bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of P63 and its correlation with prognosis in diffuse large B-cell lymphoma: a single center experience
Authors: Hu Wan-Ming , Jin Jie-Tian , Wu Chen-Yan , Lu Jia-Bin , Zhang Li-Hong , Zeng Jing , Lin Su-Xia 
Published: November 2019

Abstract

Background
Large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma among adults. In some cases, DLBCL may seem similar to carcinoma cells, presenting a round, oval, or polygonal shape and clear nuclei. We found that the expression of P63 accounted for a considerable proportion of DLBCL cases. Under the circumstances, P63 expression may lead to a misdiagnosis, especially with a small biopsy. We aim to investigate the expression status and prognostic significance of P63 in a cohort of Chinese DLBCL patients.

Methods
P63, ΔNP63(P40), P53 and Ki67 were detected by immunohistochemistry (IHC). A ROC curve was adopted to find the best cut-off value for positive P63/P53 expression and high Ki67 expression. We defined P53 as positive when ≥50% of the tumor cells showed staining. The relationship between P63 and P53/Ki67 expression was examined. Time-to-event endpoints were estimated according to the Kaplan-Meier method. Moreover, multivariate analyses were conducted to evaluate the prognostic factors in DLBCL.

Results
Out of all the 159 DLBCL cases, 76 (47.8%) expressed P63 in the nuclei, while 41 (25.8%) were determined to have high expression by using a ROC cut-off value “≥6”. Examination of the different P63 isoforms revealed that the ΔNP63(P40) was unclearly and weakly expressed in only 3 cases, showing a fuzzy yellow cytoplasm. P63 expression was not correlated with subtype (GCB or non-GCB) or P53 but was correlated with a high proliferative index (Ki67). Kaplan-Meier analyses revealed that P63 expression was correlated with overall survival, and P63 positive cases showed poor survival outcomes (P<0.05) in our cohort.

Conclusions
ΔNP63(P40) is a useful marker in the differential diagnosis of poorly differentiated squamous cell carcinoma versus DLBCL in small needle biopsy. P63 may be involved in DLBCL tumor progression, and it is an unfavorable prognostic marker in DLBCL. A subgroup of P63 and P53 coexpression DLBCL patients with an extremely poor prognosis should be noted.
Adjuvant versus early salvage radiotherapy: outcome of patients with prostate cancer treated with postoperative radiotherapy after radical prostatectomy
Authors: Vogel Marco M. E. , Kessel Kerstin A. , Schiller Kilian , Devecka Michal , Gschwend Jürgen E. , Weichert Wilko , Wilkens Jan J. , Combs Stephanie E. 
Published: November 2019

AbstractBackgroundAdjuvant (ART) and salvage radiotherapy (SRT) are two common concepts to enhance biochemical relapse free survival (BCRFS) in patients with prostate cancer (PC). We analyzed differences in outcome between ART and SRT in patients with steep decline of PSA-levels after surgery to compare outcome.MethodsWe evaluated 253 patients treated with postoperative RT with a median age of 66 years (range 42–85 years) treated between 2004 and 2014. Patients with additive radiotherapy due to PSA persistence and patients in the SRT group, who did not achieve a postoperative PSA level <0.1 ng/mL were excluded. Hence, data of 179 patients was evaluated. We used propensity score matching to build homogenous groups. A Cox regression model was used to determine differences between treatment options. Median follow-up was 32.5 months (range 1.4–128.0 months).ResultsEarly SRT at PSA levels <0.3 ng/mL was associated with significant longer BCRFS than late SRT (HR: 0.32, 95%-CI: 0.14–0.75,p = 0.009). Multiple Cox regression showed pre-RT PSA level, tumor stage, and Gleason score as predictive factors for biochemical relapse. In the overall group, patients treated with either ART or early SRT showed no significant difference in BCRFS (HR: 0.17, 95%-CI: 0.02–1.44,p = 0.1). In patients with locally advanced PC (pT3/4) BCRFS was similar in both groups as well (HR: 0.21, 95%-CI:0.02–1.79,p = 0.15).ConclusionFor patients with PSA-triggered follow-up, close observation is essential and early initiation of local treatment at low PSA levels (<0.3 ng/mL) is beneficial. Our data suggest, that SRT administered at early PSA rise might be equieffective to postoperative ART in patients with locally advanced PC. However, the individual treatment decision must be based on any adverse risk factors and the patients’ postoperative clinical condition.Study registrationThe present work is approved by the Ethics Commission of the Technical University of Munich (TUM) and is registered with the project number 320/14.
Cervical cancer in Ethiopia – predictors of advanced stage and prolonged time to diagnosis
Authors: Begoihn Matthias , Mathewos Assefa , Aynalem Abreha , Wondemagegnehu Tigeneh , Moelle Ulrike , Gizaw Muluken , Wienke Andreas , Thomssen Christoph , Worku Dawit , Addissie Adamu , Jemal Ahmedin , Kantelhardt Eva Johanna 
Published: November 2019

Abstract

Introduction
In Ethiopia, most cervical cancer patients present at advanced cancer stages, long time after they experience first symptoms. We investigated possible predictors of long time spans between symptom onset and pathologic diagnosis (patient intervals). We also aimed to seek out predictors for advanced cancer stage diagnosis.

Methods
We conducted a retrospective cohort study among 1575 cervical cancer patients who were registered at Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia between September 2008 and September 2012. Cox proportional hazards regression was used to find predictors of long patient intervals. Cumulative odds ordinal logistic regression was used to identify predictors of cancer stage at diagnosis.

Results
Median patient interval was 30 weeks, with the interval substantially longer in patients residing in rural than urban areas. Longer patient intervals were associated with more advanced cancer stages at pathologic diagnosis. HIV-positive women had an almost 1.5 times increased risk of diagnosis at a more advanced stage.

Conclusion
Cervical cancer patients are diagnosed after long time periods leading to advanced stages at diagnosis. Measures to raise awareness about cervical cancer, to increase screening and to shorten the time interval from recognition of symptoms to diagnosis are urgently needed.
Unique N-glycosylation of a recombinant exo-inulinase from Kluyveromyces cicerisporus and its effect on enzymatic activity and thermostability
Authors: Ma Junyan , Li Qian , Tan Haidong , Jiang Hao , Li Kuikui , Zhang Lihua , Shi Quan , Yin Heng 
Published: November 2019

Abstract

Background
Inulinase can hydrolyze polyfructan into high-fructose syrups and fructoligosaccharides, which are widely used in food, the medical industry and the biorefinery of Jerusalem artichoke. In the present study, a recombinant exo-inulinase (rKcINU1), derived from Kluyveromyces cicerisporus CBS4857, was proven as an N-linked glycoprotein, and the removal of N-linked glycan chains led to reduced activity.

Results
Five N-glycosylation sites with variable high mannose-type oligosaccharides (Man3–9GlcNAc2) were confirmed in the rKcINU1. The structural modeling showed that all five glycosylation sites (Asn-362, Asn-370, Asn-399, Asn-467 and Asn-526) were located at the C-terminus β-sandwich domain, which has been proven to be more conducive to the occurrence of glycosylation modification than the N-terminus domain. Single-site N-glycosylation mutants with Asn substituted by Gln were obtained, and the Mut with all five N-glycosylation sites removed was constructed, which resulted in the loss of all enzyme activity. Interestingly, the N362Q led to an 18% increase in the specific activity against inulin, while a significant decrease in thermostability (2.91 °C decrease in Tm) occurred, and other single mutations resulted in the decrease in the specific activity to various extents, among which N467Q demonstrated the lowest enzyme activity.

Conclusion
The increased enzyme activity in N362Q, combined with thermostability testing, 3D modeling, kinetics data and secondary structure analysis, implied that the N-linked glycan chains at the Asn-362 position functioned negatively, mainly as a type of steric hindrance toward its adjacent N-glycans to bring rigidity. Meanwhile, the N-glycosylation at the other four sites positively regulated enzyme activity caused by altered substrate affinity by means of fine-tuning the β-sandwich domain configuration. This may have facilitated the capture and transfer of substrates to the enzyme active cavity, in a manner quite similar to that of carbohydrate binding modules (CBMs), i.e. the chains endowed the β-sandwich domain with the functions of CBM. This study discovered a unique C-terminal sequence which is more favorable to glycosylation, thereby casting a novel view for glycoengineering of enzymes from fungi via redesigning the amino acid sequence at the C-terminal domain, so as to optimize the enzymatic properties.
Phosphorylation sites of microtubule-associated protein 1B (MAP 1B) are involved in axon growth and regeneration
Authors: Ishikawa Yuya , Okada Masayasu , Honda Atsuko , Ito Yasuyuki , Tamada Atsushi , Endo Naoto , Igarashi Michihiro 
Published: November 2019

AbstractThe growth cone is a specialized structure that forms at the tip of extending axons in developing and regenerating neurons. This structure is essential for accurate synaptogenesis at developmental stages, and is also involved in plasticity-dependent synaptogenesis and axon regeneration in the mature brain. Thus, understanding the molecular mechanisms utilized by growth cones is indispensable to understanding neuronal network formation and rearrangement. Phosphorylation is the most important and commonly utilized protein modification in signal transduction. We previously identified microtubule-associated protein 1B (MAP 1B) as the most frequently phosphorylated protein among ~ 1200 phosphorylated proteins. MAP 1B has more than 10 phosphorylation sites that were present more than 50 times among these 1200 proteins. Here, we produced phospho-specific antibodies against phosphorylated serines at positions 25 and 1201 of MAP 1B that specifically recognize growing axons both in cultured neurons and in vivo in various regions of the embryonic brain. Following sciatic nerve injury, immunoreactivity with each antibody increased compared to the sham operated group. Experiments with transected and sutured nerves revealed that regenerating axons were specifically recognized by these antibodies. These results suggest that these MAP 1B phosphorylation sites are specifically involved in axon growth and that phospho-specific antibodies against MAP 1B are useful markers of growing/regenerating axons.
Early lactate measurement is associated with better outcomes in septic patients with an elevated serum lactate level
Authors: Chen Hui , Zhao Chenyan , Wei Yao , Jin Jun 
Published: November 2019

Abstract

Background
The optimal timing of lactate measurement for septic patients in the intensive care unit (ICU) remains controversial, and whether initiating and repeating the lactate measurement earlier could make a difference for septic patients with an elevated lactate level remains unexplored.

Methods
This was a retrospective observational study that included septic patients with an initial lactate level > 2.0 mmol/L after ICU admission, and all data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The main exposure of interest was the early lactate measurement, which was defined as an initial lactate level measurement within 1 h after ICU admission. The primary outcome was 28-day mortality.

Results
A total of 2642 eligible subjects were enrolled, including 738 patients who had initial lactate measurements completed within 1 h (EL group) and 1904 patients who had initial lactate measurements completed more than 1 h after ICU admission (LL group). A significant beneficial effect of early lactate measurement in terms of 28-day mortality was observed: the adjusted odds ratio (OR) was 0.69 (95% CI 0.55–0.87; p = 0.001), and the mediation effect of the time to initial vasopressor administration was significant (average causal mediation effect (ACME) − 0.018; 95% CI − 0.005 approximately to − 0.036; p < 0.001). A strong relationship between delayed initial lactate measurement and risk-adjusted 28-day mortality was noted (OR 1.04; 95% CI 1.02–1.05; p < 0.001). Each hour of delay in remeasuring the lactate level was associated with an increase in 28-day mortality in the EL group (OR 1.09; 95% CI 1.04–1.15; p < 0.001). Further analysis demonstrated that repeating the measurement 3 h after the initial lactate measurement led to a significant difference.

Conclusions
Early lactate measurement is associated with a lower risk-adjusted 28-day mortality rate in septic patients with lactate levels > 2.0 mmol/L. A shorter time to the initial vasopressor administration may contribute to this relationship. Repeating the lactate measurement within 3 h after the initial measurement is appropriate for patients whose lactate levels were measured within 1 h of admission.
Non-real eigenvalues of nonlocal indefinite Sturm–Liouville problems
Authors: Sun Fu , Li Kun , Qi Jiangang , Liao Baochao 
Published: November 2019

Abstract
The present paper deals with non-real eigenvalues of regular nonlocal indefinite Sturm–Liouville problems. The existence of non-real eigenvalues of indefinite Sturm–Liouville differential equation with nonlocal potential $K(x,t)$K(x,t) associated with self-adjoint boundary conditions is studied. Furthermore, a priori upper bounds of non-real eigenvalues for a class of indefinite differential equation involving nonlocal point interference potential function is obtained.
Patient participation in research funding: an overview of when, why and how amongst Dutch health funds
Authors: den Oudendammer Willemijn M. , Noordhoek Jacquelien , Abma-Schouten Rebecca Y. , van Houtum Lieke , Broerse Jacqueline E. W. , Dedding Christine W. M. 
Published: November 2019

Abstract

Background
Patient participation in decision-making on health-related research has gained ground. Nineteen Dutch health-related research-funding organisations (HFs) have taken up the challenge to include patients in their funding process. A ‘Patient participation (PP) advisory team’ was set-up, with HF-representatives and patient advocates, who together initiated this study. We provide an overview of when, why, and how PP activities take place in HFs’ funding processes, share main challenges and identify possible solutions.

Methods
A qualitative research design was used. Data was gathered by questionnaires (n = 14) and semi-structured interviews (n = 18) with HF employees responsible for patient participation, followed by a workshop (n = 27) with involved employees of HFs and key players in PP from national patient organisations and research organisations. A descriptive analysis was used for the questionnaire. A semi-directed content analysis was used for the interviews and the workshop.

Results
Three stages can be identified in the funding process in which HFs carry out PP activities: (1) strategic decision-making about focus of research (e.g. shared research agendas); (2) call for and receipt of research proposals (e.g. mandatory inclusion of letter of recommendation from patient organisation); (3) decision-making about the funding of research proposals (e.g. patients reside in a patient panel to co-review research proposals). Main challenges identified to carry out PP activities include: how to accommodate diversity of the patient body (mainly encountered in stage 1 and 3); to what extent should patients receive training to successfully participate (mainly encountered in stage 1 and 3); and who is responsible for patient-researcher dialogues (mainly encountered in stage 1 and 2). All nineteen HFs agree that patients should be included in at least one stage of the funding process for health-related research. CONCLUSION: Further broadening and optimising patient involvement is still needed. The proposed solutions to the identified challenges could serve as inspiration for national and international research funding foundations that aim to structurally include patients in their funding process.
Beyond ethical approval: fostering ethical research practices within inter-sectoral research projects involving academic and NGO sector partners
Authors: McDermott Ronan , Gibbons Pat , Mpanje Desire , McGrath Sinéad , Markey Anne , Ferrandez Pablo Cortés , Haryati Dini , Azizah Nur 
Published: November 2019

Abstract
While research and innovation collaborations between NGOs and academic organisations can create considerable synergies with positive effects for the humanitarian sector, the inter-sectoral nature of such collaborations can generate challenges due to the varying mandates, objectives and ways of working of the organisations involved. By drawing on the experiences of a 4-year project involving a consortium of academic and NGO partners, this paper outlines three broad and inter-related ethical challenges that such projects can encounter and how they can be practically negotiated. Firstly, how are the knowledge-generation requirements of such projects addressed without engaging in the mere extraction of data from participants? Secondly, how are potential risks to participants arising from their participation balanced with the need to include their voices within the research project? Finally, how are the formal requirements laid down by institutional review committees, primarily within academic organisations, to be adhered to within field contexts in which there are well-established expectations and ways of working on the part of NGO partners and beneficiaries? While these dilemmas are merely illustrative of the potential ethical dilemmas that inter-sectoral collaboration might encounter, the paper highlights that ethical dilemmas ought to be addressed reflexively by all stakeholders in order to facilitate improved collaboration and, ultimately, better quality, more relevant and more ethically informed research.
Roads less traveled: understanding the “why” in simulation as an integrated continuing professional development activity
Authors: Tavares Walter 
Published: November 2019

Abstract

Background
The simulation community has experienced significant advances, strengthening the case for the use of simulation in medical education toward improving patient outcomes. However, an underlying assumption particularly regarding utilization of simulation by those who are in practice, is that simulation will be selected as a continuing professional development (CPD) strategy. Exploring reasons for choices of educational formats, particularly regarding simulation, is poorly integrated into CPD research.

Discussion
Despite significant advances the scientific simulation community has been slow to produce evidence regarding why practitioners may be reserved in engaging in simulation or not. Using examples from related education contexts the author attempts to bridge simulation science, CPD and less commonly used theoretical frameworks to address this issue. The author argues that theoretical perspectives that recognize the use of simulation for CPD as a socio-personal process and/or a personal or group issue (e.g., theories of intelligence, self-determination theory, theory of planned behavior, social identity theory) and that are conceptually distinct from educational mechanisms/ provision are necessary to advance simulation use in CPD contexts.

Conclusion
Given the close relationship practicing clinicians have to patient outcomes a new imperative may be to focus on the theoretical and practical links informing simulation use for CPD at the level of the individual and individual-among-professional groups. The simulation community may therefore need to engage in research that attempts to further uncover and address underlying issues of “why” clinicians integrate simulation as CPD activities or not.
Australian state influenza notifications and school closures in 2019
Authors: Scott Anna Mae , Bakhit Mina , Clark Justin , Vermeulen Melanie , Jones Mark , Looke David , Del Mar Chris , Glasziou Paul 
Published: November 2019

Background: The impact of school holidays on influenza rates has been sparsely documented in Australia. In 2019, the early winter influenza season coincided with mid-year school breaks, enabling us the unusual opportunity to examine how influenza incidence changed during school closure dates. Methods: The weekly influenza data from five Australian state and one territory health departments for the period of week 19 (mid-May) to week 35 (early September) 2019 were compared to each state’s public school closure dates. We used segmented regression to model the weekly counts and a negative binomial distribution to account for overdispersion due to autocorrelation. The models’ goodness-of-fit was assessed by plots of observed versus expected counts, plots of residuals versus predicted values, and Pearson’s Chi-square test. The main exposure was the July two-week school vacation period, using a lag of one week. The effect is estimated as a percent change in incidence level, and in slope. We also dichotomized the change in weekly counts into decreases versus increases (or no change). The proportion of decreases were then compared for each of three periods (pre-vacation, vacation, post-vacation) using Fishers exact test. Results: School holidays were associated with significant declines in influenza incidence. The models showed acceptable goodness-of-fit. The numbers and percentages of decreases in weekly influenza counts from the previous week for all states combined were: 19 (33%) pre-vacation; 11 (92%) decreases during the vacation; and 19 (59%) decreases post-vacation (P=0.0002). The first decline during school holidays is seen in the school aged (5-19 years) population, with the declines in the adult and infant populations being smaller and following a week later. Conclusions: Given the significant and rapid reductions in incidence, these results have important public health implications. Closure or extension of holiday periods could be an emergency option for state governments.
That Could Have Been Me: Director Deaths, CEO Mortality Salience, and Corporate Prosocial Behavior
Authors: Chen Guoli , Crossland Craig , Huang Sterling 
Published: November 2019

Mortality salience—the awareness of the inevitability of death—is often traumatic. However, it can also be associated with a range of positive, self-transcendent cognitive responses, such as a greater desire to help others, contribute to society, and make a more meaningful contribution in one’s life and career. In this study, we provide evidence of a link between chief executive officer (CEO) mortality salience—triggered by the death of a director at the same firm—and a subsequent increase in firm-level prosocial behavior or corporate social responsibility (CSR). We further show that this core relationship is amplified in situations where the death of the director is likely to have been especially salient (i.e., the director was appointed within the CEO’s tenure, or the death was sudden/expected). In supplementary analyses, we find suggestive evidence of increased CEO prosociality in other professional domains as well as evidence that prosociality seems to be preferentially directed toward ingroups. This paper was accepted by Olav Sorenson, organizations.