bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia
Authors: Walker Janek S. , Hing Zachary A. , Harrington Bonnie , Baumhardt Jordan , Ozer Hatice Gulcin , Lehman Amy , Giacopelli Brian , Beaver Larry , Williams Katie , Skinner Jordan N. , Cempre Casey B. , Sun Qingxiang , Shacham Sharon , Stromberg Benjamin R. , Summers Matthew K. , Abruzzo Lynne V. , Rassenti Laura , Kipps Thomas J. , Parikh Sameer , Kay Neil E. , Rogers Kerry A. , Woyach Jennifer A. , Coppola Vincenzo , Chook Yuh Min , Oakes Christopher , Byrd John C. , Lapalombella Rosa 
Published: January 2021

AbstractBackgroundExportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somaticXPO1point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-functionXPO1mutations in CLL is not fully understood.MethodsWe performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations inXPO1(predominantly E571K or E571G;n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G)XPO1restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor).ResultsWe report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutantXPO1could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression ofXPO1with E571K or E571G mutations andTCL1accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected byXPO1mutations at E571 in patients with CLL.ConclusionsThese findings indicate that mutations inXPO1at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.
The risks of physicians’ conformism: reflections from the opioid overflow
Authors: Cortellazzo Wiel Luisa , Cozzi Giorgio , Barbi Egidio 
Published: January 2021

AbstractOpioid-related mortality in adolescents is spreading in the US, with prescription opioids playing a crucial role in the development of addiction. We traced back to the process leading to the so called “opioid overflow”, trying to identify any modifiable attitude.Since the late 1990s, pain was labelled as the “fifth vital sign” and its proper management was prompted, encouraging the use of opioids for any pain scored at a Numerical Rating Scale (NRS) of 7 or higher. This assumption has some remarkable limitations. NRS is a proxy of pain severity in children, and pain measurement should be strengthened by a more comprehensive pain evaluation. Moreover, while remaining a fundamental therapeutic right of patients suffering postoperative or chronic severe pain, opioids show no evidence of superiority respect to non-opioid regimens in the management of pain from several acute conditions.Italy, as other European countries, is often reluctant to the use of opioids, even when highly recommendable, missing the opportunity of properly treating those selected patients with severe pain. Both attitudes can be viewed as the result of an extreme simplification of the complex process of pain evaluation and treatment, by means of a ‘one-size-fits-all’ approach.This highlights the need for a systematic and patient-tailored attitude to children in pain, avoiding applying guidelines without question. Good clinical practice must rely on guidelines, which, however, as often based on partial and insufficient data, can be questioned by emerging new evidence, and should not substitute our rational thinking, and capability to understand each patient, avoiding excessive conformism.
A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer
Authors: Schmid Peter , Sablin Marie-Paule , Bergh Jonas , Im Seock-Ah , Lu Yen-Shen , Martínez Noelia , Neven Patrick , Lee Keun Seok , Morales Serafín , Pérez-Fidalgo J. Alejandro , Adamson Douglas , Gonçalves Anthony , Prat Aleix , Jerusalem Guy , Schlieker Laura , Espadero Rosa-Maria , Bogenrieder Thomas , Huang Dennis Chin-Lun , Crown John , Cortés Javier 
Published: January 2021

Abstract
Background
Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC).

Methods
Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS).

Results
MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3–not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7–9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57–1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05–0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]).

Conclusions
Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136).

Trial registration
ClinicalTrials.gov, NCT02123823. Prospectively registered, 8 March 2013.
Using inquiry-based writing instruction to develop students’ academic writing skills
Authors: Wale Bantalem Derseh , Bogale Yenus Nurie 
Published: January 2021

AbstractThe aim of this study was to investigate the effects of using inquiry-based writing instruction on students’ academic writing skills. A pretest-posttest two groups quasi-experimental design was employed. Data were obtained through test, focus group discussion, and reflective journal from 62 first-year pharmacy students who were selected using comprehensive sampling. While the experimental group received the inquiry-based writing instruction, the control group learned using the conventional learning method. The quantitative data were analyzed using independent samples T-test and descriptive statistics when the qualitative data were analyzed thematically. The findings revealed that there was a statistical difference between the control and experimental groups in their academic writing performance. Hence, students who participated in the inquiry-based writing instruction improved their academic writing skills. Mainly, students who learned through inquiry-based writing instruction were able to produce essays that addressed task achievement, coherence and cohesion, lexical resource, grammatical range and accuracy. Thus, this study recommends researchers, teachers, and students to pay due attention to inquiry-based writing instruction in their academic journey.
Multifocal glioblastoma—two case reports and literature review
Authors: Zhang Zuo-Xin , Chen Ju-Xiang , Shi Bao-Zhong , Li Guang-Hui , Li Yao , Xiang Yan , Qin Xun , Yang Lin , Lv Sheng-Qing 
Published: January 2021

Abstract
Background
Multifocal glioblastoma is a rare type of glioblastoma with worse prognosis. In this article, we aimed to report two cases of classical multifocal glioblastoma.

Case presentation
In case 1, a 47-year-old male presented with dizziness, and once had a sudden loss of consciousness accompanied by convulsion of limbs. Contrast-enhanced MRI showed multiple lesions with heterogeneously ring-enhanced characters in the left hemisphere, diagnosed as multifocal glioblastoma. He underwent a craniotomy of all lesions, concurrent radiotherapy and chemotherapy as well as additional chemotherapy of temozolomide. After 2 cycles, repeat MRI showed that the new lesions already occurred and progressed. Eventually, he abandoned the chemotherapy after the 2 cycles and died 1 year later. In case 2, a 71-year-old male presented with a history of headache, left limb weakness, and numbness. Discontinuous convulsion of limbs once occurred. Contrast-enhanced MRI showed multiple lesions located in the right hemisphere, diagnosed as multifocal glioblastoma. He underwent a right frontoparietal craniotomy of the main lesion. Hemorrhage of the residual tumor and pulmonary artery embolism occurred synchronously. Eventually, his family decided not to pursue any further treatment and opted for hospice care and he passed away within 11 days of surgery.

Conclusions
We reported two cases of typical multifocal glioblastoma. Valid diagnosis is crucial; then, resection of multiple lesions and canonical radio-chemotherapy probably bring survival benefits.
Predictors of Survival Outcomes After Primary Treatment of Epithelial Ovarian Cancer in Lagos, Nigeria
Authors: Okunade Kehinde Sharafadeen , Adejimi Adebola A. , Ohazurike Ephraim O. , Salako Omolola , Osunwusi Benedetto , Adenekan Muisi A. , Ugwu Aloy O. , Soibi-Harry Adaiah , Dawodu Olayemi , Okunowo Adeyemi A. , Anorlu Rose I. , Berek Jonathan S. 
Published: January 2021

PURPOSE This study was designed to investigate the clinicopathologic predictors of progression-free survival (PFS) and overall survival (OS) in patients with epithelial ovarian cancer (EOC) following primary treatment in Lagos, Nigeria. MATERIALS AND METHODS Using data from a retrospective cohort of 126 patients who received treatment for EOC between 2010 and 2018, we identified 83 patients with a complete clinical record for subsequent data analysis. Patients' demographics and updated 2-year follow-up status were abstracted from medical records. Kaplan-Meier survival curves were compared using the log-rank test, and Cox proportional hazard models were used for multivariate analysis to identify independent predictors of survivals following treatment in EOC patients. RESULTS The median PFS and OS were 12 and 24 months, respectively. After adjusting for covariates in the multivariate analysis, younger age ≤ 55 years (hazard ratio [HR] = 0.40; 95% CI, 0.22 to 0.74; P = .01) and International Federation of Gynecology and Obstetrics (FIGO) stage I/II (HR = 0.02; 95% CI, 0.01 to 0.08; P = .01) were independent predictors of improved PFS, whereas being premenopausal (HR = 2.34; 95% CI, 1.16 to 4.75; P = .02) was an independent predictor of reduced OS after 2-year follow-up. CONCLUSION PFS could be predicted by the age and FIGO stage of the disease, whereas menopausal status was predictive of OS in patients with EOC. This knowledge should form the basis for counseling patients with ovarian cancer during their primary treatment and lend support to the importance of aggressive follow-up and monitoring for the older, premenopausal patients and those with an advanced stage of epithelial ovarian cancer. However, robust longitudinal research should be carried out to provide additional reliable insight to this information.
Technology of Accumulating Sampling at Mass Spectrometric Method of Tightness Inspection
Authors: Voronov Aleksandr , Kozlov Ilya , Lukashevsky Maksim 
Published: January 2021

The method of mass spectrometric method for total inspection of product tightness at atmospheric pressure is shown.
This method can be applied to products of any size and configuration with a given inspection sensitivity.
The method does not require vacuumizing of the monitoring objects.
Unlocking the biogeochemical role of beaver in state-transition of landscapes in Yellowstone's northern range
Authors: Brooks Marjorie L. 
Published: January 2021

Extirpation of wolves from the Greater Yellowstone Ecosystem in the 1920s hypothetically triggered a trophic cascade in which browsers, released from wolf (Canis lupus) predation, over-browsed riparian zones. Eventually, vast meadow-wetland complexes transitioned to grass-lodgepole systems. By 1954, beaver (Castor canadensis) virtually abandoned the Greater Yellowstone Ecosystem. In 2000, Colorado State University established experimental dams with browsing exclosures for Long Term Environmental Research in Biology (LTREB) on three streams in Lamar Valley to compare hydrologic effects of pseudo-beaver dams and browsing on willow (Salix spp.) productivity and state transitions. In 2015, beaver began recolonizing the region. I investigated how the biogeochemical role of beaver versus their hydrologic influence affects the underlying mechanisms of state transition: nutrient cycling, productivity, and stream respiration. Analyses of the 2017 field samples show that beaver streams trend toward higher nutrient levels and higher variances than the LTREB sites. The data tentatively support the role of beaver as keystone species in state transitions, although more data are needed. The unexpected and late May notice from the NPS to obtain an independent research permit—approved late August—curtailed my 2018 research to a brief field bout in September. Analysis of 2018 samples is underway.

Featured photo from Figure 1 in report.
Fibrinolysis as a target to enhance osteoporotic fracture healing by vibration therapy in a metaphyseal fracture model
Authors: Wong Ronald Man Yeung , Choy Victoria Man Huen , Li Jie , Li Tsz Kiu , Chim Yu Ning , Li Meng Chen Michelle , Cheng Jack Chun Yiu , Leung Kwok-Sui , Chow Simon Kwoon-Ho , Cheung Wing Hoi 
Published: January 2021

Aims Fibrinolysis plays a key transition step from haematoma formation to angiogenesis and fracture healing. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical modality proven to enhance fibrinolytic factors. This study investigates the effect of LMHFV on fibrinolysis in a clinically relevant animal model to accelerate osteoporotic fracture healing. Methods A total of 144 rats were randomized to four groups: sham control; sham and LMHFV; ovariectomized (OVX); and ovariectomized and LMHFV (OVX-VT). Fibrinolytic potential was evaluated by quantifying fibrin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) along with healing outcomes at three days, one week, two weeks, and six weeks post-fracture. Results All rats achieved healing, and x-ray relative radiopacity for OVX-VT was significantly higher compared to OVX at week 2. Martius Scarlet Blue (MSB) staining revealed a significant decrease of fibrin content in the callus in OVX-VT compared with OVX on day 3 (p = 0.020). Mean tPA from muscle was significantly higher for OVX-VT compared to OVX (p = 0.020) on day 3. Mechanical testing revealed the mean energy to failure was significantly higher for OVX-VT at 37.6 N mm (SD 8.4) and 71.9 N mm (SD 30.7) compared with OVX at 5.76 N mm (SD 7.1) (p = 0.010) and 17.7 N mm (SD 11.5) (p = 0.030) at week 2 and week 6, respectively. Conclusion Metaphyseal fracture healing is enhanced by LMHFV, and one of the important molecular pathways it acts on is fibrinolysis. LMHFV is a promising intervention for osteoporotic metaphyseal fracture healing. The improved mechanical properties, acceleration of fracture healing, and safety justify its role into translation to future clinical studies. Cite this article: Bone Joint Res 2021;10(1):41–50.
The role of gut microbiota in bone homeostasis
Authors: Li Jie , Ho Wing Tung Percy , Liu Chaoran , Chow Simon Kwoon-Ho , Ip Margaret , Yu Jun , Wong Hei Sunny , Cheung Wing-Hoi , Sung Joseph Jao Yiu , Wong Ronald Man Yeung 
Published: January 2021

AimsThe effect of the gut microbiota (GM) and its metabolite on bone health is termed the gut-bone axis. Multiple studies have elucidated the mechanisms but findings vary greatly. A systematic review was performed to analyze current animal models and explore the effect of GM on bone.MethodsLiterature search was performed on PubMed and Embase databases. Information on the types and strains of animals, induction of osteoporosis, intervention strategies, determination of GM, assessment on bone mineral density (BMD) and bone quality, and key findings were extracted.ResultsA total of 30 studies were included, of which six studies used rats and 24 studies used mice. Osteoporosis or bone loss was induced in 14 studies. Interventions included ten with probiotics, three with prebiotics, nine with antibiotics, two with short-chain fatty acid (SCFA), six with vitamins and proteins, two with traditional Chinese medicine (TCM), and one with neuropeptide Y1R antagonist. In general, probiotics, prebiotics, nutritional interventions, and TCM were found to reverse the GM dysbiosis and rescue bone loss.ConclusionDespite the positive therapeutic effect of probiotics, prebiotics, and nutritional or pharmaceutical interventions on osteoporosis, there is still a critical knowledge gap regarding the role of GM in rescuing bone loss and its related pathways. Cite this article: Bone Joint Res 2021;10(1):51–59.
Comparing the Voets equation and the Adrogue-Madias equation for predicting the plasma sodium response to intravenous fluid therapy in SIADH patients
Authors: Voets Philip J. G. M. , Vogtländer Nils P. J. , Kaasjager Karin A. H. 
Published: January 2021

Background
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the most common causes of hypotonic hyponatremia. In our previous work, we have derived a novel model (Voets equation) that can be used by clinicians to predict the effect of crystalloid intravenous fluid therapy on the plasma sodium concentration in SIADH.

Methods
In this retrospective chart review, the predictive accuracy of the Voets equation and the Adrogue-Madias equation for the plasma sodium response to crystalloid infusate was compared for fifteen plasma sodium response measurements (n = 15) in twelve SIADH patients. The medical records of these patients were accessed anonymously and none of the authors were their treating physicians. The Pearson correlation coefficient r and corresponding p-value were calculated for the predictions by the Voets model compared to the measured plasma sodium response and for the predictions by the Adrogue-Madias model compared to the measured plasma sodium response.

Results and conclusion
The presented results show that the Voets model (r = 0.94, p < 0.001) predicted the aforementioned plasma sodium response significantly more accurately than the Adrogue-Madias model (r = 0.49, p = 0.07) in SIADH patients and could therefore be a clinically useful addition to the existing prediction models.
A DOR DO INOCENTE: IMPLICAÇÕES DO RACISMO PARA A CRIANÇA NEGRA
Authors: Fiabani Adelmir , Fiabani Tainá 
Published: January 2021

Em tempos de discussões sobre a obrigatoriedade ou não do psicólogo nas escolas, nossas experiências no campo da Educação e da Psicologia nos levaram a produzir esta reflexão sobre o racismo e seus efeitos, sobretudo, as consequências sobre o processo de formação identitária, aproveitamento/rendimento escolar e processos de adoecimento. Somos uma nação que se construiu tendo a escravidão como base do sistema econômico e ordenamento social. As consequências deste sistema ainda se fazem sentir, como chagas abertas em um corpo doente. O racismo, a exclusão, a discriminação e o preconceito são males que precisamos combater diariamente. A Psicologia Clínica tem função essencial no processo de restituir a saúde mental das vítimas do racismo. A Psicologia Social deverá atuar como orientadora das práticas pedagógicas sadias e acolhedoras, que tornem o ambiente escolar prazeroso para todas as crianças. Há muito que fazer para erradicar o racismo da nossa sociedade. Para este artigo, revisamos alguns estudos publicados na área da Educação e da Saúde Mental. O objetivo principal desta pesquisa consiste em compreender e analisar os efeitos do racismo e da discriminação no psiquico da criança negra e, consequentemente, suas implicações sobre o rendimento escolar. Concluímos que o racismo afeta o comportamento da criança negra e é um dos causadores, possivelmente o basilar, do adoecimento mental.
LncRNA RP1-85F18.6 affects osteoblast cells by regulating the cell cycle
Authors: Song Jiangtao , Song Wenrong , Zhang Lei 
Published: January 2021

AbstractA lncRNA RP1-85F18.6 was reported to affect cell growth by regulating the cell cycle. Here we tested whether it affects the proliferation of osteoblast cells by regulating the cell cycle. We determined the expression of RP1-85F18.6 in two osteoblast cell lines hFOB and HOB by qPCR. Then we knocked down or overexpressed RP1-85F18.6 in hFOB and tested the alteration of viability, cell cycle, and cell cycle regulatory proteins. Results showed that both hFOB and HOB expressed RP1-85F18.6. The knockdown of RP1-85F18.6 decreased the viability of hFOB, while the overexpression of it increased the viability. Higher expression of RP1-85F18.6 results in higher cell viability. The knockdown of RP1-85F18.6 caused an increase in the S phase cells and a decrease in the G2/M phase cells. The overexpression of RP1-85F18.6 caused a decrease in the S phase cells and an increase in the G2/M phase cells. The knockdown of RP1-85F18.6 decreased cyclin A, cdk1, E2F, cyclin B, p53, and p21, whereas the overexpression of RP1-85F18.6 increased cyclin A, cdk1, E2F, cyclin B, p53, and p21. This study demonstrated that RP1-85F18.6 is expressed in osteoblast cell lines hFOB and HOB. RP1-85F18.6 affects the proliferation of osteoblasts by regulating the cell cycle.