bluuebunny/crossref_metadata_2025 huggingface dataset:
Unprofessional behaviour of junior doctors: a retrospective analysis of outcomes by the Singapore Medical Council disciplinary tribunals
Authors: Norman NBM , Soo JMP , Lam MYK , Thirumoorthy T
Published: March 2020

INTRODUCTION This is a retrospective analysis of outcomes by Singapore Medical Council (SMC) disciplinary tribunals in cases involving junior doctors. We aimed to classify the types of unprofessional behaviour and consider appropriate measures for remediation and prevention. METHODS SMC’s annual reports from 1979 to 2017 and published grounds of decision from 2008 to 2017 were examined using two screening levels to identify cases involving junior doctors. Cases were sorted into five outcome categories: (a) professional misconduct; (b) fraud and dishonesty; (c) defect in character; (d) disrepute to the profession; and (e) acquitted. RESULTS A total of 317 cases were identified, of which 13 (4.1%) involved junior doctors: 4 (30.8%) cases involved professional misconduct, 4 (30.8%) cases involved fraud and dishonesty, 3 (23.1%) cases saw an acquittal, and one case each involved defect in character and disrepute to the profession. The four cases of professional misconduct highlight the need to differentiate medical errors due to systems factors from those due to individual culpability, by applying analytical tools such as root cause analysis and Unsafe Act Algorithms. Disciplining the individual alone does not help prevent the recurrence of similar medical errors. We found that fraud and dishonesty was an important category of unprofessional behaviour among junior doctors. CONCLUSION While the frequency of unprofessional behaviour among junior doctors, as determined by the SMC disciplinary tribunal, is low (4.1%), this study highlights that complaints against medical doctors often involve systems issues and individual factors. Unprofessional behaviours related to fraud and dishonesty need special attention in medical school.
Molecular characterization of hybrids in Carex (Cyperaceae) by cloning: Carex paniculata × remota (= C. × boenninghausiana)

Authors: MAGUILLA ENRIQUE , MÍGUEZ MÓNICA , VILLAVERDE TAMARA , VARGAS-MONTES FRANCISCO JAVIER , LUCEÑO MODESTO
Published: March 2020

One of the most common processes shaping evolution in plants could be the introgression or hybridization between species. We sampled a putative hybrid population of Carex × boenninghausiana recently discovered from Sicily (Italy), and one specimen of each of the parent species of this hybrid (C. paniculata and C. remota) from the same area. We performed phylogenetic analyses of nuclear and plastid DNA markers after sequencing and cloning in the case of the nuclear region, as an easy and effective way of hybrid detection. Previous morphological and cytogenetic studies demonstrated the hybrid character of C. × boenninghausiana. Our results show how C. paniculata and C. remota are the parent species of this hybrid, also from a molecular DNA point of view. The use of cloning of the ITS nrDNA region to separate chains from both parents, combined with the analysis of cpDNA regions seems to be a powerful tool to detect hybridization and clarify the evolution and species’s relationships in natural populations in Carex.
Stellaria procumbens sp. nov. and S. amplexicaulis comb. & stat. nov. (Caryophyllaceae) from Southwest China

Authors: YANG FENG , LIU XIAO-LAN , LI YU-RAN , TIAN YE , WANG HUAN-CHONG
Published: March 2020

Stellaria procumbens Huan C. Wang & Feng Yang, a new species in Caryophyllaceae, is described and illustrated. The new species was found in provinces Sichuan and Yunnan, Southwest China. Stellaria procumbens is most similar to S. longifolia, but clearly differs from the latter by its stems cylindrical, 5–10 cm in length, leaves 0.4–1.5 cm long, 0.3–0.7 mm broad, the ratio of length to width of leaves from 13 to 23, cymes usually with 1–2 (–3) flowers, and peduncles 0.3–2.5 cm long. Also, the variety S. saxatilis var. amplexicaulis from southwest China, is raised to species rank based on its distinctiveness and its lectotype is designated.
New taxonomic and faunistic data on Asian species of the genus Indenicmosoma Ardoin (Coleoptera: Tenebrionidae: Lagriinae), with description of a new species from Thailand
Authors: SCHAWALLER WOLFGANG , BIGALK SONIA
Published: March 2020

The tenebrionid genus Indenicmosoma Ardoin, 1964 (type species indochinensis Kaszab, 1940), subfamily Lagriinae, is distributed in Asia and Sub-Saharan Africa. Newly collected specimens from different Palaearctic and Oriental Asian regions are presented, among them also one species new to science from Thailand (Indenicmosoma paicum sp. nov.). New synonym: Indenicmosoma nathani Ardoin, 1964 (Indenicmosoma ardoini Kaszab, 1970 syn. nov.). All treated eight Asian species are figured, and a species key is compiled.
Contribution to the knowledge of the genus Cordilura Fallén (Diptera, Scathophagidae) from Japan, with descriptions of three new species
Authors: IWASA MTSUHIRO
Published: March 2020

The Japanese species of the genus Cordilura Fallén are taxonomically revised. Three species, namely Cordilura katoi sp. nov., C. shinonagai sp. nov., and C. yezoana sp. nov. are described as new to science. The previous described Japanese species C. cuspidata Sasakawa, 1986 and C. nubecula Sasakawa, 1986 are remarked. Three species, C. albipes (Fallén, 1819), C. remmi Elberg, 1972, and C. richterae Ozerov & Krivosheina, 2015 are recorded from Japan for the first time. An identification key to the Japanese species of Cordilura is also provided.
Two new Colombian harvestmen of the genus Quindina Roewer, 1914 (Opiliones: Nomoclastidae)
Authors: MORALES CONCHITA A. PINZÓN , PINTO-DA-ROCHA RICARDO
Published: March 2020

Two new Colombian species of Quindina Roewer, 1915 are here described based on genital morphology and external characters. Quindina hermesi sp. nov. (type locality: Bolívar, San Jacinto) can be diagnosed externally by having a combination of colored tubercles on the ocularium, the anterior margin, areas I, II and IV of the dorsal scutum, and the free tergites; Q. discolor sp. nov. (type locality: Magdalena, Ciénaga) shows a different combination of colored tubercles on the ocularium and lateral margins. Phylogenetic analyses were performed by adding both new species to an existing matrix for Nomoclastidae. The analyses resulted in various topologies for the relationships among Nomoclastes Sørensen, 1932, Napostygnus Roewer, 1929, Kichua Pinto-da-Rocha & Bragagnolo, 2017, Callcosma Roewer, 1932 and Quindina Roewer, 1914, but all analyses recovered the monophyly of Callcosma and Quindina. This constitutes the first record of the family in northern Colombia.
Differentiating Experience From Cue Utilization in Radiological Assessments
Authors: Carrigan Ann J. , Magnussen John , Georgiou Andrew , Curby Kim M. , Palmeri Thomas J. , Wiggins Mark W.
Published: March 2020

Objective

This research was designed to examine the contribution of self-reported experience and cue utilization to diagnostic accuracy in the context of radiology.

Background

Within radiology, it is unclear how task-related experience contributes to the acquisition of associations between features with events in memory, or cues, and how they contribute to diagnostic performance.

Method

Data were collected from 18 trainees and 41 radiologists. The participants completed a radiology edition of the established cue utilization assessment tool EXPERTise 2.0, which provides a measure of cue utilization based on performance on a number of domain-specific tasks. The participants also completed a separate image interpretation task as an independent measure of diagnostic performance.

Results

Consistent with previous research, a k-means cluster analysis using the data from EXPERTise 2.0 delineated two groups, the pattern of centroids of which reflected higher and lower cue utilization. Controlling for years of experience, participants with higher cue utilization were more accurate on the image interpretation task compared to participants who demonstrated relatively lower cue utilization ( p = .01).

Conclusion

This study provides support for the role of cue utilization in assessments of radiology images among qualified radiologists. Importantly, it also demonstrates that cue utilization and self-reported years of experience as a radiologist make independent contributions to performance on the radiological diagnostic task.

Application

Task-related experience, including training, needs to be structured to ensure that learners have the opportunity to acquire feature–event relationships and internalize these associations in the form of cues in memory.
Cyber Sextortion: An Exploratory Analysis of Different Perpetrators Engaging in a Similar Crime
Authors: O’Malley Roberta Liggett , Holt Karen M.
Published: March 2020

Sextortion, a portmanteau of “sexual” and “extortion,” is the threat to distribute intimate, sexual materials unless a victim complies with certain demands. Cyber sextortion is part of a larger continuum of image-based sexual offending in which images are used for harm. Despite the serious nature of this crime, there exists a dearth of empirical knowledge of sextortion. This article employed a qualitative content analysis of media articles and court documents to explore the crimes of 152 cyber sextortion offenders. Characteristics of offenders, victims, demands, and methodology were identified and synthesized to generate a qualitative understanding of offenders who employed cyber sextortion. The results revealed four different themes of offenders based on crime characteristics: minor-focused cyber sextortion offenders, cybercrime cyber sextortion offenders, intimately violent cyber sextortion offenders, and transnational criminal cyber sextortion offenders. The diverse nature of cyber sextortion has implications for crime control policies. Certain offenders are more likely to be apprehended and prosecuted depending on the crime victim and methodology. In addition, there has been a lack of legislative action targeting cyber sextortion, which limits legal recourse available for victims. We discuss the contribution of this work to the broader literature on cyber sextortion and address some of the challenges that this crime presents to the criminal justice system.
Clofazimine in Mycobacterium abscessus peritonitis: A pediatric case report
Authors: Pinapala Archana , Koh Lee Jin , Ng Kar-Hui , Tambyah Paul A , Yap Hui-Kim
Published: March 2020

Peritonitis- and catheter-related infections due to nontuberculous mycobacteria (NTM) including Mycobacterium abscessus have been reported among adults on peritoneal dialysis (PD). There is no recommended antimicrobial regimen for the treatment of M. abscessus peritonitis. Clofazimine has emerged as an important adjuvant antimicrobial treatment of M. abscessus lung infection. We report, to our knowledge, the first case of M. abscessus PD peritonitis in a child treated successfully using clofazimine as a novel adjuvant therapy to amikacin and clarithromycin. Her clinical features were similar to those of bacterial peritonitis, but she had persistence of symptoms and high inflammatory markers despite empirical therapy for peritonitis. Bacterial culture of PD effluent became positive for M. abscessus after 5 days. There was complete symptom resolution after 6 days of multidrug therapy. Due to ototoxicity, amikacin was discontinued after 6 weeks, while clarithromycin and clofazimine were continued for 9 months to ensure complete pathogen eradication before a planned renal transplant. A high index of suspicion in refractory or culture-negative cases is important for the diagnosis of NTM peritonitis. Multidrug therapy is recommended for M. abscessus infections. Clofazimine was chosen as a novel adjunct antimicrobial because of its pharmacokinetics, ease of administration, cost-effectiveness, and lack of serious adverse events.
University–industry collaboration for BIM education: Lessons learned from a case study
Authors: Chen Ke , Lu Weisheng , Wang Jing
Published: March 2020

Over the past decade, the global construction industry has shown a clear and urgent need for its professionals to command building information modeling (BIM) knowledge. Many educational institutions have thus incorporated BIM into their construction engineering and management-related programs. However, BIM education faces several challenges, such as the difficulties in transforming existing programs, a lack of instructors with sufficient practical knowledge and misalignment of educational outcomes and industry needs. Many educators thus advocate university–industry collaboration, but this effort is hampered by unanswered questions, including when, what and how both parties can contribute to the collaboration to achieve a win–win situation. This article attempts to answer these key questions in BIM education by relating them to university–industry collaboration in pedagogical design, course delivery and educational outcomes. It does so by conducting a case study whereby the researchers adopted a non-participant observation approach to observe the experience of participants in teaching and learning a BIM course. Feedback from the participants showed that such collaboration could help to narrow the gap between educational outcomes and industry needs. Based on that outcome, another contribution of this research is an analytical framework developed and substantiated to provide a more structured way to guide ‘town and gown’ collaboration for BIM education.
Aligning Culturally Responsive and Trauma-Informed Pedagogies in Elementary General Music
Authors: McEvoy Carin A. , Salvador Karen
Published: March 2020

In elementary general music, the need for culturally responsive pedagogies and trauma-informed practices may coexist. Creating an environment and developing instruction in ways that are both culturally responsive and trauma-informed may be possible, because both approaches share common theoretical underpinnings and practices. In this article, we review the research on culturally responsive music education and trauma-informed practices and make practical suggestions for implementing these pedagogies in elementary general music classes.
On vibration of functionally graded sandwich nanoplates in the thermal environment
Authors: Daikh Ahmed Amine , Drai Ahmed , Bensaid Ismail , Houari Mohammed Sid Ahmed , Tounsi Abdelouahed
Published: March 2020

This paper deals with the free vibration response of rectangular functionally graded material sandwich nanoplates with simply supported boundary conditions. The material properties of the FGM layers are temperature-dependent and supposed to be graded continuously along the thickness direction. A simple power-law distribution in terms of the volume fractions of the material constituents is employed to obtained the effective material properties. Eringen’s nonlocal elasticity model is incorporated in order to take into account the small size effects. Two types of functionally graded material sandwich nanoplates are considered: a sandwich with functionally graded material face layers and homogeneous core, and a sandwich with homogeneous face layers and functionally graded material core. The equations of motion of the functionally graded material sandwich nanoplates are derived by using the higher shear deformation theory and the Hamilton’s variational principle, and solved using the Navier’s solutions. Several numerical results indicate the influence of the power–law index, the nonlocal parameter, the geometrical parameters of the nanoplate, and the temperature variation on the free vibration response are presented.
Complete loading-unloading-deflection prediction for antivibration system design using Hyperelastic-dissipation approach
Authors: Luo Robert Keqi
Published: March 2020

The complete loading–unloading–deflection response is a key requirement for the antivibration design. Hyperelastic models have already been widely used in industries over many years and are suitable for the loading predictions but not capable for the evaluation of the unloading (the stress softening or the Mullins effect) conditions. The response of antivibration components is significantly different between the upload and the unload conditions and can cause the unforeseen performance of the system. This article proposes a hyperelastic-unloading model to predict (not limited to simulate) the complete load–unload–deflection response of the rubber antivibration systems using only one parameter, i.e. resilience index. Six industrial products have successfully been used for the verification. A key finding is that the complete loading–unloading response can be obtained realistically using the resilience index [Formula: see text] for the design of brand new products without data fitting procedures. The value can be altered for existing products to suit different applications. In industries, the existing hyperelastic models can be easily modified to the hyperelastic-unloading models without changing their values of the original parameters. The suggested approach is effective and can be used in the antivibration analysis and applications.
The application of RNA sequencing for the diagnosis and genomic classification of pediatric acute lymphoblastic leukemia
Authors: Brown Lauren M. , Lonsdale Andrew , Zhu Andrea , Davidson Nadia M. , Schmidt Breon , Hawkins Anthony , Wallach Elise , Martin Michelle , Mechinaud Francoise M. , Khaw Seong Lin , Bartolo Ray C. , Ludlow Louise E. A. , Challis Jackie , Brooks Ian , Petrovic Vida , Venn Nicola C. , Sutton Rosemary , Majewski Ian J. , Oshlack Alicia , Ekert Paul G.
Published: March 2020

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and implementation of risk-adapted therapy has been instrumental in the dramatic improvements in clinical outcomes. A key to risk-adapted therapies includes the identification of genomic features of individual tumors, including chromosome number (for hyper- and hypodiploidy) and gene fusions, notably ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1 in B-cell ALL (B-ALL). RNA-sequencing (RNA-seq) of large ALL cohorts has expanded the number of recurrent gene fusions recognized as drivers in ALL, and identification of these new entities will contribute to refining ALL risk stratification. We used RNA-seq on 126 ALL patients from our clinical service to test the utility of including RNA-seq in standard-of-care diagnostic pipelines to detect gene rearrangements and IKZF1 deletions. RNA-seq identified 86% of rearrangements detected by standard-of-care diagnostics. KMT2A (MLL) rearrangements, although usually identified, were the most commonly missed by RNA-seq as a result of low expression. RNA-seq identified rearrangements that were not detected by standard-of-care testing in 9 patients. These were found in patients who were not classifiable using standard molecular assessment. We developed an approach to detect the most common IKZF1 deletion from RNA-seq data and validated this using an RQ-PCR assay. We applied an expression classifier to identify Philadelphia chromosome–like B-ALL patients. T-ALL proved a rich source of novel gene fusions, which have clinical implications or provide insights into disease biology. Our experience shows that RNA-seq can be implemented within an individual clinical service to enhance the current molecular diagnostic risk classification of ALL.
A novel C2 domain binding CD33xCD3 bispecific antibody with potent T-cell redirection activity against acute myeloid leukemia
Authors: Nair-Gupta Priyanka , Diem Michael , Reeves Dara , Wang Weirong , Schulingkamp Robert , Sproesser Katrin , Mattson Bethany , Heidrich Bradley , Mendonça Mark , Joseph Jocelin , Sendecki Jocelyn , Foulk Brad , Chu Gerald , Fink Damien , Jiao Qun , Wu Sheng-Jiun , Packman Kathryn , Elsayed Yusri , Attar Ricardo , Gaudet François
Published: March 2020

CD33 is expressed in 90% of patients with acute myeloid leukemia (AML), and its extracellular portion consists of a V domain and a C2 domain. A recent study showed that a single nucleotide polymorphism (SNP), rs12459419 (C > T), results in the reduced expression of V domain–containing CD33 and limited efficacy of V domain–binding anti-CD33 antibodies. We developed JNJ-67571244, a novel human bispecific antibody capable of binding to the C2 domain of CD33 and to CD3, to induce T-cell recruitment and CD33+ tumor cell cytotoxicity independently of their SNP genotype status. JNJ-67571244 specifically binds to CD33-expressing target cells and induces cytotoxicity of CD33+ AML cell lines in vitro along with T-cell activation and cytokine release. JNJ-67571244 also exhibited statistically significant antitumor activity in vivo in established disseminated and subcutaneous mouse models of human AML. Furthermore, this antibody depletes CD33+ blasts in AML patient blood samples with concurrent T-cell activation. JNJ-67571244 also cross-reacts with cynomolgus monkey CD33 and CD3, and dosing of JNJ-67571244 in cynomolgus monkeys resulted in T-cell activation, transient cytokine release, and sustained reduction in CD33+ leukocyte populations. JNJ-67571244 was well tolerated in cynomolgus monkeys up to 30 mg/kg. Lastly, JNJ-67571244 mediated efficient cytotoxicity of cell lines and primary samples regardless of their SNP genotype status, suggesting a potential therapeutic benefit over other V-binding antibodies. JNJ-67571244 is currently in phase 1 clinical trials in patients with relapsed/refractory AML and high-risk myelodysplastic syndrome.
Prevalence and risk factors for khat use among youth students in Ethiopia: systematic review and meta-analysis, 2018
Authors: Alemu Wondale Getinet , Zeleke Tadele Amare , Takele Wubet Worku , Mekonnen Shegaye Shumet
Published: March 2020

Background

Khat use is a widely spreading public health problem affecting the most economically productive population areas in Ethiopia. Khat use among students has been linked with mental, physical, social, and psychological problems. Reliable prevalence has not been recognized because of varying published rates. The objective of this systematic review and meta-analysis is to synthesize evidence on the prevalence and potential risk factors of khat use in Ethiopia.

Methods

We found 284 studies of which 266 were removed due to duplication, irrelevant topics, and other reasons, respectively. All studies conducted in Ethiopia on khat chewing among students irrespective of time frame were included. Subsequently, 18 studies were used for synthesis of prevalence. Figures were extracted from published reports, and any lost information was requested from investigators. The quality of the included literature was evaluated by using the Newcastle–Ottawa Scale (NOS). Prevalence was pooled using random-effects meta-analyses. The presence of association was declared using P-values and an odds ratio with a corresponding 95% CI.

Results

The pooled prevalence of khat use among students was 16.7% (13.7–19.7%). In the subgroup analysis, the highest prevalence was observed in the Oromia region, at 21.1% (15.5%, 26.7%), and an almost equal prevalence of 14.8% (10.6, 18.9) and 14.3% (10.3, 18.3) was observed in Amhara and the Southern Nation, Nationalities, and People’s Region of Ethiopia, respectively. Being male (OR: 2.43 (1.73, 3.13)), being a Muslim religion follower (OR: 2.22 (1.6, 2.8)), being an alcohol user (OR: 2.3 (1.5, 3.0)), khat use by a family member (OR: 1.8 (1.4, 2.2)), peer pressure (OR: 4.4 (3.1, 5.6)), and being a cigarette smoker (OR: 8.5 (5.3, 11.7)) were found to be risk factors for khat chewing.

Conclusions

Khat use is a common problem among students. Health promotion, awareness on effect of khat, set policy on khat and substance use on the male sex, Muslim religion, alcohol user, having a family-member khat user, peer pressure, and being a cigarette smoker as possible risk factors for khat use among students.

Limitations

Irrespective of time restriction, all studies conducted in Ethiopia are included and cross-sectional in nature. Protocol no. CRD-42017081886.
Personalized cognitive-behavioural therapy for obesity (CBT-OB): theory, strategies and procedures
Authors: Dalle Grave Riccardo , Sartirana Massimiliano , Calugi Simona
Published: March 2020

Personalized cognitive-behavioural therapy for obesity (CBT-OB) is a new treatment that combines the traditional procedures of standard behavioural therapy for obesity (i.e., self-monitoring, goal setting, stimulus control, contingency management, behavioural substitution, skills for increasing social support, problem solving and relapse prevention) with a battery of specific cognitive strategies and procedures. These enable the treatment to be individualized, and to help patients to address the cognitive processes that previous research has found to be associated with treatment discontinuation, the amount of weight lost and long-term weight-loss maintenance. The treatment programme can be delivered at three levels of care, outpatient, day hospital and residential, and includes six modules, which are introduced according to the individual patient’s needs as part of a flexible, personalized approach. The primary goals of CBT-OB are to help patients to (i) achieve, accept and maintain healthy weight loss; (ii) adopt a lifestyle conducive to weight control; and (iii) develop a stable “weight-control mindset”. A randomized controlled trial has found that 88 patients suffering from morbid obesity treated with CBT-OB followed a period of residential treatment achieved a mean weight loss of 15% after 12 months, with no tendency to regain weight between 6 and 12 months. The treatment efficacy is also supported by data from a study assessing the effects of group CBT-OB delivered in a real-world clinical setting. In that study, 77 patients with morbid obesity who completed the treatment achieved 9.9% weight loss after 18 months. These promising results, if confirmed by future clinical studies, suggest that CBT-OB has the potential to be more effective than traditional weight-loss lifestyle-modification programmes.
A novel transplantable model of lung cancer-associated tissue loss and disrupted muscle regeneration
Authors: Arneson-Wissink Paige C. , Ducharme Alexandra M. , Doles Jason D.
Published: March 2020

Background

Cancer-associated muscle wasting (CAW), a symptom of cancer cachexia, is associated with approximately 20% of lung cancer deaths and remains poorly characterized on a mechanistic level. Current animal models for lung cancer-associated cachexia are limited in that they (1) primarily employ flank transplantation methods, (2) have short survival times not reflective of the patient condition, and (3) are typically performed in young mice not representative of mean patient age. This study investigates a new model for lung cancer-associated cachexia that can address these issues and also implicates muscle regeneration as a contributor to CAW.

Methods

We used tail vein injection as a method to introduce tumor cells that seed primarily in the lungs of mice. Body composition of tumor-bearing mice was longitudinally tracked using NMR-based, echo magnetic resonance imaging (echoMRI). These data were combined with histological and molecular assessments of skeletal muscle to provide a complete analysis of muscle wasting.

Results

In this new lung CAW model, we observed (1) progressive loss in whole body weight, (2) progressive loss of lean and fat mass, (3) a circulating cytokine/inflammatory profile similar to that seen in other models of CAW, (4) histological changes associated with muscle wasting, and (5) molecular changes in muscle that implicate suppression of muscle repair/regeneration. Finally, we show that survival can be extended without lessening CAW by titrating injected cell number.

Conclusions

Overall, this study describes a new model of CAW that could be useful for further studies of lung cancer-associated wasting and accompanying changes in the regenerative capacity of muscle. Additionally, this model addresses many recent concerns with existing models such as immunocompetence, tumor location, and survival time.
Protective and therapeutic effects of nanoliposomal quercetin on acute liver injury in rats
Authors: Liu Xiangyan , Zhang Yang , Liu Ling , Pan Yifeng , Hu Yu , Yang Pu , Liao Mingmei
Published: March 2020

Background

Quercetin, a pigment (flavonoid) found in many plants and foods, has good effects on protecting liver function but poor solubility and bioavailability in vivo. A drug delivery system can improve the accumulation and bioavailability of quercetin in liver. In this study, we used liposomal nanoparticles to entrap quercetin and evaluated its protective and therapeutic effects on drug-induced liver injury in rats.

Methods

The nanoliposomal quercetin was prepared by a thin film evaporation-high pressure homogenization method and characterized by morphology, particle size and drug content. Acute liver injury was induced in rats by composite factors, including carbon tetrachloride injection, high-fat corn powder intake and ethanol drinking. After pure quercetin or nanoliposomal quercetin treatment, liver function was evaluated by detecting serum levels of glutamic-pyruvic transaminase (GPT), glutamic-oxal acetic transaminase (GOT) and direct bilirubin (DBIL). Histology of injured liver tissues was evaluated by hematoxylin and eosin staining.

Results

On histology, liposomal nanoparticles loading quercetin were evenly distributed spherical particles. The nanoliposomal quercetin showed high bioactivity and bioavailability in rat liver and markedly attenuated the liver index and pathologic changes in injured liver tissue. With nanoliposomal quercetin treatment, the serum levels of GPT, GOT and DBIL were significantly better than treated with pure quercetin. Using liposomal nanoparticles to entrap quercetin might be an effective strategy to reduce hepatic injury and protect hepatocytes against damage.

Conclusion

Liposomal nanoparticles may improve the solubility and bioavailability of quercetin in liver. Furthermore, nanoliposomal quercetin could effectively protect rats against acute liver injury and may be a new hepatoprotective and therapeutic agent for patients with liver diseases.
Targeting PI3K in alveolar rhabdomyosarcoma (aRMS)
Authors: Crosswell H. E. , Peng Q. , Prince C. , De P. , Durden D. L.
Published: March 2020

10025

Background: aRMS is a pediatric solid tumor with a poor prognosis despite aggressive therapy. HGF/c-Met & PTEN-PI3K-AKT pathways are aberrant, leading to aRMS growth & metastasis. We hypothesize that recapitulating the tumor suppressor (TS) function of PTEN with small molecular inhibitors (SMIs) may control aRMS. SMIs of HGF/c-Met & PI3K pathways were examined for their control of aRMS growth & migration. Design/Methods: Pax3/fkhr-associated aRMS cells, RH30, were infected with MIEG3/PTEN (RH30MP1), MIEG3 retroviral vector (RH30MV1) or CMV-driven luciferase (RH30Luc). Migration was assessed by a transwell migration chamber; proliferation with a MTT assay; biochemical analysis by Western blot. Tumor growth and spontaneous lung metastasis in IACUC-approved animal experiments, in which cell lines were injected s.c. in nude mice, were analysed by bioluminescent imaging (BLI) or by direct measurements. Students t-test (p<.05) determined significance. Results: Western analysis revealed RH30 cells have low PTEN, high levels of c-Met & p-AKT. HGF stimulation of RH30 cells results in increased p-Met, p-Akt & p-Erk1/2 levels, correlating with enhanced migration and proliferation (<.001). SMI of PI3K (LY294002) controls RH30 proliferation (p<.01), not migration; c-Met (PHA665752) & MAPK (PD98059) SMIs stop HGF-directed migration through control of p-Erk levels (p<.01). PTEN induction in RH30 cells via PPAR-gamma agonist, rosiglitazone, results in decreased basal p-Akt levels. RH30 cells with stable, retroviral-infected PTEN have significantly reduced migration& proliferation as compared to cells with vector alone (p<.001). In nude mice xenograft models, PTEN & novel PI3K SMI, SF1126 at 50mg/kg, control RH30 tumoriginesis. SF1126 also controls spontaneous RH30Luc metastasis to the lungs. Conclusions: High c-Met-expressing RH30 cells are sensitive to HGF-stimulated migration through MAPK & proliferation via PI3K. PTEN’s control of aRMS migration, proliferation & tumorigenesis suggests that PTEN controls both PI3K & MAPK. Novel PI3K inhibitor, SF1126, controls tumor growth in vivo & prevents spontaneous lung metastasis. Recapitulating PTEN TS function with SF1126 alone or in combination with SMIs of the HGF/c-Met or MAPK may benefit patients with aRMS & deserves further pre-clinical study.

[Table: see text]
A comparison of BRCA1 and BRCA2 risk assessment models
Authors: Panchal S. , Ennis M. , Yee H. , Contiga V. , Bordeleau L. J.
Published: March 2020

10034

Background: A number of models of varying complexity are available to calculate the risk of carrying a BRCA1 or BRCA2 mutation causing hereditary breast and ovarian cancer. A >10% risk of carrying a BRCA1 or BRCA2 mutation is commonly used to establish testing eligibility in North America (testing threshold). We have compared these risk assessment models to ascertain their utility in patients from a large breast cancer program in our tertiary referral center. Methods: Risk assessment calculations were performed using the BRCAPRO, Myriad, Manchester, and UPennII models for all new probands referred to our clinic at Mount Sinai Hospital, Toronto (Canada), between May and October 2005. Individuals with a known familial mutation were excluded. Pearson correlation coefficients and pairwise scatterplots were performed for each pair of models. Regression analyses were developed to explore how well the BRCAPRO model can be predicted by other models. Results: 103 probands were included in our analyses (97% female, mean age: 50 yrs, 22% of Ashkenazi Jewish descent, 52.4% affected with breast cancer, 67% with ≥ one 1st degree relative affected with breast or ovarian cancer). The proportion of probands meeting the testing threshold based on each model was: BRCAPRO (34.0%), Myriad (33.0%), Manchester (55.3%), and UPennII (46.6%). Correlations calculated for each pair of models were large (range: 0.48–0.86). In comparing two of the most clinically relevant models (BRCAPRO and UPennII), the proportion of probands meeting the testing threshold was significantly higher using the UPennII model (p=0.0036). Between these two models, a higher correlation was observed for BRCA1 than for BRCA2 (R=0.76, R=0.58, respectively). The UPennII model was the strongest univariate predictor of the BRCAPRO results. Conclusions: All risk assessment models predicted a substantial proportion of patients referred to our clinic to be eligible for testing (≥ 33% of probands). A significantly higher proportion of probands were eligible for testing when using the UPennII model compared to the BRCAPRO model. This difference is in part due to the differential inclusion of prostate/pancreatic cancers and of third degree relatives with cancer in these models. An exploration of the sensitivity and specificity of these models will be presented.

No significant financial relationships to disclose.
Serum antibodies specific for tumor antigens in colorectal cancer may be useful diagnostic biomarkers
Authors: Lu H. , Goodell V. , Disis M. L.
Published: March 2020

10041

Background: Colorectal cancer is immunogenic as evidenced by the presence of antibodies specific to tumor antigens in patient serum and T cell infiltration at the tumor site predicting favorable disease outcome. We questioned whether antibody immunity to tumor associated antigens (TAA) in patients with colorectal cancer could be used as a biomarker to predict disease. Methods: We evaluated serum samples for the presence of antibody immunity to six tumor antigens, cyclin D1, HER-2/neu, insulin-like growth factor binding protein 2 (IGFBP2), NY-ESO-1, p53, and topoisomerase-IIα (TOPO2α), in colorectal cancer patients (n=40) and normal donors (n=200) using ELISA. We then evaluated the diagnostic value of these potential biomarkers by measuring antibody levels to these TAA in an independent sample set which included 30 colorectal cancer patients and 135 normal donors. The samples were judged as positive or negative for colorectal cancer using measurements derived either from a single marker or a combination of the markers. Receiver operating characteristic (ROC) plots were generated to determine the diagnostic accuracy of each test. Results: Colorectal cancer patients had increased levels of antibodies to p53 (p=0.002), TOPO2α (p<0.001), and IGFBP2 (p<0.001) compared to controls. By using a combination of just two antibody measurements, TOPO2α and IGFBP2, we could discriminate colorectal cancer patients from controls with a diagnostic power of 0.775 as estimated by the area under ROC curve. At a cutoff point of 0.03 mcg/ml TAA specific IgG, the sensitivity was 100% and the specificity was 58%. Conclusions: Serum antibodies to colorectal cancer related antigens may serve as useful biomarkers for colorectal cancer diagnosis.

No significant financial relationships to disclose.
Therapy prediction in a breast cancer primary systemic chemotherapy (PST) study applying docetaxel/epirubicin/cyclophosphamide (TEC) by gene expression profiling
Authors: Vogt U. , Brandt B. , Bosse U. , Bonk U. , Adigüzel H. , Ergoenenc Y. , Kemming D. , Schlotter C.
Published: March 2020

10049

Background: Currently there are no tests to assist in selecting the optimal PST regimen for breast cancer patients. Primary study goals of this prospective, single-armed multicentric investigation are pathologically confirmed tumor response and the rate of breast conserving therapy (BCT). Secondary goals are to find histopathologic and gene profiling patterns best correlating with tumor remission in a taxane- anthracycline based neoadjuvant setting as well as to evaluate cytostatic toxicity and quality of life. Methods: In this phase II study of totally 40 eligible patients with invasive breast cancer Human Genome Survey Microarray (HGSM) expression profiling is performed on jet-biopsy sample basis. The protocol was elaborated for the treatment of patients suffering from a primary tumor with 6 cycles of TEC (3-weekly) prior to the surgical treatment. The selection of predictor genes was done with BRB-ArrayTools Version 3.3 using a model based on the Compound Covariate Predictor, Diagonal Linear Discriminant Analysis, Nearest Neighbor Classification, and Support Vector Machines with linear kernel.We estimated the prediction error of each model using leave-one-out cross-validation (LOOCV) as described by Simon R. 2000 random permutations were used. Clustering was done using Cluster 3.0 and Java TreeView 1.0.12. Results: Tumor response (pCR, pPR) of more than 70% can be achieved using neoadjuvant TEC-regimen. 22% pCR (ypT0; ypN0) and 90% BCT in this study are comparable with data of other published PST trials. Preliminary expression profiling results reveal a subset of 148 genes that classifies all patients with a complete remission (pCR), in one cluster with a very closely related gene expression pattern (n=5; PPV = 100%). Furthermore 10 patients defined as responders due to selected MIB1-expression based criteria (expressing cells in the residual tumor ≤ 5% and a Δ MIB1-expression ≥ 20%) can be correctly classified in 9 of 10 cases. Comparable separation of the groups could not be achieved by established tumor factors. Conclusions: HGSM expression profiling is promising to have the potential to figure out genes that are related to chemotherapy response, especially in PST.

No significant financial relationships to disclose.
Gene and surface-antigen expression profilings concordantly identify alpha4-integrin/CD49d as a marker for unmutated (UM) bad prognosis B-cell chronic lymphocytic leukemia (B-CLL)
Authors: Gattei V. , Benedetti D. , Marconi D. , Dal Bo M. , Zucchetto A. , Del Poeta G. , Steffan A. , Bomben R. , Campanini R. , Degan M.
Published: March 2020

10076

Background: The highly heterogeneous clinical courses of B-CLL can be foreseen by investigating IgVH gene mutations or expression of specific prognosticators. Gene and surface-antigen expression profilings (GEP and SEP) have been both employed for identifying molecules of prognostic relevance in B-CLL. Methods: i) GEP - Purified B-CLL cells from 19 UM and 38 mutated (M) cases were investigated for differential GEP by using a two-color Operon Human Genome Oligo Set 2.1 platform with normal B cells as common reference and by applying, after data pre-processing, the LIMMA (Linear Model for MicroArray) package with two combined cutoffs (Bayesian log-odds>1; adjusted p value for false discovery rate <10e−4); ii) SEP - B-CLL cells from 60 UM and 101 M cases were investigated for the expression of 36 surface markers by flow cytometry. Results: i) GEP - 77 probes (32 duplicates) were overexpressed in M B-CLLs (UM/M log-ratio range −0.79/−3.62; p range 6.72e−5/3.6e−10) and 81 probes (46 duplicates) in UM B-CLLs (UM/M log-ratio range 0.87/4.57; p range 9.49e−5/3.01e−12); the CD49d gene was overexpressed in UM cases with UM/M log-ratio of 3.21 (p=8.3e-10). ii) SEP - Six markers significantly discriminated UM to M B-CLLs (t-test, p<10ed-3) and separated most UM (49/60) from M B-CLLs by hierarchical clustering; among them, CD49d was significantly overexpressed in UM cases (median % positive cells 71.2±36 vs. 10.0±31; p=2.1e−10). By applying standardized log-rank statistics in 95 pts, all with CD49d expression and survival data, 30% of positive cells was judged optimal cutoff for identifying two groups with different survivals, 41 CD49dhigh pts showing worse prognosis than 54 CD49dlow cases (p=7.4×10e−5). Similarly, 46 UM B-CLLs had shorter survival than 77 M cases (p=1.4×10e−5). By combining IgVH mutations and CD49d expression, 42 concordant M/CD49dlow pts had better prognosis than 25 concordant UM/CD49dhigh cases (p=1.8×10e−5); noteworthy, among 28 discordant cases, 16 with a M/CD49dhigh phenotype had survival similar to bad prognosis cases. Conclusions: CD49d is a novel prognosticator for B-CLL. Given its high expression level in bad prognosis subsets, CD49d may be a promising therapeutic target.

No significant financial relationships to disclose.
Serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) as prognostic factors in malignant pleural mesothelioma (MPM)
Authors: Betta P. , Filiberti R. , Marroni P. , Neri M. , Orecchia S. , Libener R. , Bottero G. , Paganuzzi M. , Puntoni R.
Published: March 2020

10080

Background: MPM is an uncommon but extremely aggressive tumor of the serosal surfaces, which has been closely linked to asbestos exposure. Several in-vitro studies have demonstrated that HGF enhances MPM cell proliferation, migration, and invasiveness and the presence of EGF is closely related to the process of cell differentiation and the synthesis of glycosaminoglycans in MPM cells. Few studies have measured the blood levels of these growth factors in tumor patients and assessed their correlation with clinical outcome. This pilot study was designed to investigate the potential value of serum EGF and HGF measurements for the diagnosis and the prediction of survival in MPM patients. Methods: Baseline serum EGF and HGF levels (ng/ml) were determined using an ELISA method in 81 newly diagnosed MPM patients (mean age 67.5±11.0 years) and 48 patients with benign respiratory diseases (BRD; mean age 64.3±13.5 years). Results: HGF and EGF median concentrations in MPM (1.6 ng/ml and 0.5 ng/ml, respectively) were not statistically different from concentrations in BRD (1.2 ng/ml and 0.4 ng/ml). Median follow-up for MPM patients was 27 months, while overall median survival was 11.8 months. At univariate analysis, only high EGF serum levels were associated with an unfavorable survival outcome. Using a cut-off point for EGF of 0.5 ng/ml (corresponding to the median of marker concentration in MPM), the survival rate in patients with higher serum EGF was significantly worse than that in patients with lower levels (median 10.7 vs. 13.0 months, p=0.01). Multivariate analysis, after adjusting for age, sex, histology and platelet count, confirmed the independent predictive value of serum EGF concentration as a negative prognostic factor (p=0.01). Conclusions: High pre-treatment levels of serum EGF are associated with an adverse prognostic impact on survival in MPM patients.

No significant financial relationships to disclose.
Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer
Authors: Reinthaller A. , Sevelda P. , Hefler L. A.
Published: March 2020

10093

Objective: Serum vascular endothelial growth factor (VEGF) levels have been shown to be associated with an adverse outcome in patients with ovarian cancer. We studied the clinical value of serum VEGF as an independent prognostic parameter. Methods: In the present study, we ascertained preoperative serum VEGF in a series of 314 patients with ovarian cancer. VEGF serum were evaluated in 45 new cases. Serum VEGF was evaluated prior to primary surgery in all patients. The re-analysis of previously published data comprised a total of 269 cases. Patients were treated between 1990 and 2003. Mean duration of follow-up was 38.9 (32.4) months. Patients with epithelial ovarian cancer were included into the present study, patients with other malignant ovarian tumors, borderline tumors, and benign adnexal masses were excluded. Serum VEGF was evaluated prior to primary surgery using an enzyme linked immunosorbent assay (Quantikine Human VEGF Immunoassay; R&D Systems, Minneapolis, MN) in all studies. Results were correlated with clinical data. Results: Median serum VEGF was 407 (238–746) pg/mL. Serum VEGF was associated with serum CA 125 (p=0.003) and residual tumor mass (p=0.02; residual tumor mass < 1cm: 375.5 [209.5–608.9] pg/mL vs. residual tumor mass ≥ 1cm: 625.2 [320.7–1046.7] pg/mL). Serum VEGF was not associated with FIGO stage (p=0.5), lymph node involvement (p=0.2), tumor grade (p=0.2), and patients’ age (p=0.08). In a univariate Kaplan-Meier analysis, FIGO stage, residual tumor mass, tumor grade, patients’ age, serum CA 125, and preoperative serum VEGF were associated with overall survival. In a multivariate Cox regression model, higher FIGO stage, presence of residual tumor mass after primary surgery, and higher serum VEGF were independently associated with a shortened overall survival. Planned subgroup analysis was performed for patients with ovarian cancer FIGO stage I. In a multivariate Cox regression model, higher tumor grade and higher serum VEGF were the only independent prognosticators for overall survival. Patients with FIGO stage I ovarian cancer and a serum VEGF ≥ 380 pg/mL had a 8-fold increased risk for experiencing cancer related death. Conclusion: Serum VEGF is an independent prognostic parameter in patients with all stages of ovarian cancer.

No significant financial relationships to disclose.