bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR‐506‐loaded gelatin nanospheres target PENK and inactivate the ERK/Fos signaling pathway to suppress triple‐negative breast cancer aggressiveness
Authors: Liu Xin‐Li , Liu Wen‐Jing , Chen Qiang , Liu Jie , Yang Chang‐Qing , Zhang Ge , Zhang Shi‐Long , Guo Wei‐Hong , Li Jing‐Bao , Zhao Gang , Yin Da‐Chuan , Zhang Chen‐Yan 
Published: June 2021

AbstractTriple‐negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Some microRNAs (miRNAs) were abnormally expressed in TNBC, and they are closely related to the occurrence and progression of TNBC. Here, we found that miR‐506 was significantly downregulated in TNBC and relatively lower miR‐506 expression predicted a poorer prognosis. Moreover, we found that miR‐506 could inhibit MDA‐MB‐231 cell viability, colony formation, migration, and invasion, and suppress the ERK/Fos oncogenic signaling pathway through upregulating its direct target protein proenkephalin (PENK). Therefore, miR‐506 was proposed as a nucleic acid drug for TNBC therapy. However, miRNA is unstable in vivo, which limiting its application as a therapeutic drug via conventional oral or injected therapies. Here, a gelatin nanosphere (GN) delivery system was applied for the first time to load exogenous miRNA. Exogenous miR‐506 mimic was loaded on GNs and injected into the in situ TNBC animal model, and the miR‐506 could achieve sustained and controlled release. The results confirmed that overexpression of miR‐506 and PENK in vivo through loading on GNs inhibited in situ triple‐negative breast tumor growth and metastasis significantly in the xenograft model. Moreover, we indicated that the ERK/Fos signaling pathway was intensively inactivated after overexpression of miR‐506 and PENK both in vitro and in vivo, which was further validated by the ERK1/2‐specific inhibitor SCH772984. In conclusion, this study demonstrates that miR‐506‐loaded GNs have great potential in anti‐TNBC aggressiveness therapy.
Prognostic Role of Circulating Tumor Cells in Metastatic Renal Cell Carcinoma: A Large, Multicenter, Prospective Trial
Authors: Basso Umberto , Facchinetti Antonella , Rossi Elisabetta , Maruzzo Marco , Conteduca Vincenza , Aieta Michele , Massari Francesco , Fraccon Anna Paola , Mucciarini Claudia , Sava Teodoro , Santoni Matteo , Pegoraro Cristina , Durante Emilia , Nicodemo Maurizio , Perin Alessandra , Bearz Alessandra , Gatti Carlo , Fiduccia Pasquale , Diminutto Alberto , Barile Carmen , De Giorgi Ugo , Zamarchi Rita , Zagonel Vittorina 
Published: June 2021

Abstract

Background
Circulating tumor cells (CTCs) correlate with adverse prognosis in patients with breast, colorectal, lung, and prostate cancer. Little data are available for renal cell carcinoma (RCC).

Materials and Methods
We designed a multicenter prospective observational study to assess the correlation between CTC counts and progression-free survival (PFS) in patients with metastatic RCC treated with an antiangiogenic tyrosine kinase inhibitor as a first-line regimen; overall survival (OS) and response were secondary objectives. CTC counts were enumerated by the CellSearch system at four time points: day 0 of treatment, day 28, day 56 and then at progression, or at 12 months in the absence of progression.

Results
One hundred ninety-five eligible patients with a median age of 69 years were treated with sunitinib (77.5%) or pazopanib (21%). At baseline, 46.7% of patients had one or more CTCs per milliliter (range, 1 to 263). Thirty patients had at least three CTCs, with a median PFS of 5.8 versus 15 months in the remaining patients (p = .002; hazard ratio [HR], 1.99), independently of the International Metastatic RCC Database Consortium score at multivariate analysis (HR, 1.91; 95% confidence interval [CI], 1.16–3.14). Patients with at least three CTCs had a shorter estimated OS of 13.8 months versus 52.8 months in those with fewer than three CTCs (p = .003; HR, 1.99; multivariate analysis HR, 1.67; 95% CI, 0.95–2.93). Baseline CTC counts did not correlate with response; neither did having CTC sequencing counts greater than or equal to one, two, three, four, or five.

Conclusion
We provide prospective evidence that the presence of three or more CTCs at baseline is associated with a significantly shorter PFS and OS in patients with metastatic RCC.

Implications for Practice
This prospective study evaluated whether the presence of circulating tumor cells (CTCs) in the peripheral blood correlates with activity of first-line tyrosine kinase inhibitors in metastatic renal cell carcinoma (RCC). This study demonstrated that almost half of patients with metastatic RCC have at least one CTC in their blood and that those patients with at least three CTCs are at increased risk of early progressive disease and early death due to RCC. Studies incorporating CTC counts in the prognostic algorithms of metastatic RCC are warranted.
Tisagenlecleucel for treatment of children and young adults with relapsed/refractory B‐cell acute lymphoblastic leukemia
Authors: Si Lim Stephanie J. , Grupp Stephen A. , DiNofia Amanda M. 
Published: June 2021

AbstractThe treatment landscape for cancer therapy has changed drastically over the past decade. Tisagenlecleucel, the first genetically engineered adoptive cellular therapy approved by the United States Food and Drug Administration, has revolutionized this field by demonstrating impressive clinical success in children and young adults with relapsed/refractory B‐cell acute lymphoblastic leukemia (r/r B‐ALL). Now 3 years since its approval, we have gained a deeper understanding on the basic immunobiology and clinical efficacy of this drug. This review will provide an updated summary of tisagenlecleucel in childhood and young adults with r/r B‐ALL, common side effects and their associated management strategies, as well as barriers that remain to be addressed in order to realize the maximum potential of this drug.
The price of punishment: Days missed due to suspension in U.S. K‐12 public schools
Authors: Fabes Richard A. , Catherine Evandra , Quick Matthew , Blevins Darielle , Musgrave Aryn 
Published: June 2021

AbstractThe number of days missed due to suspensions (DMS) was analyzed in a national sample of K‐12 public schools in the U.S. In the 2017–2018 national sample, about 11 million days of school were missed due to suspension. Rates of DMS varied across the regions of the U.S., from state to state, and from school to school (greater in nonelementary and non‐charter public schools). Additionally, disparities were found with higher rates found for boys relative to girls and for Black children relative to White children. Regression analyses revealed that school characteristics explained the greatest amount of variance in rates of DMS, although enrollment characteristics also accounted for a significant amount of the variance. It was concluded that there is a need to for more research to better understand the factors that predict DMS and its adverse outcomes for students and to help develop effective prevention and intervention efforts to reduce its use, especially to reduce disparities in its use.
Assessment of thePETaseconformational changes induced by poly(ethylene terephthalate) binding
Authors: da Costa Clauber Henrique Souza , dos Santos Alberto M. , Alves Cláudio Nahum , Martí Sérgio , Moliner Vicent , Santana Kauê , Lameira Jerônimo 
Published: June 2021

AbstractRecently, a bacterium strain ofIdeonella sakaiensiswas identified with the uncommon ability to degrade the poly(ethylene terephthalate) (PET). The PETase fromI. sakaiensisstrain 201‐F6 (IsPETase) catalyzes the hydrolysis of PET converting it to mono(2‐hydroxyethyl) terephthalic acid (MHET), bis(2‐hydroxyethyl)‐TPA (BHET), and terephthalic acid (TPA). Despite the potential of this enzyme for mitigation or elimination of environmental contaminants, one of the limitations of the use ofIsPETase for PET degradation is the fact that it acts only at moderate temperature due to its low thermal stability. Besides, molecular details of the main interactions of PET in the active site ofIsPETase remain unclear. Herein, molecular docking and molecular dynamics (MD) simulations were applied to analyze structural changes ofIsPETase induced by PET binding. Results from the essential dynamics revealed that the β1‐β2 connecting loop is very flexible. This loop is located far from the active site ofIsPETase and we suggest that it can be considered for mutagenesis to increase the thermal stability ofIsPETase. The free energy landscape (FEL) demonstrates that the main change in the transition between the unbound to the bound state is associated with the β7‐α5 connecting loop, where the catalytic residue Asp206 is located. Overall, the present study provides insights into the molecular binding mechanism of PET into theIsPETase structure and a computational strategy for mapping flexible regions of this enzyme, which can be useful for the engineering of more efficient enzymes for recycling plastic polymers using biological systems.
Does sustainability performance impact financial performance? Evidence from Indian service sector firms
Authors: Jyoti Gaurav , Khanna Ashu 
Published: June 2021

AbstractThe present scenario of growth and development is focused on sustainable development. It can be sustainable only if it does not focus on profit maximization at any cost but also maximizes the interests and value addition of various stakeholders by not affecting the environment and natural resources. This paper examines the impact of the firm's sustainable performance on the financial performance of service sector companies listed on the Bombay Stock Exchange. The study outcomes indicate a significant negative relationship between the Environment score with Return on Assets (ROA) and Return on capital employed (ROCE) of the selected companies. In contrast, only the Social score shows a significant negative association with the Return on equity. Environmental, social, and governance combined score is also negatively significant with the ROA and ROCE. The practical implications of the study would help academicians, business entities, corporates, policymakers, regulatory authorities, and governments to understand the relationship better. It can also help and motivate organizations to operate more efficiently and implement sustainable approaches, especially in rapidly emerging economies like India.
Measuring L1 and L2 Productive Derivational Knowledge: How Many Derivatives Can L1 and L2 Learners with Differing Vocabulary Levels Produce?
Authors: Iwaizumi Emi , Webb Stuart 
Published: June 2021

AbstractDerivational knowledge, the ability to understand and produce derivatives of a word, is essential for vocabulary learners to expand their lexical knowledge. Earlier research (e.g., Schmitt & Zimmerman, 2002) has shown that L2 learners may have limited ability to produce derivatives compared to L1 speakers. However, the degree to which productive derivational knowledge differs between L1 and L2 learners, and among learners at different levels of vocabulary knowledge has yet to be examined. The present study investigated the extent to which L1 English speakers (n = 23) and L2 English learners (n = 107) at varying vocabulary levels (1000‐5000) could produce the derivatives of 90 headwords in a decontextualized derivative recall test. A generalized linear mixed model indicated that L1 and L2 productive derivational knowledge significantly differed, and L2 productive derivational knowledge differed among learners with different vocabulary levels. However, the results revealed that the L1 speakers and the learners who had mastered the higher vocabulary levels (3000–5000) produced a similar number of derivatives in the decontextualized recall test. The findings suggest that learners’ vocabulary levels could be indicative of L2 productive derivational knowledge to some degree. Lastly, the results are discussed to provide pedagogical implications for teaching and assessing L2 productive derivational knowledge.
Strategies to mitigate inequity within mandatory health insurance systems: A systematic review
Authors: Vaidya Shalvaree , Boes Stefan 
Published: June 2021

AbstractMandatory health insurance (MHI) systems carry potential inequities due to their infrastructures. However, they are difficult to categorize and compare due to a high level of global variation. Thus, we conducted a review to define MHI systems typology and set forth recommendations regarding health systems classifications. Subsequently, we also aimed to understand the strategies used within MHI systems to decrease inequity. Using a systematic literature review, we found that health system typologies tend to classify MHI systems within the overarching social health insurance category, thus using the MHI term more as a descriptor rather than an official grouping of systems. Additionally, mandatory payments toward insurance lead to vertical and horizonta\ inequities that impact health outcomes. Social benefit schemes within countries aim to mitigate these inequities, although success rates vary greatly. MHI has the potential to be highly effective in providing universal coverage, thus contributing directly to the health system goals.
Promising Biomarkers for Early Diagnosis and Prognosis Prediction
Authors: Sloan Philip , Robinson Max 
Published: June 2021

AbstractSingle molecule biomarkers are used extensively in head and neck pathology for diagnosis and increasingly for prognosis. Companion markers for therapy such as PDL-1 and NTRK are now finding applications in head and neck cancer care. Immunohistochemistry is an attractive option because of its rapid turnaround time and convenience but molecular testing is often necessary for validation. This chapter will focus on some selected biomarkers being developed for translational purposes. Adoptive T cell therapies are being trialled for head and neck cancer and have limited efficacy currently. Identification of biomarkers as targets is an attractive option for development, and the use of molecular sequencing to identify individual neo-antigens is a promising way forward for precision medicine approaches including adoptive T cell therapies.
Is there a Role for Neoadjuvant Targeted Therapy and Immunotherapy?
Authors: Beyaert Simon , Machiels Jean-Pascal 
Published: June 2021

AbstractNeoadjuvant chemotherapy in head and neck cancer is the subject of much debate. Multiple trials have shown that the concomitant addition of targeted therapies, such as cetuximab to neoadjuvant chemotherapy (docetaxel, cisplatin, 5-fluorouracil), results in increased toxicity. Furthermore, no apparent significant benefit has been demonstrated in small randomized studies. Additional trials are currently being conducted to investigate the role of neoadjuvant immunotherapy, such as anti-PD-(L)1 inhibitors.On the other hand, window of opportunity studies are trials in which patients receive one investigational compound in the period between their cancer diagnosis and the start of standard therapy. The evaluation of new compounds using this approach enables translational research and provides information on molecular and clinical activity as well as predictive biomarkers.
Is there a Role for Adjuvant Targeted and Immunotherapies in Patients with Locoregionally-Advanced Head and Neck Cancer?
Authors: Harrington Kevin J. 
Published: June 2021

AbstractDespite significant technical improvements in the management of patients with locoregionally-advanced head and neck cancers, too many patients fail to achieve durable remissions that ultimately translate into cures. Loco-regional recurrence and/or metastatic relapse after intensive local therapies remain the scourge of those who suffer from this disease, and the surgeons and physicians who treat them. Regrettably, until now, we have failed to develop effective adjuvant therapies that can be delivered after the completion of definitive loco-regional treatment in order to reduce the risk of disease relapse. In this chapter, approaches based on cytotoxic chemotherapy, targeted therapies directed against c-erbB/HER receptors and immune checkpoint inhibition will be discussed. Neither cytotoxic chemotherapy nor anti-HER-family targeted therapies have proven to be successful as adjuvant therapies for locoregionally-advanced head and neck cancers, but there is significant hope that anti-PD1/anti-PD-L1-targeted antibody therapies may deliver progress in this area for the first time.
Epidemiological Aspects in Nasopharyngeal Cancer
Authors: Gatta Gemma 
Published: June 2021

AbstractNasopharyngeal cancer (NPC) is an uncommon cancer. According to the Global Cancer Observatory, of the 129,000 new diagnoses in 2018, 85% has been made in the Asiatic population. In males the annual age adjusted rate of incidence (per 100,000) dramatically varied between 8 in South-Eastern Asia and <1 in Europe. In Europe (period of diagnosis 1999–2007), the annual incidence rate varied between 0.7 (South of Europe) and 0.2 (North of Europe). Incidence is three time higher in men than women. Elderly are more affected than young people. Five-year survival, from European population based cancer registries was 49% (period 1999–2007), survival was better in younger than in older patients (73% vs. 31%), prognosis was more favorable in women than men (54% vs. 47%). Geographical variation of survival was reported, with poor 5-year in the Eastern European countries (36%).Incidence and population based survival are crucial for public health and planning clinical study. Lifestyle and environmental factors are responsible of the decreasing trend of incidence in quite all the world countries.Being one of the rare diseases, NPC need to be centralized for diagnosis and treatment. In Europe, the European Joint Action of Rare Cancers and the European Reference Network for rare disease will play an important role to make progress and reduce geographical disparities.
NK Cells in Immunotherapy: How Important Are They?
Authors: Nerina Denaro , Merlano Marco Carlo 
Published: June 2021

AbstractNK cells are able to perform multiple functions, ranging from immunosurveillance to elimination of mutated or damaged cells, through many different cytotoxic mechanisms. Their functions can be very useful for cancer immunotherapy. But to achieve the maximum support from these extraordinary cells it is necessary to know their effector mechanisms and the mechanisms that lead to their suppression. We have briefly summarized some interesting aspect of their role in immunosurveillance of cancer and metastases, the major mechanisms of cell cytotoxicity, in particular their role in antigen dependent cell cytotoxicity, and many promising strategies currently under study to improve the anticancer function of these cells.Finally, we have taken a closer look at cell therapy in this context, comparing CAR-NK cells and CAR-T cells showing the potential advantages of the former over the latter.
Contemporary Opportunities in Nonsurgical Management of Locoregionally Advanced Head and Neck Squamous Cell Carcinoma
Authors: Huang Shao Hui , Pilar Avinash , Li Jishi , Xu Zhiyuan , O’Sullivan Brian 
Published: June 2021

AbstractThe majority of head and neck squamous cell carcinoma (HNSCC) is now classified into two major types: HPV-mediated [HPV(+)] and HPV-negative [HPV(−)]. Within this paradigm, the 8th edition TNM staging system effected modification about what is considered “locally-advanced” HNSCC. Two phase-III trials (RTOG 1016 and De-ESCALATE HPV) disappointingly showed thatcetuximabis not as effective in HPV(+) oropharyngeal cancer (OPC) compared tocisplatinwith radiotherapy. The recent NRG HN002 de-escalation trial demonstrated the presence of outcome heterogeneity within “low-risk” HPV(+) OPC, some of which continue to benefit fromcisplatincombined with reduced-dose radiotherapy. Moreover, distant metastasis (DM) has consolidated its position as the leading cause of death in HPV(+) OPC and strategies to mitigate it are necessary. Unanswered questions and ongoing-emerging concepts exist in both HPV(+) and HPV– diseases. These include understanding the importance of risk under the rubric of extranodal extension (ENE), including degrees of pathological ENE (pENE), and emerging knowledge about radiologic ENE (rENE). Strategies addressing modification of biological phenomena have become paramount and includes hypoxia modification (such as smoking cessation). In addition, contemporary evidence suggests that immunotherapy improves survival in recurrent/metastatic settings, and it is now also being explored in primary disease presentations in combination with (chemo-)radiotherapy. Induction chemotherapy achieves DM reduction in nasopharyngeal cancer but has only been explored minimally in HPV(+) OPC. Evidence that loco-regional management can be de-intensified following a favorable response to induction treatment would provide an attractive option for HPV(+) OPSCC patients while also addressing risk of developing distant disease.
Current Strategies in the Treatment of Intracranial Large and Giant Aneurysms
Authors: Gmeiner Matthias , Gruber Andreas 
Published: June 2021

AbstractIntroduction: Very large and giant aneurysms are among the most challenging cerebrovascular pathologies in neurosurgery.Methods: The aim of this paper is to review the current literature on the management of very large and giant aneurysms and to describe representative cases illustrating possible treatment strategies.Results: In view of the poor natural history, active management using multiprofessional individualized approaches is required to achieve aneurysm occlusion, relief of mass effect, and obliteration of the embolic source. Both reconstructive (clipping, coiling, stent-assisted coiling, flow diversion [FD]) and deconstructive techniques (parent artery occlusion [PAO], PAO in conjunction with bypass surgery, and strategies of flow modification) are available to achieve definitive treatment with acceptable morbidity.Conclusions: Patients harboring such lesions should be managed at high-volume cerebrovascular centers by multidisciplinary teams trained in all techniques of open and endovascular neurosurgery.
Simplified Analytical/Mechanical Procedure for Post-earthquake Safety Evaluation and Loss Assessment of Buildings
Authors: Pampanin S. 
Published: June 2021

AbstractThe crucial need to develop and implement simple and cost-effective repair and retrofit strategies and solutions for existing structures has been once again emphasized, if at all needed, by the recent catastrophic earthquake events. The significant socio-economic impacts of the Canterbury earthquakes sequence in 2010–2011 as well as of the “series” of independent events within few years in Italy (L’Aquila 2009; Emilia 2012; Central Italy 2016) have triggered a stepchange in the high-level approach towards the implementation of seismic risk reduction, introducing either a mandatory enforcement or significant financial incentives for a national-wide program to assess (and reduce by remedial intervention) the seismic vulnerability/capacity of the whole (non-dwelling) building stock, including safety and expected repairing costs (direct economic losses). This chapter provides an overview of the motivations, challenges and (possible) solutions for such a complex and delicate task with the intent to stimulate awareness, discussion and synergetic actions within the wider international community. Particular focus will be given to the development and on-going continuos refinement of a simplified analytical-mechanical methodology—referred to as SLaMA (Simple Lateral Mechanism Analysis) method—as part of a proposed integrated methodology for either pre- and post-earthquake safety evaluation and loss assessment of buildings, in order to support the engineering community and stakeholders through the various steps of the decision making process of risk (assessment and) reduction.