bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATM Paradoxically Promotes Oncogenic Transformation via Transcriptional Reprogramming
Authors: Liu Xinjian , Hu Mengjie , Liu Pei , Jiao Meng , Zhou Min , Lee Andrew K. , Li Fang , Li Chuan-Yuan 
Published: February 2020

Abstract

The role of the ataxia-telangiectasia-mutated (ATM) gene in human malignancies, especially in solid tumors, remains poorly understood. In the present study, we explored the involvement of ATM in transforming primary human cells into cancer stem cells. We show that ATM plays an unexpected role in facilitating oncogene-induced malignant transformation through transcriptional reprogramming. Exogenous expression of an oncogene cocktail induced a significant amount of DNA double-strand breaks in human fibroblasts that caused persistent activation of ATM, which in turn enabled global transcriptional reprogramming through chromatin relaxation, allowing oncogenic transcription factors to access chromatin. Consistently, deficiencies in ATM significantly attenuated oncogene-induced transformation of human cells. In addition, ATM inhibition significantly reduced tumorigenesis in a mouse model of mammary cancer. ATM and cellular DNA damage response therefore play a previously unknown role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells.

Significance:
These findings uncover a novel pro-oncogenic role for ATM and show that contrary to established theory, ATM does not always function as a tumor suppressor; its function is however dependent on cell type.
The DNA Cytosine Deaminase APOBEC3B is a Molecular Determinant of Platinum Responsiveness in Clear Cell Ovarian Cancer
Authors: Serebrenik Artur A. , Argyris Prokopios P. , Jarvis Matthew C. , Brown William L. , Bazzaro Martina , Vogel Rachel I. , Erickson Britt K. , Lee Sun-Hee , Goergen Krista M. , Maurer Matthew J. , Heinzen Ethan P. , Oberg Ann L. , Huang Yajue , Hou Xiaonan , Weroha S. John , Kaufmann Scott H. , Harris Reuben S. 
Published: February 2020

Abstract

Purpose:
Clear cell ovarian carcinoma (CCOC) is an aggressive disease that often demonstrates resistance to standard chemotherapies. Approximately 25% of patients with CCOC show a strong APOBEC mutation signature. Here, we determine which APOBEC3 enzymes are expressed in CCOC, establish clinical correlates, and identify a new biomarker for detection and intervention.

Experimental Designs:
APOBEC3 expression was analyzed by IHC and qRT-PCR in a pilot set of CCOC specimens (n = 9 tumors). The IHC analysis of APOBEC3B was extended to a larger cohort to identify clinical correlates (n = 48). Dose-response experiments with platinum-based drugs in CCOC cell lines and carboplatin treatment of patient-derived xenografts (PDXs) were done to address mechanistic linkages.

Results:
One DNA deaminase, APOBEC3B, is overexpressed in a formidable subset of CCOC tumors and is low or absent in normal ovarian and fallopian tube epithelial tissues. High APOBEC3B expression associates with improved progression-free survival (P = 0.026) and moderately with overall survival (P = 0.057). Cell-based studies link APOBEC3B activity and subsequent uracil processing to sensitivity to cisplatin and carboplatin. PDX studies extend this mechanistic relationship to CCOC tissues.

Conclusions:
These studies demonstrate that APOBEC3B is overexpressed in a subset of CCOC and, contrary to initial expectations, associated with improved (not worse) clinical outcomes. A likely molecular explanation is that APOBEC3B-induced DNA damage sensitizes cells to additional genotoxic stress by cisplatin. Thus, APOBEC3B is a molecular determinant and a candidate predictive biomarker of the therapeutic response to platinum-based chemotherapy. These findings may have broader translational relevance, as APOBEC3B is overexpressed in many different cancer types.
Early Mortality of Brain Cancer Patients and its Connection to Cytomegalovirus Reactivation During Radiochemotherapy
Authors: Goerig Nicole L. , Frey Benjamin , Korn Klaus , Fleckenstein Bernhard , Überla Klaus , Schmidt Manuel A. , Dörfler Arnd , Engelhorn Tobias , Eyüpoglu Ilker , Rühle Paul F. , Putz Florian , Semrau Sabine , Gaipl Udo S. , Fietkau Rainer 
Published: February 2020

Abstract

Purpose:
If routine diagnostics are inconclusive, neurologic deterioration and death of patients with brain cancer are attributed to tumor or therapy. Therefore, diagnosing symptoms of encephalopathy caused by human cytomegalovirus (HCMV) reactivation remains uncommon. We investigated the role of HCMV reactivation in neurologic decline and clinical outcome after the start of radiochemotherapy.

Experimental Design:
HCMV analyses and extended MRI studies including additional independent retrospective neuroradiologic evaluation were performed at predetermined intervals and in case of sudden neurologic decline for 118 adult patients: 63 histologically proven high-grade gliomas, 55 with brain metastases. Immunophenotyping from simultaneously taken whole-blood samples was carried out to detect immune cells serving as prognostic marker for HCMV-associated complications. Symptomatic viremia and overall survival (OS) were the endpoints.

Results:
Twenty-four percent (28/118) of all patients (12/44 glioblastoma, 3/13 anaplastic astrocytoma; 8/31 non–small cell lung cancer (NSCLC), 13/24 other brain metastases) developed HCMV-viremia during or within 4 weeks after radiotherapy; 21 of 28 patients experienced concurrent major neurologic decline, reversible by antiviral treatment. Identified by immunophenotyping, pretherapeutically low basophil counts predicted a high-risk for HCMV-associated encephalopathy (glioblastoma: P = 0.002, NSCLC: P = 0.02). Median OS was substantially reduced after HCMV-associated encephalopathy without MRI signs of tumor progression [glioblastoma: 99 vs. 570 days (calculated 1-year OS: 22% vs. 69%; P = 0.01) and NSCLC: 47 vs. 219 days (calculated 1-year OS: 0% vs. 32%; P = 0.02)].

Conclusions:
For patients with brain cancer, HCMV reactivation after the start of radiochemotherapy is a frequent risk for cognitively detrimental but treatable encephalopathy and premature death. Routinely performed HCMV diagnostics, assessing basophil counts and study-based anti-viral regimens, are necessary to combat this hidden threat.
See related commentary by Lawler et al., p. 3077
The Prognostic Significance of Quantitative Myocardial Perfusion: An Artificial Intelligence Based Approach Using Perfusion Mapping
Authors: Knott Kristopher D. , Seraphim Andreas , Augusto Joao B. , Xue Hui , Chacko Liza , Aung Nay , Petersen Steffen E. , Cooper Jackie A. , Manisty Charlotte , Bhuva Anish N. , Kotecha Tushar , Bourantas Christos V. , Davies Rhodri H. , Brown Louise A.E. , Plein Sven , Fontana Marianna , Kellman Peter , Moon James C. 
Published: February 2020

Background:Myocardial perfusion reflects the macro- and microvascular coronary circulation. Recent quantitation developments using cardiovascular magnetic resonance (CMR) perfusion permit automated measurement clinically. We explored the prognostic significance of stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR, the ratio of stress to rest MBF).Methods:A two center study of patients with both suspected and known coronary artery disease referred clinically for perfusion assessment. Image analysis was performed automatically using a novel artificial intelligence approach deriving global and regional stress and rest MBF and MPR. Cox proportional hazard models adjusting for co-morbidities and CMR parameters sought associations of stress MBF and MPR with death and major adverse cardiovascular events (MACE), including myocardial infarction, stroke, heart failure hospitalization, late (>90 day) revascularization and death.Results:1049 patients were included with median follow-up 605 (interquartile range 464-814) days. There were 42 (4.0%) deaths and 188 MACE in 174 (16.6%) patients. Stress MBF and MPR were independently associated with both death and MACE. For each 1ml/g/min decrease in stress MBF the adjusted hazard ratio (HR) for death and MACE were 1.93 (95% CI 1.08-3.48, P=0.028) and 2.14 (95% CI 1.58-2.90, P<0.0001) respectively, even after adjusting for age and co-morbidity. For each 1 unit decrease in MPR the adjusted HR for death and MACE were 2.45 (95% CI 1.42-4.24, P=0.001) and 1.74 (95% CI 1.36-2.22, P<0.0001) respectively. In patients without regional perfusion defects on clinical read and no known macrovascular coronary artery disease (n=783), MPR remained independently associated with death and MACE, with stress MBF remaining associated with MACE only.Conclusions:In patients with known or suspected coronary artery disease, reduced MBF and MPR measured automatically inline using artificial intelligence quantification of CMR perfusion mapping provides a strong, independent predictor of adverse cardiovascular outcomes.
Effect of Behavioral Realism on Social Interactions Inside Collaborative Virtual Environments
Authors: Herrera Fernanda , Oh Soo Youn , Bailenson Jeremy N. 
Published: February 2020

Abstract
Collaborative virtual environments (CVEs), wherein people can virtually interact with each other via avatars, are becoming increasingly prominent. However, CVEs differ in type of avatar representation and level of behavioral realism afforded to users. The present investigation compared the effect of behavioral realism on users' nonverbal behavior, self-presence, social presence, and interpersonal attraction during a dyadic interaction. Fifty-one dyads (aged 18 to 26) embodied either a full-bodied avatar with mapped hands and inferred arm movements, an avatar consisting of only a floating head and mapped hands, or a static full-bodied avatar. Planned contrasts compared the effect of behavioral realism against no behavioral realism, and compared the effect of low versus high behavioral realism. Results show that participants who embodied the avatar with only a floating head and hands experienced greater social presence, self-presence, and interpersonal attraction than participants who embodied a full-bodied avatar with mapped hands. In contrast, there were no significant differences on these measures between participants in the two mapped-hands conditions and those who embodied a static avatar. Participants in the static-avatar condition rotated their own physical head and hands significantly less than participants in the other two conditions during the dyadic interaction. Additionally, side-to-side head movements were negatively correlated with interpersonal attraction regardless of condition. We discuss implications of the finding that behavioral realism influences nonverbal behavior and communication outcomes.
Depth Perception and Manipulation in Projection-Based Spatial Augmented Reality
Authors: Schmidt Susanne , Bruder Gerd , Steinicke Frank 
Published: February 2020

Abstract
Spatial augmented reality (SAR) technology allows one to change the appearance of objects by projecting directly onto their surface without the requirement of wearing glasses, and therefore can be used in many practical applications. In this article, we present a human–subject study, which investigates the research question whether it is possible to use SAR to change one's perception of depth and spatial relationships among objects and humans in a real-world environment. Such projected illusions could open up new possibilities, for example, supporting people who suffer from poor depth perception by compensating distance and size misperceptions. We present three monoscopic projection-based techniques that we adapted from visual arts: (i) color temperature, (ii) luminance contrast, and (iii) blur, and show that each of them can significantly change depth perception, even in a real-world environment when displayed with other distance cues. We discuss practical implications and individual differences in the perception of depth between observers, and we outline future directions to influence and improve human depth perception in the real world.
Epidemiological investigation on the cervical health of lesbians in Beijing, China
Authors: Chen Xiangfan , Yan Hong , Cao Yingnan , Li Shiyue , Yang Ningxi , Li Xiaoyan 
Published: February 2020

Objective To investigate human papillomavirus (HPV) infection status and influencing factors among lesbians. Methods In August to October 2018, 300 lesbians were recruited in Beijing using snowball sampling. Sociodemographic characteristics, behavioural indices and HPV status were measured. Colposcopy was performed on participants with HPV genotypes 16 and 18 and on participants with other high-risk HPV subtypes and positive ThinPrep (TCT) results. Results The overall HPV-positive rate was 25%. High number of sexual partners, smoking, drinking, not using condoms and using sex toys during intercourse were identified as HPV infection risk factors. Of the HPV subtypes detected, 84% were high-risk HPV subtypes. The colposcopy results showed that 20 participants (80%) with HPV 16 and HPV 18 had cervical intraepithelial neoplasia I (CIN I) or above lesions. The colposcopy results also showed that 16 participants (64%) infected with other high-risk types of HPV virus and who had positive TCT results had CIN I or above lesions. Conclusions The cervical health of lesbians should not be neglected, and appropriate health education should be improved for this group.
Bullying, health complaints, and self-rated health among school-aged children and adolescents
Authors: Hansson Erika , Garmy Pernilla , Vilhjálmsson Rúnar , Kristjánsdóttir Gudrún 
Published: February 2020

Objective The aim of the current study was to examine whether health complaints and self-reported health were associated with bullying victimization in a large cohort of Icelandic children and adolescents. Methods In this study, we used data from a school-based cross-sectional survey, specifically, the Icelandic contribution to the international research network Health Behavior in School-aged Children (HBSC). The study population included all students throughout Iceland in grades 6, 8, and 10 (mean age 13 years, standard deviation 1.61). The participation rate was 84% (N = 11,018). Participating students completed an anonymous standardized questionnaire in their classrooms. Results Bullying victimization was associated with feeling depressed (odds ratio 2.61), having difficulty falling asleep, dizziness, and low self-reported health. No differences were found between sex and age groups. Conclusions Children and adolescents who are bullied appear to more often experience depression, difficulties falling asleep, dizziness, and poor health; however, health complaints were also relatively high among non-bullied children and adolescents. Bullying prevention measures must be implemented in children’s and adolescents’ social environments. In addition to assessing bullying interventions, further research should focus on methods of enhancing resilience in this population.
Des-gamma-carboxyprothrombin is a favorable biomarker for the early diagnosis of alfa-fetoprotein-negative hepatitis B virus-related hepatocellular carcinoma
Authors: Liu Zhaobo , Wu Min , Lin Dongdong , Li Ning 
Published: February 2020

Objectives Des-gamma-carboxyprothrombin (DCP) is an important serum biomarker for the clinical screening of hepatocellular carcinoma (HCC). This study aimed to evaluate the value of DCP for the early diagnosis of alpha-fetoprotein (AFP)-negative hepatitis B virus (HBV)-related HCC. Methods We retrospectively enrolled patients with AFP-negative HBV-related HCC and benign liver disease. Serum DCP levels in all participants were measured by chemiluminescent enzyme immunoassay. The value of DCP for the early diagnosis of AFP-negative HBV-related HCC was evaluated by receiver operating characteristic curve (ROC) and area under the curve (AUC) analyses. Results A total of 210 patients, including 87 cases with AFP-negative HBV-related HCC and 123 control cases with chronic HBV infection (CHB) or liver cirrhosis (LC), were included. Serum DCP levels were significantly increased in patients with AFP-negative HBV-related HCC compared with those with CHB or LC. The AUC for DCP for distinguishing between the two groups was 0.731 (95% confidence interval (CI), 0.657 to 0.805) and that for early diagnosis was 0.685 (95%CI, 0.596 to 0.774). Conclusions DCP may be a favorable biomarker to improve the early diagnosis rate of AFP-negative HBV-related HCC.
Clinical features of transverse myelitis associated with systemic lupus erythematosus
Authors: Zhang S , Wang Z , Zhao J , Wu D i , Li J , Wang Q , Su J , Xu D , Wang Y , Li M , Zeng X 
Published: February 2020

Objective This study aimed to identify the clinical characteristics and prognostic factors of systemic lupus erythematosus with transverse myelitis (SLE-TM) in a relatively large patient series. Methods This retrospective study considered 45 SLE-TM individuals treated as inpatients and outpatients at Peking Union Medical College Hospital between 1993 and 2018. SLE-TM patients were compared with 180 controls, and SLE-TM patients with neuromyelitis optica spectrum disorder (NMOSD) were compared to those without NMOSD. Results Compared to controls, the SLE-TM group frequently had a fever and had a significantly higher positive rate of anticardiolipin and lupus anticoagulant. Among the 45 patients, 22 met the NMOSD criteria. Compared to non-NMOSD patients, NMOSD patients had a lower incidence of rash ( p = 0.023), serositis ( p = 0.042) and renal disorder ( p = 0.073); a lower prevalence of decreased complement ( p = 0.083); and lower rates of positive anti-dsDNA ( p = 0.074) and anti-Sm ( p = 0.042). Among 22 SLE-TM patients with NMOSD, 18 underwent aquaporin 4 antibody testing, with 11 showing positive results. Out of the 45 patients, 39 were given methylprednisolone pulse treatment. After treatment, 32 patients had lower-limb muscle strength recovery (recovered group), whereas 13 had no change and persistent severe neurological deficits (non-recovered group). Compared to the recovered group, the non-recovered group were younger ( p = 0.002), had a higher likelihood of having a fever ( p = 0.020), initial severe myelitis ( p < 0.001), long spinal segment involvement ( p = 0.017) and higher C-reactive protein levels ( p = 0.020). Methylprednisolone pulse given within two weeks of onset was more frequent in the recovered group than in the non-recovered group ( p = 0.082). Conclusions Disease characteristics differed between SLE-TM patients with and without NMOSD. SLE and NMOSD tended to be co-morbidities. Initial severe neurological impairment, extensive spinal cord lesions, hyper-inflammation and delayed steroid impulse treatment could be predictors of poor outcome for SLE-TM.
5-azacitidine reversing “spent” phase polycythemia vera back to proliferative phase and need for phlebotomy
Authors: Lerner Jaren , Michel Miguel , Dasanu Constantin A 
Published: February 2020

Introduction Polycythemia vera is a myeloproliferative neoplasm (MPN) characterized by increased red blood cell mass. The natural evolution of this MPN is to progress to an anemic/cytopenic phase also known as “spent” phase prior to transformation into an accelerated and/or an overt leukemic phase. Case Report Herein, we describe a case of a patient with polycythemia vera transitioning though a “spent” phase to an MPN in accelerated phase (MPN-AP). The patient had anemia, thrombocytopenia, neutrophilia and increased blasts in the bone marrow. Management and outcome: Upon treatment with four cycles of 5-azacitidine, the patient’s polycythemia vera reversed back to the proliferative phase. Serial phlebotomies were again required. Discussion Reversal of a “spent” phase by 5-azacitidine back to a proliferative polycythemia vera phase requiring phlebotomies has not been previously reported in the scientific literature. We might witness similar cases in the literature in the future years, which could lead to yet another therapeutic indication of this important pharmacologic agent.
Life-threatening hypertriglyceridemia-induced pancreatitis related to alectinib successfully treated by plasmapheresis: A review of the literature on metabolic toxicities associated with anaplastic lymphoma kinase inhibitors
Authors: Rao Arundati , Reddy Aswanth , Dinunno Corey , Elali Ibrahim 
Published: February 2020

Introduction Actionable mutations are tested as standard of care for all new metastatic non-small cell lung cancers. Tumors harboring an anaplastic lymphoma kinase mutation respond to tyrosine kinase inhibitors targeting anaplastic lymphoma kinase pathway. Patients are monitored for common adverse effects, although we occasionally encounter unexpected side effects. Case report A 52-year-old male presented with a right hilar lung mass, and workup revealed a stage IIIA adenocarcinoma. He underwent treatment with concurrent chemoradiation; however, disease recurred one year later with a right hilar mass and contralateral mediastinal lymphadenopathy, biopsy of which resulted positive for adenocarcinoma. Molecular analysis showed anaplastic lymphoma kinase rearrangement and alectinib was started. Six months into therapy, he presented with hematochezia, nausea, and epigastric pain and was diagnosed with acute pancreatitis. Triglyceride level resulted above the measurable level at >5680mg/dL, thought to be the inciting event of pancreatitis. Management and outcome: Despite treatment with intravenous hydration, insulin infusion, and antibiotics, he decompensated with development of respiratory failure, shock requiring intensive care. Therapeutic plasmapheresis was initiated due to persistently elevated triglyceride. Following the third plasmapheresis, triglyceride level decreased to 359 mg/dL. With aggressive multidisciplinary management, he made a complete recovery. Follow-up imaging studies at three and six months show a stable mass-like abnormality in the right hilum without evidence of disease progression. Discussion Prior to starting alectinib, our patient’s triglyceride level was 420 mg/dL. While he consumed alcohol, he had no other traditional risk factor. To our knowledge, this is the first reported case of hypertriglyceridemia-induced acute pancreatitis related to treatment with an anaplastic lymphoma kinase inhibitor.
Bortezomib-induced motor neuropathy: A case report
Authors: Singh Meghana , Thomas Vinay M , Mulay Sudhanshu 
Published: February 2020

Introduction Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma, Waldenström’s macroglobulinemia, mantle cell lymphoma. The most reported adverse effects include fatigue, thrombocytopenia, gastrointestinal symptoms, and peripheral neuropathy, which mostly manifests as sensory neuropathic symptoms. We present a case of a patient who experienced motor neuropathy after initiating treatment with bortezomib. Case report An 87-year-old male was diagnosed with multiple myeloma and started on treatment with bortezomib, dexamethasone, and lenalidomide (VRd). After five cycles of therapy, he developed lower extremity weakness, which was severely debilitating, affecting his ability to walk, and this prompted his visit to the emergency department. Management and outcome The patient was admitted for further workup and underwent electromyography, which was consistent with demyelinating polyneuropathy with active denervation. His symptoms were attributed to bortezomib, and his VRd regimen was held. His symptoms failed to improve despite discontinuation of bortezomib. He then received steroids and intravenous immunoglobulin (IViG) with a gradual resolution of his symptoms. He was thereafter restarted on only lenalidomide and dexamethasone with no recurrence of his neuropathy. Discussion Clinicians need to be aware of the likely risk for motor neuropathy associated with bortezomib. Risk factors like older age and pre-existing neuropathy can predispose patients to this adverse effect, and clinicians should monitor for this toxicity and facilitate dose reduction or discontinuation of therapy if warranted. Sometimes, patients may also need further treatment with steroids or IVIG.