclusions

We showed that viscosupplementation may be effective in providing arthrokinematics improvement, but with a relatively short period of duration. This phenomenon is observed as decreased vibroacoustic emission, which reflects a more smooth movement in the joint.
Update on the role of venetoclax and rituximab in the treatment of relapsed or refractory CLL
Authors: D’Rozario James , Bennett Samuel K.
Published: May 2019

For the treatment of mature B cell malignancies including chronic lymphocytic leukemia (CLL), the last 5 years has brought major advances in the application of targeted therapies. Whilst monoclonal anti-CD20 agents such as rituximab have a central role in combination with traditional cytotoxic therapy, their combination with novel agents that target the B cell receptor signaling pathway and other intracellular mechanisms of B cell proliferation is a new approach to treatment. Venetoclax is a highly specific novel agent inhibiting the bcl-2 anti-apoptotic pathway and has potent activity in CLL. Its combination with rituximab results in deeper and more durable responses and this regimen is a valuable option in the treatment of relapsed or refractory CLL including adverse prognostic variants such as cases that are fludarabine refractory or harbor the 17p chromosomal deletion. This review centers on the use of venetoclax and rituximab in relapsed or refractory CLL.
Image Content Enhancement Through Salient Regions Segmentation for People With Color Vision Deficiencies
Authors: Bruno Alessandro , Gugliuzza Francesco , Ardizzone Edoardo , Giunta Calogero Carlo , Pirrone Roberto
Published: May 2019

Color vision deficiencies affect visual perception of colors and, more generally, color images. Several sciences such as genetics, biology, medicine, and computer vision are involved in studying and analyzing vision deficiencies. As we know from visual saliency findings, human visual system tends to fix some specific points and regions of the image in the first seconds of observation summing up the most important and meaningful parts of the scene. In this article, we provide some studies about human visual system behavior differences between normal and color vision-deficient visual systems. We eye-tracked the human fixations in first 3 seconds of observation of color images to build real fixation point maps. One of our contributions is to detect the main differences between the aforementioned human visual systems related to color vision deficiencies by analyzing real fixation maps among people with and without color vision deficiencies. Another contribution is to provide a method to enhance color regions of the image by using a detailed color mapping of the segmented salient regions of the given image. The segmentation is performed by using the difference between the original input image and the corresponding color blind altered image. A second eye-tracking of color blind people with the images enhanced by using recoloring of segmented salient regions reveals that the real fixation points are then more coherent (up to 10%) with the normal visual system. The eye-tracking data collected during our experiments are in a publicly available dataset called Eye-Tracking of Color Vision Deficiencies.
Salmonella and Shigella among patients with diarrhea at public health facilities in Adama, Ethiopia: Prevalence, antimicrobial susceptibility pattern, and associated factors
Authors: Teshome Bedada , Teklemariam Zelalem , Admassu Ayana Desalegn , Marami Dadi , Asaminew Nega
Published: May 2019

Background:

The frequent occurrence of bacteria-associated diarrhea together with increased antimicrobial resistance poses a significant public health challenge worldwide.

Objectives:

The aim of this study was to assess the prevalence, antimicrobial susceptibility pattern, and associated factors of Salmonella and Shigella among patients with diarrhea at public health facilities in Adama, Ethiopia.

Methods:

A cross-sectional study was conducted among 232 patients with diarrhea at public health facilities in Adama, Ethiopia, from February 2017 to March 2017. Data were collected using a structured questionnaire. Stool samples were examined for Salmonella and Shigella species using the culture and serological methods. Descriptive statistics were used to summarize the findings. Logistic regression models were used to assess the association of independent variables with the outcome. A p-value ⩽ 0.05 was considered to be statistically significant.

Results:

The prevalence of Salmonella and Shigella-associated acute diarrhea was 18.1%. The most common isolates were Shigella dysenteriae (23.8%) and Salmonella typhi (21.4%). S. dysenteriae was 80% resistant to both chloramphenicol and tetracycline. S. typhi was 66.7% resistant to ampicillin, ciprofloxacin, and tetracycline. Those patients aged 11–20 years (adjusted odds ratio: 4.61, 95% confidence interval: 2.48, 7.34), who feed raw vegetables (adjusted odds ratio: 3.67, 95% confidence interval: 1.32, 8.59), and who did not wash hands with soap before a meal (adjusted odds ratio: 2.68, 95% confidence interval: 1.96, 7.48) and after using the toilet (adjusted odds ratio: 3.25, 95% confidence interval: 1.43, 7.36) had higher odds of acute bacterial diarrhea.

Conclusion:

S. dysenteriae and S. typhi were the major causes of acute diarrhea. Most of the isolates showed resistance to ampicillin, ciprofloxacin, and tetracycline. Patients aged 11–20 years, who feed raw vegetables, and who did not wash hands with soap before the meal and after using the toilet had higher odds of acute bacterial diarrhea. Continuous surveillance and the implementation of infection prevention strategies are needed to mitigate acute bacterial diarrhea.
Between and betwixt: Catholic teachers in English secular schools
Authors: Mihovilović Mary , Boulton Helen
Published: May 2019

This article gives voice to Catholic teachers working in secular English schools. Their experience is an under-researched area and, despite a wealth of teaching on the vocation of the teacher, the specific vocation of the Catholic teacher in a secular school receives scant attention from the Catholic Church and researchers. Through in-depth interviews, participants articulated their idiographic experiences of inhabiting a liminal space. The main themes arising from the data were a strong sense of vocation, the absence of a metanarrative in the schools and the teachers’ strong awareness of their Catholic identity. The findings challenge school leaders, the Catholic Church and the government to recognise the presence and experience of Catholic teachers in secular schools and to be attentive to their experiences and needs. The teachers themselves are challenged to acknowledge and value their own worldview and develop their understanding of the relationship between their religious commitment and their practice.
Unused and Expired Medications: Are They a Threat? A Facility-Based Cross-Sectional Study
Authors: Ebrahim Awol Jemal , Teni Fitsum Sebsibe , Yimenu Dawit Kumilachew
Published: May 2019

Background: A significant amount of potentially effective and lifesaving medications were wasted at the health facilities due to lack of a system for checking their effectiveness and returning them to the system. Objectives: To assess the prevalence of unused medications and related consequences in selected health facilities of Awi zone, Amhara regional state, Ethiopia. Methods: A facility-based cross-sectional study design supplemented by a qualitative approach was employed. Descriptive data were collected using checklists while interviews were conducted with respective personnel at the health facilities. Results: A total of 4 health facilities were included in the study. During the 1 month of study period, 56 types of medications were found unused at the health facilities. Anti-infective medications were the most commonly unused medications 36.4%. At the in-patient departments of the 4 hospitals, a total of 173 medications were found unused. Similarly, 605 medications were found wasted at the pharmacy stores of those hospitals in the 2009 fiscal year. Conclusion: A significant amount of unused medications were present at the health facilities. Health facilities need to monitor health professionals strictly follow national and international treatment guidelines and monitor the rational use of medications.
Management of Severe Proximal Femur Bone Loss With a Modular Articulating Antibiotic Spacer
Authors: Mayes Wesley , Edwards Paul K. , Mears Simon C.
Published: May 2019

Introduction:

Management of periprosthetic infection in total hip arthroplasties is challenging, especially when there is severe loss of proximal femoral bone stock. When a 2-stage approach is used, either a static or an articulating spacer may be considered. Static spacers leave the patient with a flail leg, which can be very difficult with massive bone loss. The purpose of this study is to report a novel technique for articulating antibiotic spacers and report our results.

Materials and Methods:

We describe a technique for an articulating hip spacer in the setting of a large amount of proximal femoral bone loss using a locked intramedullary nail, modular femoral body, and an all-polyethylene constrained acetabular component. This technique allowed for mobilization of the patient without a flail leg. Four patients underwent 2-stage reconstruction, and the case series is reported here.

Results:

No complications occurred due to the spacer, and in all cases, a second reconstruction was later carried out after treatment with intravenous antibiotics. Three of 4 patients did well after 2-stage reconstruction, with 1 patient ultimately requiring an amputation.

Discussion:

We feel this technique improves upon previously reported large spacers due to the stability and maintenance of leg length.

Conclusion:

This technique offers a modular solution to address massive bone loss of the proximal femur in the face of periprosthetic joint infection.
Customer Satisfaction Towards Food Service Apps in Indian Metro Cities
Authors: Chakraborty Debarun
Published: May 2019

The appearance of the internet, together with the development of related advancements, has made a noteworthy effect on the lives of individuals around the world. For advertisers, a standout among the various effects has been the rise of virtual stores that sell items and administrations online. Consumers are now be able to buy products and ventures for all intents and purposes anywhere, 24 hours daily, 7 days and without land and fleeting limits. While numerous advertisers recognize the significance of utilizing the internet in their promoting blends, little research has exactly tried the basic factors that impact a person’s choice when purchasing items or administrations on the web. This investigation looks at the determinants of the client-requesting knowledge, which incorporates information quality of the app, payment system and design of the app, customer services, customer satisfaction and the quality of food. The levels of determinants are indicated site quality and administration quality. Study information of 369 online sustenance-requesting clients was used to test the examination display, utilizing multiple regression analysis. Results uncover that not exclusively is there a huge positive relationship between customer services and satisfaction, yet additionally a huge positive relationship between quality of food and consumer satisfaction. Moreover, huge positive connections are additionally found not just between the app and consumer satisfaction but in addition between services and satisfaction also. There is a negative and insignificant connection between design of the app and satisfaction. By and large, the examination gives important bits of knowledge for working on web sustenance-requesting administrations effectively.
Glass Ceiling for Women and Work Engagement: The Moderating Effect of Marital Status
Authors: Sharma Sakshi , Kaur Rajvir
Published: May 2019

Women face several obstacles and barriers in order to attain high managerial positions as compared to men. They struggle to get fair representation in corporate boards and higher management levels. This is known as ‘glass ceiling’. The present study aims to explore the level of glass ceiling for women (GCW) in terms of its three major barriers, that is, personal barriers, organizational barriers and societal barriers among women managers working in the Indian service sector and identify the impact of GCW on their work engagement level as well as the moderating effect of marital status (single or married) on the relationship of GCW and work engagement. A total of 553 women managers working in the three major industries of the service sector, that is, banking, hospitality and information technology (IT), operating in the state of northern India (Punjab) were selected by using multistage sampling technique. The hypotheses were tested through one-sample t-test and moderated hierarchical regression analysis using ‘Statistical Package for Social Sciences’. It was apparent from the findings of the study that the women managers face glass ceiling in terms of organizational and societal barriers at an above-average level. The study also revealed that the organizational and societal barriers had a major impact of 39 per cent on work engagement. Additionally, marital status of the women managers acted as a moderator between the organizational and societal barriers of GCW and their work engagement level. On the basis of the results, the study provides recommendations to raze the GCW in terms of organizational barriers and societal barriers and to increase the work engagement level among the women managers.
Understanding Racial/Ethnic Diversity Gaps Among Early Career Teachers
Authors: Redding Christopher , Baker Dominique J.
Published: May 2019

The growing evidence on the importance of teacher representation points to the need to better understand the factors shaping the lack of racial/ethnic diversity in the teacher workforce. In this study, we examine the extent to which college major choice explains racial/ethnic gaps in teaching. Drawing on data from the Baccalaureate and Beyond Longitudinal Study, we find that White college graduates are close to twice as likely to major in education compared to Black, Latinx, and other graduates of color. Even among college graduates, respondents who identify as White are 5 percentage points more likely to enter teaching than respondents who identify as Black and 2 percentage points more likely to enter teaching than graduates who identify as Latinx. Regression and decomposition analyses demonstrate that the observed racial/ethnic gaps in entry to teaching can largely be explained by whether a graduate studied education in college.
Seniors Who Experienced the Lac-Mégantic Train Derailment Tragedy: What Are the Consequences on Physical and Mental Health?
Authors: Maltais Danielle , Tremblay Anne-Julie , Labra Oscar , Fortin Geneviève , Généreux Mélissa , Roy Mathieu , Lansard Anne-Lise
Published: May 2019

Introduction: In July 2013, a train derailment caused the death of 47 people and destroyed the downtown area in the city of Lac-Mégantic (Quebec, Canada). This tragedy had several impacts on this small community. Method: Three years after this disaster, we used a representative population-based survey conducted among 800 adults (including 265 seniors aged 65 or above) to assess the physical and mental health of seniors. Results: Several differences were observed in seniors’ physical and mental health based on their level of exposure to the tragedy. Nearly half of seniors highly exposed to the train derailment (41.7%) believe that their health has deteriorated in the past 3 years. The majority of seniors highly exposed to the train derailment (68.7%) also show symptoms of posttraumatic stress disorders. Seniors highly or moderately exposed to the tragedy were also more likely to have found positive changes in their personal and social life as compared with nonexposed seniors. Discussion: A technological disaster such as a train derailment still had negative impacts on seniors’ physical and mental health 3 years later. Conclusion: Public health authorities must tailor prevention and promotion programs to restore health and well-being in this population.
Depressive Disorders and Religious Engagement in Very Old People
Authors: Strinnholm Sofia , Gustafson Yngve , Niklasson Johan
Published: May 2019

Objective: To examine associations between religious engagement and depressive disorders in very old people. Method: This cross-sectional study uses data from the Umeå 85+/Gerontological Regional Database (GERDA) study. Every other 85-year-old, every 90-year-old, and everyone more than 95 years from eight municipalities in northern Sweden and Finland were invited: 1,014 persons accepted participation. Data were gathered using questionnaires and assessment scales during structured home visits. Results: The prevalence of depressive disorders was 35.8%. In a logistic regression model, several factors were adjusted for, such as demographic variables including social factors, diseases, and cognitive and physical functional level. A high level of self-reported religious engagement was independently associated with not having depressive disorders (odds ratio [OR] = 0.58, confidence interval [CI] = [0.38, 0.89]). After stratifying by gender, religious engagement was only significant for women (OR = 0.49, CI = [0.29, 0.82]). Discussion: There is an association between a high level of religious engagement and being free from diagnosis of depressive disorders among very old women.
Are Robots Stealing Our Jobs?
Authors: Dahlin Eric
Published: May 2019

The media and popular business press often invoke narratives that reflect widespread anxiety that robots may be rendering humans obsolete in the workplace. However, upon closer examination, many argue that automation, including robotics and artificial intelligence, is spreading unevenly throughout the labor market, such that middle-skill occupations that do not require a college degree are more likely to be affected adversely because they are easier to automate than high-skill occupations. In this article, the author examines the effect of industrial robots on occupations in the United States in 2010 and 2015. Results from regression models indicate that an increase in industrial robots is associated with increases in high-skill and some middle-skill occupations but not for other types of occupations. These findings may indicate the ushering in of a new era in which robots are more technologically advanced and able to collaborate better with human employees.
Charity Fundraising Project: A Team-Based Project for Developing Problem-Structuring Skills
Authors: Owen Chris
Published: May 2019

Increasingly, graduates of business schools will face business and organizational situations with a high degree of complexity and ambiguity. In this context, teaching and learning strategies need to develop students’ abilities in problem structuring and complex problem solving. This article describes a team-based project set to teams of four or five students, who are required to design and deliver a fundraising event for their chosen charity. The goal of the fundraising activity is to raise as much money as they can in a 24-hour period. Using ideas from problem-based learning (PBL), students learn frameworks and tools to increase their confidence in these situations. This article describes this activity and will be of interest to teachers of final-year undergraduate and master’s programs looking for a fun and inspiring activity to do with students.
Advancing knowledge on human resource management in family firms: An introduction and integrative framework
Authors: Hoon Christina , Hack Andreas , Kellermanns Franz W
Published: May 2019

Over the last decades, human resource management has received increasing attention in family business scholarship. However, works on human resource management in the context of family firms remain relatively low as compared to the more general body of studies on human resource management. This article introduces our special issue of the German Journal of Human Resource Management, which discusses facets of how family firms configure human resource management and set human resource practices. We first give a brief overview on the conceptual and empirical research that relates to and informs human resource management within family firms, resulting in a human resource system framework. We then discuss ideas for future human resource management research, namely, the influence of the owning family on human resource orientation, non-family employees as human resource recipients and the role of human resource professionals in delivering human resource management. Furthermore, we call for making psychological foundations part of the human resource management scholarship agenda. There is still work to be done before human resource management can find its ‘place in the sun’ in the family business community. Hence, this special issue contributes to developing family business human resource management scholarship further by offering the human resource system framework, by suggesting directions for future research and by advancing our conceptual and empirical understanding of human resource management in the context of family firms.
Achilles Tendinopathy and Associated Disorders
Authors: Ferguson Adam , Christophersen Christy , Elattar Osama , Farber Daniel C.
Published: May 2019

Degenerative disorders of the Achilles tendon are common, affecting up to 18% of the adult population. A thorough evaluation including a focused history, physical examination, and diagnostic studies helps in choosing the appropriate treatment. Initial treatment is usually nonoperative, consisting of activity modification, bracing, and physical therapy. Patents who fail nonoperative management may be treated operatively with a wide range of procedures from endoscopic surgery to open debridement and tendon transfer. Understanding a patient’s expectations and educating patients about potential treatments and their outcomes enables informed collaborative decision making. This article will review the evaluation and management Achilles tendinopathy and associated disorders.
Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy
Authors: van Bruggen Jaco A. C. , Martens Anne W. J. , Fraietta Joseph A. , Hofland Tom , Tonino Sanne H. , Eldering Eric , Levin Mark-David , Siska Peter J. , Endstra Sanne , Rathmell Jeffrey C. , June Carl H. , Porter David L. , Melenhorst J. Joseph , Kater Arnon P. , van der Windt Gerritje J. W.
Published: May 2019

In chronic lymphocytic leukemia (CLL), acquired T-cell dysfunction impedes development of effective immunotherapeutic strategies, through as-yet unresolved mechanisms. We have previously shown that CD8+ T cells in CLL exhibit impaired activation and reduced glucose uptake after stimulation. CD8+ T cells in CLL patients are chronically exposed to leukemic B cells, which potentially impacts metabolic homeostasis resulting in aberrant metabolic reprogramming upon stimulation. Here, we report that resting CD8+ T cells in CLL have reduced intracellular glucose transporter 1 (GLUT1) reserves, and have an altered mitochondrial metabolic profile as displayed by increased mitochondrial respiration, membrane potential, and levels of reactive oxygen species. This coincided with decreased levels of peroxisome proliferator-activated receptor γ coactivator 1-α, and in line with that, CLL-derived CD8+ T cells showed impaired mitochondrial biogenesis upon stimulation. In search of a therapeutic correlate of these findings, we analyzed mitochondrial biogenesis in CD19-directed chimeric antigen receptor (CAR) CD8+ T cells prior to infusion in CLL patients (who were enrolled in NCT01747486 and NCT01029366 [https://clinicaltrials.gov]). Interestingly, in cases with a subsequent complete response, the infused CD8+ CAR T cells had increased mitochondrial mass compared with nonresponders, which positively correlated with the expansion and persistence of CAR T cells. Our findings demonstrate that GLUT1 reserves and mitochondrial fitness of CD8+ T cells are impaired in CLL. Therefore, boosting mitochondrial biogenesis in CAR T cells might improve the efficacy of CAR T-cell therapy and other emerging cellular immunotherapies.
A life cycle model of major innovations in operations management
Authors: Chikán Attila , Sprague Linda G.
Published: May 2019

This paper analyses the means by which major innovations in the operations management (OM) practice develop. It describes the process as having a life cycle pattern that starts with a big idea. The big idea concept promises breakthrough operating results, ultimately providing lower price, better quality, faster delivery, or combinations of these and other attributes that add value for the customer. A successful big idea goes through the phases of provenance, experimentation, penetration, consolidation, and absorption. At that point, it is being incorporated into business operations throughout the industry. If the original idea reaches the end of its useful life or proves unsuccessful during development, it is supplanted. Materials requirements planning (MRP) and supply chain management (SCM) are used to illustrate the general life cycle model. The analysis of these two successful major OM innovations discloses a similar development pattern but different final absorption outcomes. While MRP became an everyday tool for tactical level operations, SCM is an important strategic tool for integrated company management. The similarity of their development patterns, however, supports the general nature of the life cycle model introduced.
Concordance of Genomic Variants in Matched Primary Breast Cancer, Metastatic Tumor, and Circulating Tumor DNA: The MIRROR Study
Authors: Moreno Fernando , Gayarre Javier , López-Tarruella Sara , del Monte-Millán María , Picornell Antonio C. , Álvarez Enrique , García-Saenz José Ángel , Jerez Yolanda , Márquez-Rodas Iván , Echavarría Isabel , Palomero Maribel , Bueno Coralia , Aragón Bodí Ana María , Muñoz Marta Sanchez , González del Val Ricardo , Bueno Oscar , Cebollero-Presmanes María , Ocaña Inmaculada , Arias Ainhoa , Romero Paula , Massarrah Tatiana , Ramos-Medina Rocío , Martín Miguel
Published: May 2019

PURPOSE

Genetic heterogeneity between primary tumors and their metastatic lesions has been documented in several breast cancer studies. However, the selection of therapy for patients with metastatic breast cancer and the search for biomarkers for targeted therapy are often based on findings from the primary tumor, mainly because of the difficulty of distant metastasis core biopsies. New methods for monitoring genomic changes in metastatic breast cancer are needed (ie, circulating tumor DNA [ctDNA] genomic analysis). The objectives of this study were to assess the concordance of genomic variants between primary and metastatic tumor tissues and the sensitivity of plasma ctDNA analysis to identify variants detected in tumor biopsies.

PATIENTS AND METHODS

Next-generation sequencing technology was used to assess the genomic mutation profile of a panel of 54 cancer genes in matched samples of primary tumor, metastatic tumor, and plasma from 40 patients with metastatic breast cancer.

RESULTS

Using Ion Torrent technology (ThermoFisher Scientific, Waltham, MA), we identified 110 variants that were common to the primary and metastatic tumors. ctDNA analysis had a sensitivity of 0.972 in detecting variants present in both primary and metastatic tissues. In addition, we identified 13 variants in metastatic tissue and ctDNA not present in primary tumor.

CONCLUSION

We identified genomic variants present in metastatic biopsies and plasma ctDNA that were not present in the primary tumor. Deep sequencing of plasma ctDNA detected most DNA variants previously identified in matched primary and metastatic tissues. ctDNA might aid in therapy selection and in the search for biomarkers for drug development in metastatic breast cancer.
Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors
Authors: Chung Jon H. , Dewal Ninad , Sokol Ethan , Mathew Paul , Whitehead Robert , Millis Sherri Z. , Frampton Garrett M. , Bratslavsky Gennady , Pal Sumanta K. , Lee Richard J. , Necchi Andrea , Gregg Jeffrey P. , Lara Primo , Antonarakis Emmanuel S. , Miller Vincent A. , Ross Jeffrey S. , Ali Siraj M. , Agarwal Neeraj
Published: May 2019

PURPOSE

Comprehensive genomic profiling (CGP) is increasingly used for routine clinical management of prostate cancer. To inform targeted treatment strategies, 3,476 clinically advanced prostate tumors were analyzed by CGP for genomic alterations (GAs) and signatures of genomic instability.

METHODS

Prostate cancer samples (1,660 primary site and 1,816 metastatic site tumors from unmatched patients) were prospectively analyzed by CGP (FoundationOne Assay; Foundation Medicine, Cambridge, MA) for GAs and genomic signatures (genome-wide loss of heterozygosity [gLOH], microsatellite instability [MSI] status, tumor mutational burden [TMB]).

RESULTS

Frequently altered genes were TP53 (44%), PTEN (32%), TMPRSS2-ERG (31%), and AR (23%). Potentially targetable GAs were frequently identified in DNA repair, phosphatidylinositol 3-kinase, and RAS/RAF/MEK pathways. DNA repair pathway GAs included homologous recombination repair (23%), Fanconi anemia (5%), CDK12 (6%), and mismatch repair (4%) GAs. BRCA1/2, ATR, and FANCA GAs were associated with high gLOH, whereas CDK12-altered tumors were infrequently gLOH high. Median TMB was low (2.6 mutations/Mb). A subset of cases (3%) had high TMB, of which 71% also had high MSI. Metastatic site tumors were enriched for the 11q13 amplicon ( CCND1/ FGF19/ FGF4/FGF3) and GAs in AR, LYN, MYC, NCOR1, PIK3CB, and RB1 compared with primary tumors.

CONCLUSION

Routine clinical CGP in the real-world setting identified GAs that are investigational biomarkers for targeted therapies in 57% of cases. gLOH and MSI/TMB signatures could further inform selection of poly (ADP-ribose) polymerase inhibitors and immunotherapies, respectively. Correlation of DNA repair GAs with gLOH identified genes associated with homologous recombination repair deficiency. GAs enriched in metastatic site tumors suggest therapeutic strategies for metastatic prostate cancer. Lack of clinical outcome correlation was a limitation of this study.
Impact of KRAS and TP53 Co-Mutations on Outcomes After First-Line Systemic Therapy Among Patients With STK11-Mutated Advanced Non–Small-Cell Lung Cancer
Authors: Bange Erin , Marmarelis Melina E. , Hwang Wei-Ting , Yang Yu-Xiao , Thompson Jeffrey C. , Rosenbaum Jason , Bauml Joshua M. , Ciunci Christine , Alley Evan W. , Cohen Roger B. , Langer Corey J. , Carpenter Erica , Aggarwal Charu
Published: May 2019

PURPOSE

The STK11 gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non–small-cell lung cancer (NSCLC) and STK11 mutations often have other co-mutations. We evaluated the impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors STK11 mutations.

METHODS

We conducted a retrospective review of patients with metastatic NSCLC and STK11 mutations treated at the University of Pennsylvania. STK11 mutations were identified through next-generation sequencing (NGS) in tissue or plasma. Cox proportional hazard models were used to determine the relationship between STK11 co-mutations and survival outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS).

RESULTS

From February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored an STK11 mutation (n = 56, tissue; n = 21, plasma). Of the 62 patients included, 18 had an STK11 mutation alone, 19 had STK11/ KRAS, 18 had STK11/ TP53, and seven had STK11/ KRAS/ TP53. Patients with STK11/ KRAS co-mutations had a worse median PFS (2.4 months) compared with STK11 alone (5.1 months; log-rank P = .048), STK11/ TP53 (4.3 months; log-rank P = .043), and STK11/ KRAS/ TP53 (13 months; log-rank P = .03). Patients with STK11/ KRAS co-mutation experienced shorter median OS (7.1 months) compared with STK11 alone (16.1 months; log-rank P < .001), STK11/ TP53 (28.3 months; log-rank P < .001), and STK11/ KRAS/ TP53 (22 months; log-rank P = .025).

CONCLUSION

Among patients with advanced NSCLC and STK11 mutations treated with first-line systemic therapy, co-mutation with KRAS was associated with significantly worse PFS and OS. By contrast, co-mutation of STK11 with TP53 conferred a better prognosis.
Identification of Distinct Prognostic Groups: Implications for Patient Selection to Targeted Therapies Among Anti-Endocrine Therapy–Resistant Early Breast Cancers
Authors: Bayani Jane , Kornaga Elizabeth N. , Crozier Cheryl , Jang Gun Ho , Bathurst Lauren , Kalatskaya Irina , Trinh Quang M. , Yao Cindy Q. , Livingstone Julie , Boutros Paul C. , Spears Melanie , McPherson John D. , Stein Lincoln D. , Rea Daniel , Bartlett John M.S.
Published: May 2019

PURPOSE

Hormone receptor–positive breast cancer remains an ongoing therapeutic challenge, despite optimal anti-endocrine therapies. In this study, we assessed the prognostic ability of genomic signatures to identify patients at risk for recurrence after endocrine therapy. Analysis was performed on the basis of an a priori hypothesis related to molecular pathways, which might predict response to existing targeted therapies.

PATIENTS AND METHODS

A subset of patients from the Tamoxifen Versus Exemestane Adjuvant Multinational trial ( ClinicalTrials.gov identifiers: NCT00279448 and NCT00032136, and NCT00036270) pathology cohort were analyzed to determine the prognostic ability of mutational and copy number aberration biomarkers that represent the cyclin D/cyclin-dependent kinase (CCND/CDK), fibroblast growth factor receptor/fibroblast growth factor (FGFR/FGF), and phosphatidylinositol 3-kinase/protein kinase B (PI3K/ATK) pathways to inform the potential choice of additional therapies to standard endocrine treatment. Copy number analysis and targeted sequencing was performed. Pathways were identified as aberrant if there were copy number aberrations and/or mutations in any of the predetermined pathway genes: CCND1/CCND2/CCND3/CDK4/CDK6, FGFR1/FGFR2/FGFR2/FGFR4, and AKT1/AKT2/PIK3CA/PTEN.

RESULTS

The 390 of 420 samples that passed quality control were analyzed for distant metastasis–free survival between groups. Patients with no changes in the CCND/CDK pathway experienced a better distant metastasis–free survival (hazard ratio, 1.94; 95% CI, 1.45 to 2.61; P < .001) than those who possessed aberrations. In the FGFR/FGF and PI3K/AKT pathways, a similar outcome was observed (hazard ratio, 1.43 [95% CI, 1.07 to 1.92; P = .017] and 1.34 [95% CI, 1.00 to 1.81; P = .053], respectively).

CONCLUSION

We show that aberrations of genes in these pathways are independently linked to a higher risk of relapse after endocrine treatment. Improvement of the clinical management of early breast cancers could be made by identifying those for whom current endocrine therapies are sufficient, thus reducing unnecessary treatment, and secondly, by identifying those who are at high risk for recurrence and linking molecular features that drive these cancers to treatment with targeted therapies.
MON-LB052 Efficacy and Safety of Minimed 670G Automode in Children with Type 1 Diabetes Less Than 8 Years Old
Authors: Salehi Parisa , Roberts Alissa , Kim Grace
Published: May 2019

Introduction: The Medtronic MiniMed 670G system with SmartGuardTM (Medtronic, Northridge, CA) is a commercial hybrid closed-loop (HCL) system approved for use in 2017 for children >8 years of age. Studies of the system in children >7 years old, adolescents, and adults show improvement in glycemic control when using the HCL system or automode (AM) [1]. There has been no study describing the use of the system in young children. Children <8 can have extensive glucose variability related to eating patterns, activity, and growth. Glycemic excursions may be better controlled with a HCL system. We reviewed patients at our institution with type 1 diabetes (T1D) <7 years of age who were on the 670G HCL system for at least 3 months to see if glycemic control improved. Case Series: We reviewed children <8 years of age with T1D at our institution who had been on the 670G for at least 3 months. We compared 2 week data obtained from Carelink while in an open loop system or manual mode (MM) to those in AM. We excluded those who did not have available hemoglobin A1C +/- 30 days from the download. We used 2 tailed t-test to compare A1C, percentage time in range (TIR), percentage of hypoglycemia, average sensor glucose, average sensor glucose standard deviation (SD). Results: 16 children were reviewed (age of AM start: range 2-6, average 4.3 years; 10 male). The time in AM was average 6.3 +/- 2.9 months (range 3-12). Average percent time in AM was 79 +/- 13.6 (range 57-98). There was a statistically significant change for A1C (MM 7.9%, AM 7.4%; p-value <0.001), percentage TIR (MM 42.8%, AM 56.2%; p-value <0.001), percentage hypoglycemia (MM 1.3%, AM 2.4%; p-value 0.04), average sensor glucose (MM 200, AM 176; p-value <0.001). There was no significant difference in average sensor SD. No adverse events were noted during the time of review. Conclusion: This case series showed an improvement in glycemic control noted by A1C, percentage TIR, average sensor glucose. We did note significantly more hypoglycemia although no serious adverse events were reported. A HCL system can be used in young children with T1DM safely and effectively and should be an option for children < 7 years. 1. Forlenza, G.P., et al., Safety Evaluation of the MiniMed 670G System in Children 7-13 Years of Age with Type 1 Diabetes. Diabetes Technol Ther, 2019. 21(1): p. 11-19. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.
Making Way for Ghosts and Mothers
Authors: Charania Moon
Published: May 2019

This essay takes on ghosts as an explicit analytic lever to examine the storied archive of one racial and racialized mother. It defines ghosts as conglomerating and attached energies whose nodes of human connection rely on the lived experience of violence, violation, and volatility. Through three narrated encounters, the essay uses social and affective memory and autoethnographic matter as food for critical thought, building on philosophy, postcolonial, feminist, and queer criticism, in order to address the hauntology of the necropartriarchal and necropolitical against the backdrop of late liberal globalization and its enduring injustices. In writing at the limit of the unspeakable and the unknown, this essay mimes the violence of the archive. However, this essay does more than recount the violence deposited in the fragment of this archive. It tells the story of ghosts to retrieve what remains dormant in critical feminist theorizations of violence against women. Using a cross-genre form, a secret collection of memories that includes elements of hauntology, this essay exposes some of the cracks and fissures in feminist theorizing on sexual violence, migration, and the figure of the other mother.