bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Chemo-enzymatically Linked Bispecific Antibody Retargets T Cells to a Sialylated Epitope on CD43 in Acute Myeloid Leukemia
Authors: Bartels Lina , de Jong Greta , Gillissen Marijn A. , Yasuda Etsuko , Kattler Veronika , Bru Camille , Fatmawati Christien , van Hal-van Veen Susan E. , Cercel Madalina G. , Moiset Gemma , Bakker Arjen Q. , van Helden Pauline M. , Villaudy Julien , Hazenberg Mette D. , Spits Hergen , Wagner Koen 
Published: May 2019

Abstract

Acute myeloid leukemia (AML) is a high-risk disease with a poor prognosis, particularly in elderly patients. Because current AML treatment relies primarily on untargeted therapies with severe side effects that limit patient eligibility, identification of novel therapeutic AML targets is highly desired. We recently described AT1413, an antibody produced by donor B cells of a patient with AML cured after allogeneic hematopoietic stem cell transplantation. AT1413 binds CD43s, a unique sialylated epitope on CD43, which is weakly expressed on normal myeloid cells and overexpressed on AML cells. Because of its selectivity for AML cells, we considered CD43s as a target for a bispecific T-cell–engaging antibody (bTCE) and generated a bTCE by coupling AT1413 to two T-cell–targeting fragments using chemo-enzymatic linkage. In vitro, AT1413 bTCE efficiently induced T-cell–mediated cytotoxicity toward different AML cell lines and patient-derived AML blasts, whereas endothelial cells with low binding capacity for AT1413 remained unaffected. In the presence of AML cells, AT1413 bTCE induced upregulation of T-cell activation markers, cytokine release, and T-cell proliferation. AT1413 bTCE was also effective in vivo. Mice either coinjected with human peripheral blood mononuclear cells or engrafted with human hematopoietic stem cells [human immune system (HIS) mice] were inoculated with an AML cell line or patient-derived primary AML blasts. AT1413 bTCE treatment strongly inhibited tumor growth and, in HIS mice, had minimal effects on normal human hematopoietic cells. Taken together, our results indicate that CD43s is a promising target for T-cell–engaging antibodies and that AT1413 holds therapeutic potential in a bTCE-format.

Significance:
These findings offer preclinical evidence for the therapeutic potential of a bTCE antibody that targets a sialylated epitope on CD43 in AML.
Upregulation of Scavenger Receptor B1 Is Required for Steroidogenic and Nonsteroidogenic Cholesterol Metabolism in Prostate Cancer
Authors: Gordon Jacob A. , Noble Jake W. , Midha Ankur , Derakhshan Fatemeh , Wang Gang , Adomat Hans H. , Tomlinson Guns Emma S. , Lin Yen-Yi , Ren Shancheng , Collins Collin C. , Nelson Peter S. , Morrissey Colm , Wasan Kishor M. , Cox Michael E. 
Published: May 2019

Abstract

Aberrant cholesterol metabolism is increasingly appreciated to be essential for prostate cancer initiation and progression. Transcript expression of the high-density lipoprotein-cholesterol receptor scavenger receptor B1 (SR-B1) is elevated in primary prostate cancer. Hypothesizing that SR-B1 expression may help facilitate malignant transformation, we document increased SR-B1 protein and transcript expression in prostate cancer relative to normal prostate epithelium that persists in lethal castration-resistant prostate cancer (CRPC) metastasis. As intratumoral steroid synthesis from the precursor cholesterol can drive androgen receptor (AR) pathway activity in CRPC, we screened androgenic benign and cancer cell lines for sensitivity to SR-B1 antagonism. Benign cells were insensitive to SR-B1 antagonism, and cancer line sensitivity inversely correlated with expression levels of full-length and splice variant AR. In androgen-responsive CRPC cell model C4-2, SR-B1 antagonism suppressed cholesterol uptake, de novo steroidogenesis, and AR activity. SR-B1 antagonism also suppressed growth and viability and induced endoplasmic reticulum stress and autophagy. The inability of exogenous steroids to reverse these effects indicates that AR pathway activation is insufficient to overcome cytotoxic stress caused by a decrease in the availability of cholesterol. Furthermore, SR-B1 antagonism decreased cholesterol uptake, growth, and viability of the AR-null CRPC cell model PC-3, and the small-molecule SR-B1 antagonist block lipid transport-1 decreased xenograft growth rate despite poor pharmacologic properties. Overall, our findings show that SR-B1 is upregulated in primary and castration-resistant disease and is essential for cholesterol uptake needed to drive both steroidogenic and nonsteroidogenic biogenic pathways, thus implicating SR-B1 as a novel and potentially actionable target in CRPC.

Significance:
These findings highlight SR-B1 as a potential target in primary and castration-resistant prostate cancer that is essential for cholesterol uptake needed to drive steroidogenic and nonsteroidogenic biogenic pathways.
Financial Hardship and Quality of Life among African American and White Cancer Survivors: The Role of Limiting Care Due to Cost
Authors: Hastert Theresa A. , Kyko Jaclyn M. , Reed Amanda R. , Harper Felicity W.K. , Beebe-Dimmer Jennifer L. , Baird Tara E. , Schwartz Ann G. 
Published: May 2019

Abstract

Background:
Financial hardship is common among cancer survivors and is associated with both limiting care due to cost and with poor health-related quality of life (HRQOL). This study estimates the association between limiting care due to cost and HRQOL in a diverse population of cancer survivors and tests whether limiting care mediates the association between financial hardship and HRQOL.

Methods:
We used data from 988 participants (579 African American, 409 white) in the Detroit Research on Cancer Survivors (ROCS) pilot, a hospital-based cohort of breast, colorectal, lung, and prostate cancer survivors. We assessed associations between financial hardship, limiting care, and HRQOL [measured by the Functional Assessment of Cancer Therapy—General (FACT-G)] using linear regression and mediation analysis controlling for demographic, socioeconomic, and cancer-related variables.

Results:
FACT-G scores were 4.2 [95% confidence interval (CI), 2.0–6.4] points lower among survivors who reported financial hardship compared with those who did not in adjusted models. Limiting care due to cost was associated with a −7.8 (95% CI, −5.1 to −10.5) point difference in FACT-G scores. Limiting care due to cost explained 40.5% (95% CI, 25.5%–92.7%) of the association between financial hardship and HRQOL overall, and 50.5% (95% CI, 29.1%–188.1%) of the association for African American survivors.

Conclusions:
Financial hardship and limiting care due to cost are both associated with lower HRQOL among diverse cancer survivors, and this association is partially explained by limiting care due to cost.

Impact:
Actions to ensure patients with cancer can access appropriate care could lessen the impact of financial hardship on HRQOL.
Aurora Kinase A Inhibition Provides Clinical Benefit, Normalizes Megakaryocytes, and Reduces Bone Marrow Fibrosis in Patients with Myelofibrosis: A Phase I Trial
Authors: Gangat Naseema , Marinaccio Christian , Swords Ronan , Watts Justin M. , Gurbuxani Sandeep , Rademaker Alfred , Fought Angela J. , Frankfurt Olga , Altman Jessica K. , Wen Qiang Jeremy , Farnoud Noushin , Famulare Christopher A. , Patel Akshar , Tapia Roberto , Vallapureddy Rangit R. , Barath Stephanie , Graf Amy , Handlogten Amy , Zblewski Darci , Patnaik Mrinal M. , Al-kali Aref , Dinh Yvonne Trang , Englund Prahl Kristen , Patel Shradha , Nobrega Juan Carlos , Tejera Dalissa , Thomassen Amber , Gao Juehua , Ji Peng , Rampal Raajit K. , Giles Francis J. , Tefferi Ayalew , Stein Brady , Crispino John D. 
Published: May 2019

Abstract

Purpose:
Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis.

Patients and Methods:
Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis.

Results:
In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients.

Conclusions:
Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis.
See related commentary by Piszczatowski and Steidl, p. 4868
Electronic Neurostatus-EDSS increases the quality of expanded disability status scale assessments: Experience from two phase 3 clinical trials
Authors: D’Souza Marcus , Heikkilä Antti , Lorscheider Johannes , Haller Vanessa , Kravalis Kristina , Gysin Shauna , Fuertes Nuria Alicia Cerdá , Fricker Evy , Lam Elaine , Higgins Peter , Tomic Davorka , Papadopoulou Athina , Kappos Ludwig 
Published: May 2019

Background: The Neurostatus-eEDSS is an electronic tool providing automated real-time feedback on inconsistencies of Neurostatus-EDSS calculations. Objective: To analyze the performance of the Neurostatus-eEDSS in two multicenter phase 3 multiple sclerosis (MS) trials. Methods: All assessments captured with the Neurostatus-eEDSS web service during a period of 2.5 years were analyzed. Results: Of the total 10,789 assessments, 40.1% had inconsistencies after first entry, reduced to 22.1% due to the real-time feedback. The entire checking process resulted in a change of the expanded disability status scale (EDSS) score in 14.8% of the assessments. Conclusion: The Neurostatus-eEDSS can increase consistency and reliability of EDSS assessments in clinical MS trials.
Comparison of side-to-end vs. side-to-side proximal arteriovenous fistula anastomosis in chronic renal failure patients
Authors: Mestres Gaspar , Gonzalo Begoña , Mateos Eduardo , Yugueros Xavier , Martínez-Rico Carlos , Marcos Lidia , Blanco Carla 
Published: May 2019

Introduction Anastomotic creation of autogenous arteriovenous fistulas can be performed in different ways, side-to-end or side-to-side. However, there is a paucity of evidence to recommend them. The aim of this study is to compare both anastomosis types in elbow arteriovenous fistulas. Material and methods A prospective observational national multicenter study (ISRCTN62033470) was designed, including patients receiving a native arteriovenous fistula in the elbow using side-to-end or side-to-side anastomosis, between September, 2016 and September, 2017, with six-month postoperative follow-up period. Patient characteristics, surgical details, and follow-up data (primary, assisted primary and secondary patency, maturation, functionality, complications) were recorded and compared between both anastomosis groups using Kaplan–Meier curves estimations, at one and six-month follow-up, and finally a multivariate analysis with Cox regression was performed. Results Three centers participated in the study, including 133 cases (96 side-to-end, 37 side-to-side). The cephalic vein was more often used for side-to-end (58.3%) and basilic for side-to-side (78.4%; P < 0.001). Side-to-end anastomoses were faster to create (65.1–75.1 min; P = 0.009). During follow-up, 23 cases were lost (transplanted, dead, ligated, or lost), with no differences at one month. At six months, primary patency was better for the side-to-end group (78.5 − 55.9%; P = 0.038), but it was not confirmed as an independent predictor in the multivariate analysis. Furthermore, no significant differences in assisted primary or secondary patency, maturation or functionality were seen. Patients with side-to-side anastomosis more often required vein superficialization (2.1–16.2%; P = 0.002) and presented more frequent puncture hematomas (4.9–30.0%; P = 0.015). Conclusions Anastomosis type was not significantly related to different outcomes in the follow-up. Even though side-to-end anastomosis showed better primary patency at six months with lower need of vein superficialization and fewer puncture hematomas during follow-up, it was not confirmed as an independent predictor in the multivariate analysis, and similar assisted primary and secondary patency, maturation, and functionality rates have been seen after arteriovenous fistula creation.
Hyperfiltration predicts long-term renal outcomes in humanized sickle cell mice
Authors: Kasztan Malgorzata , Fox Brandon M. , Lebensburger Jeffrey D. , Hyndman Kelly A. , Speed Joshua S. , Pollock Jennifer S. , Pollock David M. 
Published: May 2019

Key PointsIn HbSS mice, hyperfiltration predicts long-term kidney damage and tubular injury occurs prior to glomerular damage. Sex contributes to the progression of kidney injury in HbSS mice.
Cell adhesion molecule expression in the dorsolateral prefrontal cortex and anterior cingulate cortex in major depression in the elderly
Authors: Thomas Alan J. , Ferrier I. Nicol , Kalaria Rajesh N. , Davis Sue , O'Brien John T. 
Published: May 2019

BackgroundNeuroimaging studies have demonstrated changes in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in major depression.AimsWe investigated the expression of cell adhesion molecules (CAMs) in the prefrontal cortex in depression.MethodImmunohistochemistry to localise CAMs in post-mortem tissue from 20 subjects with major depression and 20 controls, and image analysis to quantify their expression.ResultsWe found significant increases in CAMs in the grey matter ofthe DLPFC in the depression group but no comparable differences in the ACC or occipital cortex. In the white matter there was a non-significant increase in intercellular adhesion molecule-1 in the DLPFC in the depression group but no increase in the other areas or for vascular cell adhesion molecule-1 in any area. Paired tests showed specificity for the DLPFC in the depression group only.ConclusionsTheincreasein CAM expression in the DLPFC suggests an inflammatory reaction and is consistent with ischaemia.
Effects on the brain of a psychological treatment: Cognitive remediation therapy
Authors: Wykes Til , Brammer Michael , Mellers John , Bray Peter , Reeder Clare , Williams Clare , Corner Julia 
Published: May 2019

BackgroundThe results of one randomised control trial testing a psychological rehabilitation programme aimed at information processing strategies showed improvements in cognition post-treatment.AimsTo determine whether there are concomitant brain activation changes as a result of engaging in cognitive remediation therapy (CRT).MethodThree groups (patients receiving control therapyor CRT and a healthy control group) were investigated in a repeated measures design using the two-back test. Functional magnetic resonance imaging (fMRI) data and a broad assessment of executive functioning were completed at baseline and post-treatment. Brain activation changes were identified after accounting for possible task-correlated motion artefact.ResultsfMRI analyses indicate that the control group showed decreased activation butthetwo patient groups showed an increase in activation over time. The patient group that received successful CRT had significantly increased brain activation in regions associated with working memory particularly the frontocortical areas.ConclusionsThis isthefirsttimethat brain activation changes in a seriously disabled group of patients with schizophrenia can be associated clearly with psychological rather than pharmacological therapy.
The effect of perioperative blood transfusion on kidney functions in total knee Arthroplasty
Authors: Sen Baran , OZMANEVRA Ramadan 
Published: May 2019

Objective: Various studies have examined the effects of perioperative blood transfusion on kidney functions. In this study, we investigated the effects of blood transfusion on the kidney functions of patients undergoing total knee arthroplasty.
Methods: This retrospective study was carried out on 216 patients who had undergone total knee arthroplasty between January 2016 and January 2017. The patients were divided into two groups according to the level of blood transfusion used during surgery. Group-1 comprised 157 patients (72.7%) needing a blood transfusion of less than three units, while the 59 (27.3) patients in Group-2 required three or more than three units.
Results: No statistical difference was found between the two groups regarding hypertension before surgery, diabetes mellitus, chronic kidney failure, smoking habits or lung disease (p> 0.05). Likewise, there was no significant difference related to pulmonary and other complications or mortality (p> 0.05). When the groups were compared according to their blood parameters, no statistical differences in postoperative renal or other system functions were found (p> 0.05).
Conclusions: Blood transfusion does not have a negative effect on postoperative blood urea nitrogen (BUN) and creatinine levels, or glomerular filtration rate in total knee arthroplasty.
doi: https://doi.org/10.12669/pjms.35.3.259
How to cite this:Sen B, Ozmanevra R. The effect of perioperative blood transfusion on kidney functions in total knee Arthroplasty. Pak J Med Sci. 2019;35(3):663-667. doi: https://doi.org/10.12669/pjms.35.3.259
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ametropia in children with headache
Authors: Mehboob Mohammad Asim , Nisar Haider , Khan Memoona 
Published: May 2019

Objective: To measure the frequency of uncorrected ametropia in children with 2 to 8 weeks of persistent headache referred to ophthalmic outpatient department for evaluation.
Methods: This cross sectional study was conducted at CMH Gujranwala from March 2018 to November 2018.A total of 262 children, aged from 5 to 16 years, with 2 to 8 weeks history of persistent headache underwent detailed ophthalmic assessment for refractive errors, and other ophthalmic evaluation. Children with ametropia, confirmed with cycloplegic refraction and post-mydriatic testing were prescribed with glasses. Patients without any ophthalmic findings were referred back to pediatrics department for further evaluation.
Results: Mean age of study population was 8.97 ± 3.16 years. Mean duration of headache was 5.03 ± 1.81 weeks. Ametropia was found in 56 (21.4%) children, while 206 (78.6%) had no refractive error. Out of children with ametropia, 20 (35.7%) had myopia, 24 (42.8%) had astigmatism and 12 (21.5%) had hypermetropia. There was no difference in ametropic children and children without ametropia with respect to gender (p=0.73), age (p=0.54) and duration of headache (p=0.71).
Conclusion: A significant proportion of children with ametropia have initial symptoms of headache. Any child with un-explained headache must undergo ophthalmic evaluation to diagnose refractive error, if any.
doi: https://doi.org/10.12669/pjms.35.3.268
How to cite this:Mehboob MA, Nisar H, Khan M. Ametropia in children with headache. Pak J Med Sci. 2019;35(3):701-704. doi: https://doi.org/10.12669/pjms.35.3.268
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Reorientações éticas da política social: do primado do ethos solidário ao império da moral individualista possessiva | Ethical reorientations of social policy: from the primacy of the solidarity ethos to the empire of possessive individualistic morals
Authors: Pereira Potyara Amazoneida P. 
Published: May 2019

Este texto privilegia as mudanças dos fundamentos éticos solidários da política social, tendo como pedra de toque o aforismo burguês de que o trabalho assalariado é a melhor fonte de bem-estar. Tem, como cenário, tanto países capitalistas centrais quanto periféricos, particularmente o Brasil. Discute a prevalência contemporânea de moralidades que privilegiam a autorresponsabilização dos indivíduos pela sua segurança social, sob a égide de um sistema caracterizado pela junção de forças neoliberais e neoconservadoras, denominado “Nova Direita”, que renega a democracia.Palavras-Chave: política social; democracia; trabalho; moral burguesa; autorresponsabilização. Abstract – This text highlights the changes of social policy’s ethical foundations of solidarity, having as touchstone the bourgeois aphorism that salaried work is the best form of welfare. It has as its scenario both central and peripheral capitalist countries, particularly Brazil. It discusses the contemporary prevalence of moralities that privilege the individuals’ self-responsibilization for their own social security, under the auspices of a system characterized by the combination of neoliberal and neoconservatives forces called “New Right,” which rejects democracy.Keywords: social policy; democracy; work; bourgeois morality; self-responsibilization.