bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma
Authors: Prukova Dana , Andera Ladislav , Nahacka Zuzana , Karolova Jana , Svaton Michael , Klanova Magdalena , Havranek Ondrej , Soukup Jan , Svobodova Karla , Zemanova Zuzana , Tuskova Diana , Pokorna Eva , Helman Karel , Forsterova Kristina , Pacheco-Blanco Mariana , Vockova Petra , Berkova Adela , Fronkova Eva , Trneny Marek , Klener Pavel 
Published: April 2019

Abstract

Purpose:
Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug, venetoclax, has promising anticancer activity in MCL. We analyzed molecular mechanisms of venetoclax resistance in MCL cells and tested strategies to overcome it.

Experimental Design:
We confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. Both BIM and NOXA are, however, differentially expressed in cell lines compared with primary cells. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, deletions of BIM gene harbored by three commonly used MCL cell lines (JEKO-1, MINO, and Z138) were not found by array comparative genomic hybridization using a validation set of 24 primary MCL samples.

Results:
We demonstrated that MCL1 and NOXA play important roles in mediating resistance to venetoclax. Consequently, we tested an experimental treatment strategy based on cotargeting BCL2 with venetoclax and MCL1 with a highly specific small-molecule MCL1 inhibitor S63845. The combination of venetoclax and S63845 demonstrated synthetic lethality in vivo on a panel of five patient-derived xenografts established from patients with relapsed MCL with adverse cytogenetics.

Conclusions:
Our data strongly support investigation of venetoclax in combination with S63845 as an innovative treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds.
Tumor Lysis, Adverse Events, and Dose Adjustments in 297 Venetoclax-Treated CLL Patients in Routine Clinical Practice
Authors: Roeker Lindsey E. , Fox Christopher P. , Eyre Toby A. , Brander Danielle M. , Allan John N. , Schuster Stephen J. , Nabhan Chadi , Hill Brian T. , Shah Nirav N. , Lansigan Frederick , Yazdy Maryam , Cheson Bruce D. , Lamanna Nicole , Singavi Arun K. , Coombs Catherine C. , Barr Paul M. , Skarbnik Alan P. , Shadman Mazyar , Ujjani Chaitra S. , Tuncer Hande H. , Winter Allison M. , Rhodes Joanna , Dorsey Colleen , Morse Hannah , Kabel Charlene , Pagel John M. , Williams Annalynn M. , Jacobs Ryan , Goy Andre , Muralikrishnan Sivraj , Pearson Laurie , Sitlinger Andrea , Bailey Neil , Schuh Anna , Kirkwood Amy A. , Mato Anthony R. 
Published: April 2019

Abstract

Purpose:
Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.

Experimental Design:
This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.

Results:
The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.

Conclusions:
These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.
“A Natural Progression”: Australian Women's Attitudes About an Individualized Breast Screening Model
Authors: Lippey Jocelyn , Keogh Louise A. , Mann G. Bruce , Campbell Ian G. , Forrest Laura E. 
Published: April 2019

Abstract
Individualized screening is our logical next step to improve population breast cancer screening in Australia. To explore breast screening participants' views of the current program in Victoria, Australia, examine their openness to change, and attitudes toward an individualized screening model, this qualitative work was performed from a population-based breast screening cohort. This work was designed to inform the development of a decision aid to facilitate women's decisions about participating in individualized screening, and to elicit Australian consumer perspectives on the international movement toward individualized breast screening. A total of 52 women participated in one of four focus groups, and were experienced with screening with 90% of participants having had more than three mammograms. Focus group discussion was facilitated following three main themes: (i) experience of breast screening; (ii) breast cancer risk perception, and (iii) views on individualized screening. Participants had strong, positive, emotional ties to breast screening in its current structure but were supportive, with some reservations, of the idea of individualized screening. There was good understanding about the factors contributing to personalized risk and a wide range of opinions about the inclusion of genetic testing with genetic testing being considered a foreign and evolving domain. Individualized breast screening that takes account of risk factors such as mammographic density, lifestyle, and genetic factors would be acceptable to a population of women who are invested in the current system. The communication and implementation of a new program would be critical to its acceptance and potential success. Reservations may be had in regards to uptake of genetic testing, motivations behind the change, and management of the women allocated to a lower risk category.
Increasing Incidence rates of Oropharyngeal Squamous Cell Carcinoma in Germany and Significance of Disease Burden Attributed to Human Papillomavirus
Authors: Wittekindt Claus , Wagner Steffen , Bushnak Ayman , Prigge Elena-Sophie , von Knebel Doeberitz Magnus , Würdemann Nora , Bernhardt Katharina , Pons-Kühnemann Jörn , Maulbecker-Armstrong Catharina , Klussmann Jens Peter 
Published: April 2019

Abstract
Increasing incidences of head and neck cancers and rising proportions of these associated with human papillomavirus (HPV), especially in the oropharynx, have been reported in international studies. So far, the trends and contribution of HPV to the number of newly diagnosed cases of oropharyngeal squamous cell carcinomas (OPSCC) in Germany are uncertain. We investigated HPV association and incidence rates in a cohort of consecutively included patients with OPSCC in Giessen 2000–2017, and compared our results with regional (Giessen and the federal state of Hesse), national (Germany), and international (United States) databases. Regional data show a significant increase in the overall incidence rates of oropharyngeal cancers and in the incidence of HPV-associated cancers of the subsites tonsils and oropharynx, whereas other oropharyngeal subsites show no significant change. Analysis of national databases shows a significant incidence increase in Germany and in the United States. The rise in incidence is predominantly attributable to male patients in the US population, whereas in Germany rising OPSCC incidence is more associated with females. There is a significant elevation of OPSCC incidence rates in Germany, which corresponds to the recognized incidence increase of HPV-related oropharyngeal cancers based on experimental data from consecutively included patients of our cohort. Our investigation shows different patterns of this increase in Germany and in the United States, which demonstrates spatial heterogeneity and the need for population-based investigations regarding the role of HPV in oropharyngeal cancer.
The Impact of Environmental Stress on Cognitive Performance: A Systematic Review
Authors: Martin Kristy , McLeod Emily , Périard Julien , Rattray Ben , Keegan Richard , Pyne David B. 
Published: April 2019

Objective: In this review, we detail the impact of environmental stress on cognitive and military task performance and highlight any individual characteristics or interventions which may mitigate any negative effect. Background: Military personnel are often deployed in regions markedly different from their own, experiencing hot days, cold nights, and trips both above and below sea level. In spite of these stressors, high-level cognitive and operational performance must be maintained. Method: A systematic review of the electronic databases Medline (PubMed), EMBASE (Scopus), PsycINFO, and Web of Science was conducted from inception up to September 2018. Eligibility criteria included a healthy human cohort, an outcome of cognition or military task performance and assessment of an environmental condition. Results: The search returned 113,850 records, of which 124 were included in the systematic review. Thirty-one studies examined the impact of heat stress on cognition; 20 of cold stress; 59 of altitude exposure; and 18 of being below sea level. Conclusion: The severity and duration of exposure to the environmental stressor affects the degree to which cognitive performance can be impaired, as does the complexity of the cognitive task and the skill or familiarity of the individual performing the task. Application: Strategies to improve cognitive performance in extreme environmental conditions should focus on reducing the magnitude of the physiological and perceptual disturbance caused by the stressor. Strategies may include acclimatization and habituation, being well skilled on the task, and reducing sensations of thermal stress with approaches such as head and neck cooling.
Communicative Capitalism and Revolutionary Form
Authors: Dean Jodi 
Published: April 2019

This essay considers the political form that is presupposed in questions of resistance and revolution. It situates resistance and revolution in communicative capitalism, a setting characterised by intense winner-take-all inequality, the decline of symbolic efficiency, and the shift from the use to the circulation value of communicative utterances. It draws out the way that this setting inflects the body the question of resistance and revolution presupposes. Is it the world, the individual, the network, or the party? I argue that the party is the form we need to assume when we ask about revolution because it is the party that has the capacity to strategise, to plan and to arrange itself with an eye to revolution. Capitalismo comunicativo y forma revolucionaria
Determinants of Infant Feeding Practices Among HIV-Infected Mothers in Urban Kano, Nigeria
Authors: Iliyasu Zubairu , Galadanci Hadiza S. , Iliyasu Miyassaratu L. , Babashani Musa , Gajida Auwalu U , Nass Nafisa S. , Aliyu Muktar H. 
Published: April 2019

Background: Despite advances in prevention of mother-to-child HIV transmission, infants in Africa remain at risk of HIV acquisition from inappropriate feeding practices. Research aims: To assess maternal knowledge and predictors of appropriate infant feeding practices among HIV-infected mothers attending a tertiary facility in Kano, Nigeria. Method: A cross section of 203 HIV-positive mothers were interviewed using structured, pretested survey questionnaires. Knowledge scores and infant feeding practices were analyzed. Multivariate logistic regression was employed to ascertain independent correlates of infant feeding practices in the study sample. Results: Over a third (37.4%) of the participants were aware of the risk of HIV transmission through breastfeeding. The proportion of participants with good, fair, and poor knowledge of recommended feeding options for HIV-exposed infants was 4.4%, 73.4%, and 22.2%, respectively. About three in four participants (73.9%) breastfed their index infants exclusively for the first six months. Approximately 7.4% of respondents practiced mixed feeding (breastfeeding plus infant formula). Counseling on infant feeding (Adjusted Odds Ratio [AOR] = 2.16, 95% Confidence Interval [CI] = [1.58, 4.15]) and hospital delivery (AOR = 3.02, 95% CI = [2.67, 7.84]) predicted appropriate infant feeding practice. Conclusion: Appropriate infant feeding practices were significantly associated with prior infant feeding counseling and delivery in a hospital setting. HIV-infected mothers in this setting should receive counseling on infant feeding early in their pregnancy and be educated on the importance of hospital delivery.
Predictors of reversible airway obstruction with omalizumab in severe asthma: a real-life study
Authors: Solidoro Paolo , Patrucco Filippo , de Blasio Francesca , Brussino Luisa , Bellocchia Michela , Dassetto Davide , Pivetta Emanuele , Riccio Annamaria , Heffler Enrico , Canonica Walter , Rolla Giovanni , Bucca Caterina 
Published: April 2019

Background: Omalizumab may modulate airway remodeling in severe asthma. Using forced expiratory volume in 1 second (FEV1) as a surrogate of airway remodeling, we aimed to investigate if an omalizumab add-on in severe allergic asthma may lead to a persistent reversal of airway obstruction and to evaluate the potential biomarkers of airway obstruction reversibility. Methods: Data were collected before (T0) and after omalizumab add-on for 1 year (T1, 32 patients), 2 years (T2, 26 patients) and 4 years (T4, 13 patients). All patients had baseline FEV1 below 80 % predicted (60.5 ± 12.5 %). After omalizumab, 18 patients showed FEV1 normalization (reversible airway obstruction; RAO+) already at T1 (88.7 ± 14.9 %, p < 0.0001) that persisted up to T4 (83.2 ± 7.9, p < 0.01), while 14 patients (RAO−) had FEV1 persistently decreased, from T1 (65.2 ± 8.4%, p < 0.05) up to T4 (61.4 ± 6.2%, not significant). Both groups had significant improvement of symptoms and exacerbations after omalizumab at T1, which persisted up to T4. The comparison between pretreatment characteristics of the two groups showed that RAO+ patients, had higher values of circulating eosinophils, exhaled nitric oxide (FENO), prevalence of rhinitis and nasal polyps, need of oral corticosteroids, shorter asthma duration, higher FEV1 and response to albuterol test. The optimal cut-off points predicting FEV1 normalization after omalizumab add-on were 30.5 ppb for FENO and 305 cells/µl for eosinophils. Conclusions: This study suggests that omalizumab add-on contributes to the persistent reversal of airway obstruction in a consistent number of patients with severe allergic asthma, and this beneficial effect is predicted by elevated pretreatment FENO and circulating eosinophils.
The Safety and Effectiveness of the Percutaneous Flexor Tenotomy in Healing Neuropathic Apical Toe Ulcers in the Outpatient Setting
Authors: Smith Simon E. , Miller Julie 
Published: April 2019

Percutaneous flexor tenotomy is a minimally invasive procedure that involves cutting one or both flexor digitorum tendons underneath the toe. It is an alternative to open surgical procedures performed in an operating theatre. This project is a prospective case series investigating the utility, effectiveness, and participant satisfaction of the percutaneous flexor tenotomy when performed in the outpatient setting. People with diabetes, digital flexion deformity, and loss of protective sensation with an apical ulcer or preulcerative lesion presenting to the Austin Health Foot Ulcer Specialist Outpatient Clinic were enrolled in the study. The procedure was performed under sterile technique with an 18-gauge needle or fine scalpel blade. Participants were reviewed weekly until the incision and/ or ulcer healed. Participants were then followed up at 3 and 6 months. Time to ulcer healing, reulceration rate, frequency of complications, and patient satisfaction were recorded. There were 11 toe ulcers and 41 preulcerative lesions. A total of 76 tenotomy procedures were performed on the 23 participants across 35 episodes of care. The mean time to ulcer healing following tenotomy was 10.2 ± 4.3 days. There were no recurrences of ulceration. The infection rate per episode of care was 2.8%. There were 11 toes (14.5%) that sustained a transfer lesion post the index procedure. The mean time to development of a transfer lesion was 95.5 ± 98.1 days. All participants strongly agreed that they were satisfied with the outcome of the procedure. The flexor tenotomy is an effective procedure to expedite the healing of apical toe ulcers in people with loss of protective sensation and flexion digital deformity. It has a low infection rate and high patient satisfaction rate when performed in the outpatient setting. There is a moderate risk of transfer preulcerative lesions to an adjacent digit. Levels of Evidence: Level IV: Prospective case series
Nonwalking response to fampridine in patients with multiple sclerosis in a real-world setting
Authors: Rodriguez-Leal Francisco Alejandro , Haase Rocco , Akgün Katja , Eisele Judith , Proschmann Undine , Schultheiss Thorsten , Kern Raimar , Ziemssen Tjalf 
Published: April 2019

Objectives: Mobility impairments constitute a long-term burden in patients with multiple sclerosis (MS). Currently there is evidence that the drug fampridine may improve nonwalking symptoms in MS patients. The main objective of this study is to analyze whether participants showing a beneficial walking response to fampridine, also show a positive response in nonwalking assessments in a real-world clinical setting. Methods: Subjects enrolled were part of a study analyzing gait parameters, for which response to treatment with fampridine was monitored after a period of 2 weeks. Neurologists then decided whether patients were responders to fampridine (RF) according to their global impression of patients’ gait improvement. As nonwalking outcomes, we included the nine-hole peg test (9-HPT), the EuroQoL five dimensions questionnaire (EQ-5D) for quality of life, The Würzburger Fatigue Inventory for MS (WEIMuS), the Center for Epidemiologic Studies depression scale (CES-D), and the Paced Auditory Serial Addition Test (PASAT). Minimal clinically important difference (MCID) was evaluated for each test. Results: A total of 189 participants were included: 122 were women (64.55%), with a mean age of 53.55 (±10.83). RFs showed significant improvement in all of the nonwalking outcomes ( p < 0.05), except for a nonsignificant improvement in nondominant upper limb function and PASAT; the largest score improvement was seen in the physical and cognitive sections of the WEIMuS (25.69% and 29.81%, respectively, p < 0.001). Conclusion: We provide evidence that physician’s global judgement of walking improvement is a reliable measure for determining response to fampridine in nonwalking parameters, with fatigue showing the greatest score improvement after 2 weeks.
Vitamin K antagonism impairs the bone marrow microenvironment and hematopoiesis
Authors: Verma Divij , Kumar Rahul , Pereira Raquel S. , Karantanou Christina , Zanetti Costanza , Minciacchi Valentina R. , Fulzele Keertik , Kunz Kathrin , Hoelper Soraya , Zia-Chahabi Sara , Jabagi Marie-Joëlle , Emmerich Joseph , Dray-Spira Rosemary , Kuhlee Franziska , Hackmann Karl , Schroeck Evelin , Wenzel Philip , Müller Stefan , Filmann Natalie , Fontenay Michaela , Pajevic Paola Divieti , Krause Daniela S. 
Published: April 2019

Abstract
Vitamin K antagonists (VKAs) have been used in 1% of the world’s population for prophylaxis or treatment of thromboembolic events for 64 years. Impairment of osteoblast function and osteoporosis has been described in patients receiving VKAs. Given the involvement of cells of the bone marrow microenvironment (BMM), such as mesenchymal stem cells (MSCs) and macrophages, as well as other factors such as the extracellular matrix for the maintenance of normal hematopoietic stem cells (HSCs), we investigated a possible effect of VKAs on hematopoiesis via the BMM. Using various transplantation and in vitro assays, we show here that VKAs alter parameters of bone physiology and reduce functional HSCs 8-fold. We implicate impairment of the functional, secreted, vitamin K-dependent, γ-carboxylated form of periostin by macrophages and, to a lesser extent, MSCs of the BMM and integrin β3-AKT signaling in HSCs as at least partly causative of this effect, with VKAs not being directly toxic to HSCs. In patients, VKA use associates with modestly reduced leukocyte and monocyte counts, albeit within the normal reference range. VKAs decrease human HSC engraftment in immunosuppressed mice. Following published examples that alteration of the BMM can lead to hematological malignancies in mice, we describe, without providing a causal link, that the odds of VKA use are higher in patients with vs without a diagnosis of myelodysplastic syndrome (MDS). These results demonstrate that VKA treatment impairs HSC function via impairment of the BMM and the periostin/integrin β3 axis, possibly associating with increased MDS risk.
Simulating Time-Dependent Patterns of Nonadherence by Patients With Breast Cancer to Adjuvant Oral Endocrine Therapy
Authors: Shinn Eileen H. , Broderick Gordon , Fellman Bryan , Johnson Ainslee , Wieland Elizabeth , Moulder Stacy , Symmans William Fraser 
Published: April 2019

PURPOSE Nearly 40% of patients with breast cancer discontinue their adjuvant oral endocrine treatment (ET). We measured discontinuation rates of ET at a comprehensive cancer center. We then used an iterative approach to model patterns of determinants associated with discontinuation of ET. METHODS Patients with nonmetastatic breast cancer receiving active adjuvant ET were approached by nurse practitioners to complete an anonymous survey at one time point. We simulated a prospective model by iteratively regressing adverse effects onto adherence status across windowed time periods of 2 to 3 consecutive years, bootstrapping the smaller group of nonadherent patients and subsampling the larger adherent group. RESULTS From February to April 2013, 216 participants were enrolled in the study. Forty patients (18.5%) reported that they had discontinued ET during the first 5 years of ET, and an additional four patients (1.9%) missed > 20% of their doses. Using two-sided significance tests, simulations showed that all 13 ET adverse effects and reasons for discontinuation were significantly related to discontinuation at some time point during ET. Worry about ET cost (odds ratio [OR], 1.79), emotional distress (OR, 1.72), and bone and joint pain (OR, 1.69) were the three most impactful reasons for discontinuation, with varying patterns of influence over time. CONCLUSION These analyses provide preliminary evidence that there are varying patterns of discontinuation of ET. Although some reasons for discontinuation exerted a steady influence over the 6-year ET trajectory (ie, bone and joint pain), other reasons, such as cost, cognitive complaints, and general dislike of pills, became more important in the later years of ET.