bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Psychosocial Factors in Effective Design of Solid Waste Management Programmes: Evidence from India
Authors: Pratap Vidya , Dayashankar Maurya , Biju Seena
Published: August 2020

The critical need for behavioural change for effective solid waste management is well known. However, policies and programmes continue to underemphasize this crucial component in their design, especially in developing countries such as India. Further, empirical research on the psychosocial factors in solid waste management in developing countries is limited, including within India, where a large national programme for solid waste management is currently being implemented. Using a household survey based on the theory of planned behavioural change, we examine the psychosocial factors towards household waste segregation. We find that more than knowledge and attitude, consequences to behaviour play a critical role in intention as well as actual behaviour towards household waste segregation. Based on our findings, we draw implications for redesigning the national programme and contribute to empirical evidence on the role of psychosocial factors in solid waste management in the context of developing countries.
Methodological Dimensions of Delineating Peri-urban Areas: The Case of Kolkata Metropolis
Authors: Mondal Dinabandhu , Sen Sucharita
Published: August 2020

In the past few decades, due to urbanization and spatial expansion of cities beyond their municipal boundaries, complex interactions between the city and its surrounding rural areas have occurred, resulting in the formation of peri-urban spaces or zones of transition. There is a plurality of definitions for these peri-urban spaces, due to their diverse character in terms of land and water use, livelihood shifts, demographic and social transitions. Most peri-urban areas, specifically those around large metropolitan cities, are increasingly assuming complex characters, which call for governance structures beyond rural–urban binaries. For any administrative intervention of a serious nature in peri-urban areas, a standard methodology for demarcation of these spaces is required. This article is an attempt to develop and apply such a methodology beyond the existing ones, using government sources of data, in the case of Kolkata Metropolis. This article uses socio-economic and land-use characteristics to achieve this objective. It finds that peri-urban spaces do not necessarily develop uniformly around the city; instead, they are fragmented and could be located both near or relatively far from urban areas.
Cable Wakeboarding for the First Time: How Young People Make Sense of Risk in Adventure Recreation
Authors: Wall Erika
Published: August 2020

Cable wakeboarding can be defined as a risky adventure recreation activity in which young people are the primary participants. Based on interviews and observations focusing on cable wakeboarding in Sweden, young people’s understanding of the risks associated with this activity was analysed. According to the thematic content analysis of the interview transcripts and field notes, the participants’ interpretations of risk were related to the social/spatial context of the adventure recreation activity. Furthermore, the analysis resulted in the identification of two themes: the content of the cable wakeboarding information and procedures, and the city beach community. Overall, the participants’ sense-making of risk in adventure recreation was explored and found to be framed by local attachment and a combination of individualistic and collectivistic perspectives of risk.
The Crowding-in/ out Debate in Investments in India: Fresh Evidence from NARDL Application
Authors: Akber Nusrat , Gupta Megha , Paltasingh Kirtti Ranjan
Published: August 2020

The purpose of the study is to re-examine the issue of the crowding-in/out effect of public investment on private investment by adopting an improved methodology of the ‘nonlinear autoregressive distributive lag’ (NARDL) model. Taking data from 1970 to 2016, the study finds that public investment crowds-in private investment both in the long-run as well as the short-run. However, the short-run elasticity is statistically more significant and larger in magnitude than the long-run elasticity. It has also been found that macroeconomic uncertainty significantly affects private investment both in the long-run and the short-run. Among other determinants of private investment, we observe foreign direct investment (FDI) inflow, credit flow to the private sector, household savings, real rate of interest and expected output affect private investment significantly. The policy implication of the study calls for the designing of public sector policies that enthuse more private investments. More credit flow to private sectors and FDI in different sectors of the economy should be prioritized.

JEL Codes: E22, H54, C32
Imaging the rapid yet transient accumulation of regulatory lipids, lipid kinases, and protein kinases during membrane fusion, at sites of exocytosis of MMP-9 in MCF-7 cells
Authors: Stephens Dominique C. , Powell Tyrel W. , Taraska Justin W. , Harris Dinari A.
Published: August 2020

Background

The regulation of exocytosis is physiologically vital in cells and requires a variety of distinct proteins and lipids that facilitate efficient, fast, and timely release of secretory vesicle cargo. Growing evidence suggests that regulatory lipids act as important lipid signals and regulate various biological processes including exocytosis. Though functional roles of many of these regulatory lipids has been linked to exocytosis, the dynamic behavior of these lipids during membrane fusion at sites of exocytosis in cell culture remains unknown.

Methods

Total internal reflection fluorescence microscopy (TIRF) was used to observe the spatial organization and temporal dynamics (i.e. spatial positioning and timing patterns) of several lipids, and accessory proteins, like lipid kinases and protein kinases, in the form of protein kinase C (PRKC) associated with sites of exocytosis of matrix metalloproteinase-9 (MMP-9) in living MCF-7 cancer cells.

Results

Following stimulation with phorbol myristate acetate (PMA) to promote exocytosis, a transient accumulation of several distinct regulatory lipids, lipid kinases, and protein kinases at exocytic sites was observed. This transient accumulation centered at the time of membrane fusion is followed by a rapid diffusion away from the fusion sites. Additionally, the synthesis of these regulatory lipids, degradation of these lipids, and the downstream effectors activated by these lipids, are also achieved by the recruitment and accumulation of key enzymes at exocytic sites (during the moment of cargo release). This includes key enzymes like lipid kinases, protein kinases, and phospholipases that facilitate membrane fusion and exocytosis of MMP-9.

Conclusions

This work suggests that these regulatory lipids and associated effector proteins are locally synthesized and/or recruited to sites of exocytosis, during membrane fusion and cargo release. More importantly, their enrichment at fusion sites serves as an important spatial and temporal organizing “element” defining individual exocytic sites.
Reversal of rivaroxaban anticoagulant effect by prothrombin complex concentrates: which dose is sufficient to restore normal thrombin generation?
Authors: Giffard-Quillon Lorine , Desmurs-Clavel Helene , Grange Claire , Jourdy Yohann , Dargaud Yesim
Published: August 2020

Rivaroxaban has the most available data to support the use of prothrombin complex concentrates (PCC) as a reversal agent. However, PCC might increase the incidence of thrombotic events by shifting the haemostatic balance towards hypercoagulability. We assessed the in vitro efficacy and safety of three 4-factor PCCs for reversing rivaroxaban anticoagulant effect. Our in vitro finding indicates that 4-factor PCCs at the dose of 25 U.kg− 1 may be sufficient to reverse rivaroxaban anticoagulant effect.
Myeloproliferative blood cancers as a human neuroinflammation model for development of Alzheimer’s disease: evidences and perspectives
Authors: Hasselbalch Hans C. , Skov Vibe , Kjær Lasse , Sørensen Torben L. , Ellervik Christina , Wienecke Troels
Published: August 2020

Chronic inflammation and involvement of myeloid blood cells are associated with the development of Alzheimer’s disease (AD). Chronic inflammation is a highly important driving force for the development and progression of the chronic myeloproliferative blood cancers (MPNs), which are characterized by repeated thrombotic episodes years before MPN-diagnosis, being elicited by elevated erythrocytes, leukocytes, and platelets. Mutations in blood cells, the JAK2V617F and TET2-mutations, contribute to the inflammatory and thrombogenic state. Herein, we discuss the MPNs as a human neuroinflammation model for AD development, taking into account the many shared cellular mechanisms for reduction in cerebral blood, including capillary stalling with plugging of blood cells in the cerebral microcirculation. The therapeutic consequences of an association between MPNs and AD are immense, including reduction in elevated cell counts by interferon-alpha2 or hydroxyurea and targeting the chronic inflammatory state by JAK1-2 inhibitors, e.g., ruxolitinib, in the future treatment of AD.
The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours
Authors: Chamera Katarzyna , Kotarska Katarzyna , Szuster-Głuszczak Magdalena , Trojan Ewa , Skórkowska Alicja , Pomierny Bartosz , Krzyżanowska Weronika , Bryniarska Natalia , Basta-Kaim Agnieszka
Published: August 2020

Background

The bidirectional communication between neurons and microglia is fundamental for the homeostasis and biological function of the central nervous system. Maternal immune activation (MIA) is considered to be one of the factors affecting these interactions. Accordingly, MIA has been suggested to be involved in several neuropsychiatric diseases, including schizophrenia. The crucial regulatory systems for neuron-microglia crosstalk are the CX3CL1-CX3CR1 and CD200-CD200R axes.

Methods

We aimed to clarify the impact of MIA on CX3CL1-CX3CR1 and CD200-CD200R signalling pathways in the brains of male Wistar rats in early and adult life by employing two neurodevelopmental models of schizophrenia based on the prenatal challenge with lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (Poly I:C). We also examined the effect of MIA on the expression of microglial markers and the profile of cytokines released in the brains of young offspring, as well as the behaviour of adult animals. Moreover, we visualized the localization of ligand-receptor systems in the hippocampal regions (CA1, CA3 and DG) and the frontal cortex of young rats exposed to MIA. The differences between groups were analysed using Student’s t test.

Results

We observed that MIA altered developmental trajectories in neuron-microglia communication in the brains of young offspring, as evidenced by the disruption of CX3CL1-CX3CR1 and/or CD200-CD200R axes. Our data demonstrated the presence of abnormalities after LPS-induced MIA in levels of Cd40, Il-1β, Tnf-α, Arg1, Tgf-β and Il-10, as well as IBA1, IL-1β and IL-4, while after Poly I:C-generated MIA in levels of Cd40, iNos, Il-6, Tgf-β, Il-10, and IBA1, IL-1β, TNF-α, IL-6, TGF-β and IL-4 early in the life of male animals. In adult male rats that experienced prenatal exposure to MIA, we observed behavioural changes resembling a schizophrenia-like phenotype.

Conclusions

Our study provides evidence that altered CX3CL1-CX3CR1 and/or CD200-CD200R pathways, emerging after prenatal immune challenge with LPS and Poly I:C, might be involved in the aetiology of schizophrenia.
Evaluation of open bite closure using clear aligners: a retrospective study
Authors: Harris Kayla , Ojima Kenji , Dan Chisato , Upadhyay Madhur , Alshehri Abdulrahman , Kuo Chia-Ling , Mu Jinjian , Uribe Flavio , Nanda Ravindra
Published: August 2020

Objectives

To evaluate the dental and skeletal effects that occur in the correction of anterior open bite with clear aligners.

Materials and method

In this single-center retrospective study, the mechanism of anterior open bite closure using clear aligners (Invisalign, Align Technology, Santa Clara, CA, USA) was evaluated by cephalometric superimposition based on records of patients consecutively treated by a single, experienced Invisalign provider. Inclusion criteria consisted of anterior open bite (overbite < 0.5 mm), adult patients (18+) at the beginning of treatment, consecutive records, and good quality pre- and post-treatment records, where the required landmarks were clearly visible.

Results

A total of 45 patients were included for data analysis with a mean age of 30.73 ± 8.0 years and initial open bite of − 1.21 ± 1.15 mm. During treatment, the upper incisors showed significant (p < 0.05) retraction [U1-SN′(°) = − 10.91 ± 6.95°], [U1-SN′perp(mm) = − 2.57 ± 1.75 mm] and extrusion [U1-SN′(mm) = 1.45 ± 0.89 mm]. The lower incisors also showed significant retraction [IMPA(°) = − 3.73 ± 4.91°), (ΔL1-MP′perp (mm) = − 1.08 ± 1.59] and extrusion (ΔL1-MP′(mm) = 0.53 ± 0.74). Regarding molar position, no significant changes were noted in the anteroposterior position of the upper [ΔU6-SN′perp(mm) = 0.01 ± 1.08 mm] and lower molar [ΔL6-MP′perp(mm) = 0.03 ± 0.87 mm]; however, there was a statistically significant intrusion of the upper [ΔU6-SN′(mm) = − 0.47 ± 0.59 mm] and lower molar [ΔL6-MP′(mm) = − 0.39 ± 0.76 mm].

Conclusion

Open bite closure with clear aligners occurred due to a combination of maxillary and mandibular incisor extrusion and maxillary and mandibular molar intrusion, with slight mandibular auto rotation. Significant retraction of maxillary and mandibular incisors was also observed with treatment. Clear aligners are effective in reducing/controlling the vertical dimension in open bite patients.
Lebanese pharmacists’ confidence and self-perceptions of computer literacy: scale validation and correlates
Authors: Hallit Souheil , Tawil Samah , Sacre Hala , Rahme Clara , Hajj Aline , Salameh Pascale
Published: August 2020

Background

Most pharmacists agree that continuing education (CE) programs positively affect their practice and increase their knowledge, with computer-based courses being their preferred type of CE (60.6%). The route to using medical e-services and e-learning is not straightforward. High setup costs and time commitments to sustain quality are issues brought up in this respect. Therefore, the objectives of this study were to validate the general confidence with computer use (GCWCU) scale and assess computer literacy and its associated factors among Lebanese pharmacists.

Methods

This cross-sectional study was conducted, using a random sample of Lebanese pharmacists from all districts of Lebanon. The general confidence with computer use (GCWCU) scale was used to assess computer literacy.

Results

This study enrolled 628 (83.73%) pharmacists. The GCWCU items converged over two factors (Cronbach’s alpha = 0.716). A higher GCWCU was associated with the ease of access to the Order of Pharmacists of Lebanon e-library (beta = 2.58), owning a tablet (beta = 2.80), being connected for 4 h daily (beta = 2.71), the ease of access to the learning management system (beta = 2.39), holding a PhD (beta = 4.28) or a PharmD (beta = 1.16), and working in hospitals (beta = 2.60).

Conclusion

This study showed that the GCWCU is adequate to assess computer literacy in Lebanese pharmacists and identified factors affecting and/or associated with computer literacy. It presented insights into essential computer skills and abilities of Lebanese pharmacists and identified factors associated with their general confidence with computer use in their practice. These findings would help decision-makers and CE providers design learning materials for pharmacists to improve their computer literacy for better practice and patient care.
Balloon-assisted Transcatheter arterial embolization using N-butyl cyanoacrylate for iatrogenic arterial bleeding by groin puncture: a new technology
Authors: Ueda Tatsuo , Murata Satoru , Saito Hidemasa , Miki Izumi , Yasui Daisuke , Sugihara Fumie , Shimizu Wataru , Kumita Shin-Ichiro
Published: August 2020

Background

Balloon-assisted transcatheter arterial embolization (TAE) using n-butyl cyanoacrylate (NBCA) and lipiodol (Lp) mixture is a new endovascular treatment technique for iatrogenic arterial bleeding by groin puncture. It is less invasive compared to surgical repair, and NBCA migration into the circulation can be prevented by temporary balloon occlusion of the parent artery without ultrasound-guidance. This study aimed to report on the technical aspects and evaluate the efficacy and safety of fluoroscopically guided balloon-assisted transcatheter arterial embolization using NBCA for iatrogenic arterial bleeding by groin puncture.

Materials and methods

The study included five patients (mean age 54.6 years; 3 male and 2 female) with iatrogenic arterial bleeding by groin puncture. We performed transcatheter arterial embolization using NBCA while occluding the responsible artery with a balloon catheter during the embolization to prevent NBCA migration. Two sheaths were inserted into the common femoral artery. A microcatheter was advanced into the pseudoaneurysm or extravasation via the contralateral sheath. A balloon catheter was advanced into the responsible artery until the balloon portion covered the leakage site via another sheath. After balloon inflation, the NBCA and Lip mixture was slowly injected until the pseudoaneurysm, or the extravasation was filled without touching the balloon. The microcatheter was removed immediately after the filling. We assessed technical success, overall success, and complications.

Results

The injured arteries were the external iliac artery (n = 1), the common femoral artery (n = 2), and the proximal portion of the superficial femoral artery (n = 2). NBCA was injected once in four cases and twice in one case where complete hemostasis could not be achieved with one injection. The technical and overall success rate was 100% with no complications, including distal embolization of NBCA.

Conclusions

Balloon-assisted TAE using NBCA is a feasible, effective, and safe treatment for iatrogenic arterial bleeding by groin puncture. It may also be applicable in other arterial bleeding situations where the potential risk of distal embolization can be decreased by applying the balloon-assisted technique.
Prognostic significance of DNMT3a gene expression and reactive nitrogen species in newly diagnosed Egyptian de novo adult acute myeloid leukemia patients
Authors: Asfour Inas A. , Hegab Hany M. , El-Salakawy Walaa A. , Hamza Mohamed T. , Mansour Dina A. , Saeed Alia M.
Published: August 2020

Background

DNA methyltransferase 3a (DNMT3a) gene is a frequently dysregulated epigenetic modifier gene involved in the process of carcinogenesis. Also, there is a dichotomous nature of nitric oxide action with the ability to both promote and repress cancers. There is a host of research work delineating the frequency of DNMT3a mutation in acute myeloid leukemia (AML), but little is known about its level of expression in AML patients or its probable relationship to nitrosative stress. This study aims at the assessment DNMT3a gene expression as well as nitric oxide levels in newly diagnosed adult patients with de novo AML. Moreover, it aims at relating these two variables to other disease features and prognostic indicators as well as treatment outcomes. The study included 45 adult de novo AML patients and 10 healthy control subjects. Measurement of DNMT3a messenger ribonucleic acid (mRNA) transcripts was done by real-time quantitative polymerase chain reaction (RQ-PCR) followed by Sanger sequencing to identify the presence or absence of DNMT3a arginine 882 (R882) mutation. This was followed by the assessment of serum nitrite level as a surrogate marker for nitric oxide radical (NO) using colorimetric methods.

Results

DNMT3a gene expression, as well as serum nitrite levels, were significantly higher among AML cases in relation to controls before chemotherapy with P values of < 0.001 and 0.035, respectively. Dividing patients into low and high expressors in relation to the hotspot mutation demonstrated no difference between the two groups in terms of demographic, clinical, and laboratory characteristics or treatment outcomes.

Conclusion

DNMT3a gene expression is increased among the AML population in relation to normal healthy controls. This may point out the need for the assessment of the influence of this gene expression on methylcytosine content of tumor samples with the subsequent implementation of hypomethylating agents as a line of therapy in cases exhibiting excessive hypermethylation.
Correlation of a family history of cancer with risk of relapse and death in pediatric cancer patients
Authors: Eichstadt S. L. , Dahl G. V. , Fisher P. G. , Ford J. M. , Schiffman J. D.
Published: August 2020

10029

Background: The association between family history of cancer (FHC) and outcome remains uncertain. Relapse and survival of children with FHC has not been well studied. Such information would be valuable for prognosis, refining treatment protocols, and long-term follow-up in pediatric patients with FHC. Methods: An historical cohort study of all pediatric patients diagnosed with cancer at Lucile Packard Children's Hospital at Stanford from 1999 - 2002 was performed (n = 363, mean age: 8.4 yrs [0–28 yrs]). FHC among 1st, 2nd and 3rd degree relatives was obtained from the first 10 consecutive encounters in the electronic medical record. Relapse, secondary malignancy, and survival data were also acquired. The relative risks for these endpoints were calculated between patients with FHC among 1st and/or 2nd degree relatives and those with negative FHC. Patients without documented FHC were excluded (n = 100). Results: 108 (41%) newly diagnosed pediatric patients had reported FHC (1st Degree: n = 14 [5%], 2nd Degree: n = 58 [22%], 3rd Degree: n = 36 [14%]). Patients with reported FHC among 1st and/or 2nd degree relatives were at increased relative risk [RR] for relapse (1.96, 95% confidence interval [CI] 1.27–3.02) compared to patients with negative FHC (n = 191). In particular, patients with Hodgkin Disease (HD) and FHC (n = 12) were more likely to relapse (RR 1.79, 95% CI 1.19–2.72) and at increased risk of death (RR 1.72, 95% CI 1.18–2.53), compared to HD with negative FHC (n = 8). Similarly, patients diagnosed with ALL and FHC (n = 22) had increased risk of death (RR 2.25, 95% CI 1.06–4.8) compared to ALL patients with negative FHC (n = 56). For patients diagnosed with any pediatric cancer and positive FHC in 1st degree relative, RR of death was significantly elevated (3.74, 95% CI 1.20–11.70). Conclusions: Pediatric cancer patients with positive FHC among 1st and/or 2nd degree relatives appear to have higher relative risk of relapse compared to those with negative FHC. Additionally, an increased risk of death was associated with HD and ALL patients with positive FHC. Patients with 1st degree relative with malignancy had an increased risk for death compared to those without cancer among 1st degree relatives. These findings may reflect underlying genetic predispositions in children which contribute to outcome.

No significant financial relationships to disclose.
Developing a prediction model for benefit from fulvestrant in heavily pretreated metastatic breast cancer (MBC) patients
Authors: Amir E. , Freedman O. C. , Dranitsaris G. , Napolskikh J. , Chia S. , Petrella T. , Dent S. , Kumar R. , Fralick M. , Clemons M.
Published: August 2020

1041

Background: Fulvestrant use in heavily pretreated patients with MBC is associated with highly variable responses. This study aimed to characterize the benefit of fulvestrant therapy and develop a prediction model for clinical benefit in this setting. Methods: A nationwide, retrospective chart review of patients enrolled in a Canadian compassionate use program was performed. This program mandated prior therapy with tamoxifen and both steroidal and non-steroidal aromatase inhibitors. Charts from the seven highest accruing centers were reviewed. Sample size was based on the derivation of a model to predict the probability of a patient remaining on fulvestrant and free from chemotherapy for at least 3 months. Results: 305 women received at least one dose of fulvestrant; 207 went on to receive chemotherapy (68%). Of these, 48 (23%) required chemotherapy at 3 months, 113 (55%) at 6 months, and 170 (82%) by 12 months. Median duration of fulvestrant treatment was 126 days (range 23–1920). Median overall survival from start of fulvestrant was 698 days (25th percentile 316 days-75th percentile 1,359 days). The preliminary prediction model showed that older age (OR 0.96, 95% CI 0.93–0.99) and having received no adjuvant hormonal therapy (OR 0.5, 95% CI 0.2–1.25) predicted a greater chance of remaining chemotherapy-free at 3 months. Presence of lung (OR 2.55, 95% CI 1.1–5.9) or brain metastases (OR12.8, 95% CI 4.1–55.4) predicted a lower chance of remaining chemotherapy-free at 3 months. Conclusions: Older age and having received no prior adjuvant hormonal therapy predicted a greater chance of remaining chemotherapy free at 3 months, while lung and brain metastases predicted a lower chance. These factors will be validated in an international data set, and may be considered when prescribing fulvestrant. A 6-month prediction model is currently under development.

[Table: see text]
Effect of estrogen receptor-positive progenitor cells on a tamoxifen resistance phenotype in breast cancer cells
Authors: Selever J. , Barone I. , Lewis M. T. , Corona-Rodriguez A. , Tsimelzon A. , Di Pietro A. , Boumemdjel A. , Fuqua S.
Published: August 2020

1042

Background: The antiestrogen tamoxifen and aromatase inhibitors are the most frequently prescribed hormonal agents for the treatment of estrogen receptor (ER) α-positive breast cancer. An important question is whether there is a group of hormone resistant, ERα-positive patients who may derive additional benefit from the addition of chemotherapy to endocrine therapy, or who may be candidates for “targeted” biologics. Dicer1 is an RNase III-containing enzyme that processes microRNA precursors into mature microRNA, which have been implicated in breast tumor invasion and metastasis. BCRP1 is a transmembrane transport protein known to efflux a number of chemotherapeutic agents, but also steroid hormones. In the present study, we investigated whether Dicer might affect response to tamoxifen in breast cancer cells, and generated estrogen receptor-positive MCF-7 human breast cancer cells stably overexpressing Dicer1, and they exhibited elevated BCRP1 protein. Methods: We utilized preclinical approaches to study the function of BCRP1 in Dicer-overexpressing breast cancer cells using in vitro growth assays in soft agar, mammosphere formation assays, and in vivo tumor initiation. Results: Microarray analyses of human breast tumors, suggested that Dicer overexpression was associated with tamoxifen resistance. Dicer-overexpressing MCF-7 cells express elevated levels of BCRP1, ALDH, and cErbB2/HER-2 evident by immunoblot analysis. The Dicer1-overexpressing cells formed soft agar colonies in the presence of tamoxifen, however Fumitremorgin C (FTC) or MBLI-97, both BCRP inhibitors, reversed resistance, and sensitized cells to tamoxifen therapy. Preclinical in vivo tumor xenograft experiments confirmed the tamoxifen-resistant phenotype. Mammosphere potential was enhanced in Dicer-overexpressing cells suggesting an enrichment of stem-like breast cancer cells. Conclusions: Our results suggest that Dicer-overexpressing breast cancer cells are a novel preclinical model for an estrogen receptor-positive breast cancer progenitor phenotype and tamoxifen resistance. Based on our data Dicer1 is a potential predictive biomarker in breast cancer, and predicts that clinical BCRP1 inhibition may facilitate tumor sensitization to hormonal therapy.

No significant financial relationships to disclose.
Evaluation of the antitumor activity of sunitinib malate (SM) in solitary fibrous tumor (SFT)
Authors: Casali P. G. , Stacchiotti S. , Palassini E. , Marrari A. , Negri T. , Morosi C. , Messina A. , Pastorino U. , Gronchi A. , Pilotti S.
Published: August 2020

10571

Background: SFT is a rare soft tissue tumor, with an unpredictable metastatic potential. When medical therapy is needed, cytotoxic chemotherapy is poorly active in this sarcoma subtype, but the activity of bevacizumab + temozolomide was recently reported. We explored the activity of SM in SFT, given the vascular pattern of this tumor and our preliminary observations about RTK activation (with upregulation of the PDGFR family, VEGFR and EGFR). Methods: From April 2008, 5 patients with progressive metastatic SFT resistant to conventional chemotherapy (male/female: 3/2 - mean-age: 58 years - PS: 0–3 - site: peritoneum 3, pleura 1, bladder 1) have been treated with continuous-dosing SM 37.5 mg/day, on an individual use basis. All patients were evaluated for response at least once, while 2 more patients are now starting therapy. RTK biochemical analysis was performed in 3 patients of this series, in addition to a group of other patients with malignant SFT whose cryopreserved material was available. Results: Between 3 weeks and 3 months, 4 in 5 patients had a tumor response according to Choi's criteria (all with RECIST stable disease) . The other patient stopped therapy for progression after 3 weeks and died 2 weeks later. Baseline PET was negative in 4 out of 5 patients. One responsive patient stopped therapy after 3 weeks for side effects and depression. The remaining 3 responsive patients are currently on treatment, although one had a focal progression after 9 months. In two, surgery of residual disease is planned, and downstream RTK signaling analysis will be performed on the specimen. Conclusions: SM has antitumor activity in SFT. This might help address an unmet clinical need in a rare sarcoma subtype. Biomolecular assessments are ongoing.

[Table: see text]
Detection of local recurrences of limb soft-tissue sarcomas: Is magnetic resonance imaging (MRI) relevant?
Authors: Ferron G. , Aziza R. , Delannes M. , Filleron T. , Marquès B. , Labarre D. , Labarre D. , Chevreau C.
Published: August 2020

10582

Background: The role of systematic magnetic resonance imaging (MRI) surveillance after resection of soft-tissue sarcomas (STS) of the limb is opened to debate. The aim of our study was to retrospectively evaluate the effectiveness of a MRI surveillance schedule performed in adult patients. Methods: 124 adult patients have been treated from 1996 to 2006 for a non-metastatic limb STS at our centre: 86 patients (70%) had clear resection margins (R0) and 111 patients (90%) received an adjuvant radiotherapy. 663 MRI examinations were performed, with a median of 5 per patient [range: 1 to 5]. The rythm of surveillance schedule was respected in 57% of the examinations. Results: Forty-one patients (33%) prematurely withdrew from the planned radiological surveillance due to metastasis diagnosis (15 cases), 5-year remission duration (5 cases), other reasons (12 cases), and drop out (9 cases). Among the 11 local recurrences (9%) which were observed, MRI was able to detect only 2 asymptomatic local recurrences, 1 with and 1 without synchronous metastasis, both had microscopically involved margins (R1). In contrast, MRI showed 11 false-positive cases. As the predictive positive value of MRI was 42%, clinical surveillance seems to be more effective. The evaluation of the cost of the systematic MRI surveillance is 200,000 euros. Clinical examination failed in 2 cases (2 asymptomatic local recurrences detected by MRI) as did MRI surveillance (2 false negative cases). In our study, cost-effectiveness was better with clinical examination than MRI surveillance. Conclusions: As observed in our study, systematic MRI surveillance is not relevant for the follow-up of all limb soft-tissue sarcomas. A prospective study could be promoted to evaluate the MRI surveillance of patient at high risk of local recurrence.

No significant financial relationships to disclose.
Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma
Authors: Stevenson M. M. , Mostertz W. , Acharya C. , Walters K. , Barry W. , Tuchman S. , Ready N. , Onaitis M. , Crawford J. , Potti A.
Published: August 2020

11001

Background: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities between normal/embryonic stem cells and mature tumor cells, specific to lung cancer, are a result of underlying biologic processes, such as specific molecular pathways and regulatory networks. Methods: Using a large cohort of lung cancer cell lines with associated gene expression data, genes associated with an embryonic stem cell identity were used to develop a ‘signature’ representative of embryonic stemness (ES) activity specific to lung adenocarcinoma. Differential biology was evaluated using Gene Set Enrichment Analysis (GSEA) and signatures of oncogenic pathway deregulation. The ES signature was applied to three independent early (stage I - IIIa) lung adenocarcinoma data sets (N = 634) with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin sensitivity was also evaluated. Results: Using Bayesian regression analysis, a 100 gene signature representative of ES activity in lung adenocarcinoma was developed and validated in a leave-one-out-analysis. GSEA identified gene sets significantly represented in the ES signature: signature of neoplastic transformation, signature of undifferentiated cancer, BRCA pathway, and fibroblast serum response pathway, all associated with cancer invasiveness. Adenocarcinomas with ES demonstrated increased activation of RAS (p = 0.0002), MYC (p = 0.0057), wound healing (angiogenesis) (p < 0.0001), chromosomal instability (p < 0.0001), and invasiveness (p < 0.0001) gene signatures. Adenocarcinomas (N= 634) with ES had a decreased survival (p<0.04). The ES signature was not prognostic in prostate, ovarian, or breast adenocarcinomas. Lung tumors (N=634) and adenocarcinoma cell lines (N=31) with ES were more resistant to cisplatin (p<0.0001 and p=0.0063, respectively). Conclusions: Lung adenocarcinomas that share a common gene expression pattern with normal stem cells were associated with decreased survival and increased likelihood of resistance to cisplatin, indicating the aggressiveness of lung tumors with a stem cell phenotype.

No significant financial relationships to disclose.
IKZF1 (IKAROS) deletions as a prognostic marker in BCR-ABL1 positive acute lymphoblastic leukemia patients: A GIMEMA ALL WP Report
Authors: Iacobucci I. , Storlazzi C. , Lonetti A. , Ferrari A. , Messina M. , Cilloni D. , Papayannidis C. , Baccarani M. , Foà R. , Martinelli G.
Published: August 2020

11005

Expression of BCR-ABL1 in hematopoietic stem cells can alone induce a chronic myeloid leukemia (CML) but cooperating oncogenic lesions are required for the generation of a blastic leukemia. To identify oncogenic sub-microscopic lesions that cooperate with BCR-ABL1 to induce ALL, by high resolution single nucleotide polymorphism (SNP) arrays (250K NspI and SNP 6.0, Affymetrix) we studied 106 patients (pts) with de novo adult BCR-ABL1-positive ALL. The most frequent somatic copy number alteration was deletion on 7p12 of IKZF1 (68/106, 64%), which encodes the transcription factor Ikaros required for the earliest stages of lymphoid lineage commitment. We characterized and mapped all breakpoints in IKZF1 gene to recognize that two major deletions occur: the first one characterized by loss of exons 4–7 (44%) and due to breakpoints in introns 3 and 7; the second one characterized by removal of exons 2–7 (19%) and due to a variable pattern of breakpoints in introns 1 and 7. In two pts we had both Δ2–7 and Δ4–7 deletions and in one we identified a deletion of all IKZF1 gene and part of GRB10. A variable number of nucleotides (patient-specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. Gene expression profiling analysis of pts with IKZF1 deletion vs wild-type pts identified a unique signature characterized by a down-regulation of genes involved in pre-B-cell differentiation (e.g. VPREB1, VPREB3, IGLL3, BLK), demonstrating that genomic IKZF1 alterations have a strong impact on trascriptoma and contribute to an impaired B-cell differentiation. Univariate analysis showed that the IKZF1 deletion is a negative prognostic marker influencing the cumulative incidence of relapse (10.1 months for pts with deletion vs 56.1 months for wild-type pts, p=0.0103) and disease-free survival (DFS) (10.1 months vs 32.1 months, respectively, p=0.0229). The negative prognostic impact of the IKZF1 deletion on DFS was also confirmed by multivariate analysis (p=0.0445). In conclusion, deletion of IKZF1 is an important event in the development of BCR-ABL1 B-progenitor ALL which significantly influences clinical outcome. Supported by European LeukemiaNet, AIL, AIRC, FIRB 2006, Strategico di Ateneo, GIMEMA Onlus.

No significant financial relationships to disclose.
Mechanistic evaluation of the combination effect of paclitaxel (Pac) and bevacizumab (Bev) in breast cancer xenografts
Authors: Alvarez R. H. , Valero V. , Bassett R. L. , Lu C. , Dallas N. , Kiriakova G. , Bankson J. A. , Madden T. L. , Hortobagyi G. N. , Price J. E.
Published: August 2020

11007

Background: Chemosensitization is the ability to augment the effects of standard chemotherapy. One of the possible mechanisms for chemosensitization is improving intratumoral chemotherapy concentrations by increasing total or regional delivery of chemotherapy to the tumor. This mechanism potentially leads to a decreased tumor interstitial fluid pressure (IFP). This study evaluates the interaction between tumor IFP, intra-tumor drug accumulation and blood vessel perfusion. Methods: GILM2 human breast cancer (triple negative phenotype) cells were injected into the mammary fat pad of female nude mice. Mice were randomized to 4 arms: Control, Pac 24 mg/Kg, Bev 10 mg/Kg, and the same dose for the combination Pac + Bev, twice a week for 3 weeks. Tumor IFP was assessed using an ultraminiature catheter-tip technique (Ozerdem 2005). Concentration of Pac in tumor tissue was measured using liquid chromatography mass spectrometry (LC/MS) and blood vessel perfusion was assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Ultrastructural morphology changes were assessed by electron microscopy (EM). Results: Treatment started 35 days after implantation; tumor tissue concentration of Pac was significantly increased when combined with Bev (P = 0.03). In mice treated with the combination of Pac + Bev, IFP values decreased more gradually, with sustained and significant reduction at the end of the treatment (P = 0.0068; mean SEM day 0: 28,44 ± 6,1; mean SEM day 21: 7,41 ± 2,0). The IFP changes in the other 3 experimental arms did not reach statistical significance. The combination of Pac and Bev produced substantial changes to the proportions of endothelial cell/pericytes and increased apoptosis in tumor cells by 75% (detected by immunostaining for cleaved-caspase 3). Conclusions: The combination of Pac and Bev produces significant tumor reduction and increases three-fold the concentration of Pac in the tumor. This intra-tumor augmentation of Pac was correlated with the decrease of tumor IFP, which was independent of the action of Bev alone. Results of DCE-MRI and EM analyses of the treated tumors will also be presented.

No significant financial relationships to disclose.
Predictive value of novel and existing activating EGFR mutations for improved survival in malignant peritoneal mesothelioma (MPM) and response to EGFR-TK inhibitors (EGFR-TKI)
Authors: Foster J. M. , Uppala R. , Govindarajan V. , Carreau J. H. , Stan L. , Nath S. , Poonam S. , Galatica Z. , Loggie B. W.
Published: August 2020

11030

Background: MPMs are highly aggressive tumors with most patients diagnosed surviving 8–12 months. Currently there is a paucity of information about the molecular/biological perturbations involved in tumor formation. Previously we presented (at ASCO 2007) that novel EGFR-TK mutations occurred in these tumors predictive of optimal surgical cytoreduction; but the EGFR activity of these mutations was being investigated. Here we present the EGFR activity of these mutations as well as matured outcome data. Methods: Twenty-nine MPM patients were evaluated at a single tertiary center and tumors were probed for mutations in the TK domain of EGF receptor (mut+). All specimens were examined for somatic mutations by PCR amplification and confirmed by multiple independent PCRs. Twenty-five patients were treated with cytoreductive surgery (CRS) ± IPHC and clinical data including age, sex, cytoreductive score, histology, mutation, and survival was available for comparison of the mut+ and mut- groups. A COS-7 cell expression model was used to determine the time dependent activating profile of these mutations, as well as response to EGFR-TKI-inhibitor. Results: Mutations were found in 31% (9/29) of the tumors; 7 of these mutations were novel. All 7 novel mutations and L858R mutation identified were activating mutations with similar activation profiles. All mutations were responsive to EGFR-TKI treatment. Of the 25 patients managed surgically there were 7 mut+ and 18 mut-. Two of 7 (29%) mut+ have progressed and died of disease with a MFT of 22 months; while 13/18 (72%) mut- had progressive disease and 10/18 (56%) died with median TTP and survival of 12 months and14 months respectively. Estimated 3-year PFS was 70% mut+ and 25% mut- on log rank analysis p=0.099. Conclusions: This is the first report that MPM-EGFR mutations are activating mutations and responsive to EGFR-TKI-therapy. The mut+ subset has a “relative” improved outcome compared to wild type, but still developed progressive disease. TKIs may be a promising therapy in mut+ MPMs patients. Further elucidation of other molecular and pathway perturbations in this disease is necessary, as well as, validation of these results in a larger cohort.

No significant financial relationships to disclose.
Absence of the CHEK2*1100delC mutation in non-BRCA1/2 families with multiple cancer types in a high-risk clinic population of Caucasian ancestry
Authors: Gorin M. A. , Iniesta M. D. , Douglas J. A. , Milliron K. J. , Merajver S. D.
Published: August 2020

11040

Background: Checkpoint kinase 2(CHEK2) is a cell-cycle-checkpoint kinase that phosphorylates p53 and BRCA1 in response to DNA damage. The contribution of CHEK2 mutations to familial cancer has been widely studied in breast cancer. Most notably, the CHEK2*1100delC mutation has been characterized to confer a 2-fold increased risk for breast cancer in carriers. This finding comes from studies performed on Northern and Eastern European populations. Few studies, however, have been conducted in North American. In contrast to the work done in Europe, these studies suggest a lower frequency of CHEK2*1100delC mutations in breast cancer families. The aim of this study was to determine the frequency of CHEK2*1100delC in members of breast cancer families who tested negative for a deleterious mutation in BRCA1/2. Methods: DNA sequencing was used to genotype 115 individuals for CHEK2*1100delC. Families were characterized by the presence of several cases of breast and/or ovarian cancer and multiple members with other cancers in a single lineage. Given the broad variety of cancers associated with CHEK2 mutations and its function in DNA repair, we hypothesized that these families would be enriched for harboring the CHEK2*1100delC in the germline. Results: No CHEK2*1100delC mutations were detected in 115 individuals, including 39 women diagnosed with breast cancer at an early age, 7 women with bilateral cancer, 2 men with breast cancer and 6 women with ovarian cancer, all of whom were negative for mutations in BRCA1/2.The CHEK2 Breast Cancer Consortium previously reported a frequency of 2.3% for the CHEK2*1100delC mutation among breast cancer cases from families with at least 2 cases of breast cancer (or breast and ovarian cancer) in a first- or second-degree relationship. Based on that, we had approximately 92% power to detect at least one mutation among our study cohort. Conclusions: Our data are consistent with previous reports that suggest a lower frequency of CHEK2*1100delC mutations in North American hereditary breast cancer families without BRCA1/2 mutations and enriched for multiple cancer types. The low frequency of the CHEK2*1100delC in the North American population limits its clinical relevance as a cancer predisposing gene.

No significant financial relationships to disclose.
The effect of androgen deprivation therapy on CD4/CD8 T cells in HIV-negative patients receiving definitive 3D radiation treatment for their prostate carcinoma: Final report of a prospective study
Authors: Elshaikh M. A. , Abdel Hafeez Z. , Lu M. , Ibrahim D. , El Masry T. , Yousef A.
Published: August 2020

11056

Background: CD4 and CD8 T cells play critical roles in human immunity. The aim of this prospective study is to explore the correlation of the absolute CD4/CD8 T cell counts and total testosterone in patients receiving androgen deprivation therapy (ADT) with goserelin acetate and definitive radiation treatment (RT) for their prostate cancer. Methods: Thirty-four HIV-negative patients were included in this study between June 2006 and January 2007. All patients had a baseline total testosterone level (T), PSA, CD4 and CD8 T cell counts. CD4/8 T cells count was measured using flow cytometry. All patients received 6 months of ADT prior to (baseline) and during RT to the prostate. Subsequent blood samples were taken at 2, 8, 12 and 24 months. Blood samples were taken between 8–10 am to control for diurnal variations in CD4/CD8 T cell counts and T levels. To study the correlation of T with CD4/8 T cell changes, the Spearman correlation coefficient was calculated. The study was approved by the appropriate Ethics Committee. Results: Median age for the study patients was 68 years. At baseline, median testosterone level was 350 ng/dL, median CD4 T cell count was 1055 mm3, and median CD8 T cell count was 644 mm3. None of the patients received anti-androgens. At two months, testosterone was at the castrate and subnormal levels in 85% and 100% of the patients, respectively. The lower testosterone levels resulted in significant reduction of CD4 and CD8 T cell counts at 2, 8, 12 and 24 months compared to baseline counts. This effect was more pronounced for CD4 T cells at all time points (p=<0.02). At 24 months, when total testosterone levels were increasing, CD4 and CD8 T cell counts were also following these upward trends. The seen correlation between lower testosterone and decline in CD4 and CD8 T cells was only statistically significant in older patients (>65 years) and was not associated with significant decline in total white blood cell counts. Conclusions: CD4/CD8 T cell counts are sensitive to changes in total testosterone levels. Lower testosterone levels negatively affecting CD4/CD8 T cells counts at all study time points. Since CD4/CD8 T cells play major roles in cellular immunity, further studies are warranted

No significant financial relationships to disclose.