bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sustained Tumor Regression of Human Colorectal Cancer Xenografts Using a Multifunctional Mannosylated Fusion Protein in Antibody-Directed Enzyme Prodrug Therapy
Authors: Sharma Surinder K. , Pedley R. Barbara , Bhatia Jeetendra , Boxer Geoffrey M. , El-Emir Ethaar , Qureshi Uzma , Tolner Berend , Lowe Helen , Michael N. Paul , Minton Nigel , Begent Richard H. J. , Chester Kerry A. 
Published: June 2022

AbstractPurpose: Antibody-directed enzyme prodrug therapy (ADEPT) requires highly selective antibody-mediated delivery of enzyme to tumor. MFE-CP, a multifunctional genetic fusion protein of antibody and enzyme, was designed to achieve this by two mechanisms. First by using a high affinity and high specificity single chain Fv antibody directed to carcinoembryonic antigen. Second by rapid removal of antibody-enzyme from normal tissues by virtue of post-translational mannosylation. The purpose of this paper is to investigate these dual functions in an animal model of pharmacokinetics, pharmacodynamics, toxicity, and efficacy.Experimental Design: MFE-CP was expressed in the yeast Pichia pastoris and purified via an engineered hexahistidine tag. Biodistribution and therapeutic effect of a single ADEPT cycle (1,000 units/kg MFE-CP followed by 70 mg/kg ZD2767P prodrug at 6, 7, and 8 hours) and multiple ADEPT cycles (9-10 cycles within 21-24 days) was studied in established human colon carcinoma xenografts, LS174T, and SW1222.Results: Selective localization of functional enzyme in tumors and rapid clearance from plasma was observed within 6 hours, resulting in tumor to plasma ratios of 1,400:1 and 339:1, respectively for the LS174T and SW1222 models. A single ADEPT cycle produced reproducible tumor growth delay in both models. Multiple ADEPT cycles significantly enhanced the therapeutic effect of a single cycle in the LS174T xenografts (P = 0.001) and produced regressions in the SW1222 xenografts (P = 0.0001), with minimal toxicity.Conclusions: MFE-CP fusion protein, in combination with ZD2767P, provides a new and successful ADEPT system, which offers the potential for multiple cycles and antitumor efficacy. These results provide a basis for the next stage in clinical development of ADEPT.
Gene Expression Profiling of Breast Cancer in Relation to Estrogen Receptor Status and Estrogen-Metabolizing Enzymes: Clinical Implications
Authors: Kristensen Vessela N. , Sørlie Therese , Geisler Jurgen , Langerød Anita , Yoshimura Noriko , Kåresen Rolf , Harada Nobuhiro , Lønning P.E. , Børresen-Dale Anne-Lise 
Published: June 2022

Abstract
Interactions between luminal epithelial cells and their surrounding microenvironment govern the normal development and function of the mammary gland. Estradiol plays a key role in abnormal intracellular signaling, which contributes to the development and progression of breast tumors. The present article summarizes the results from a microarray whole genome gene expression analysis as well as a quantitative analysis of the mRNA expression of members of the estradiol metabolic and signaling pathways in the tumors of postmenopausal breast cancer patients. The analysis of the variation in whole genome gene expression resulted in a tumor classification comprising several distinct groups with distinct expression of the estrogen receptor (ER). The parallel study on the expression of only nine mRNA transcripts of members of the estradiol pathways resulted in two main clusters, representing ER− and ER tumors. The mRNA expression of the estradiol-metabolizing enzymes did not follow the expression of the ER in all cases, leading to the recognition of several further subclasses of tumors. When the tumor classes obtained by whole genome gene expression analysis were compared with those obtained by independent quantitation of the estradiol-metabolizing enzymes, a statistically significant association between both classification groups was observed. These findings point to a possible association between development of a tumor with a particular expression profile and its capacity to synthesize estradiol as measured by the expression of the transcripts for the necessary key enzymes. Further, whole genome expression patterns were studied in 12 patients treated with anastrozole. Using significance analysis of microarrays, we identified 298 genes significantly differently expressed between partial response and progressive disease groups.
Therapeutic Observations in MCF-7 Aromatase Xenografts
Authors: Brodie Angela , Jelovac Danijela , Macedo Luciana , Sabnis Gauri , Tilghman Syreeta , Goloubeva Olga 
Published: June 2022

Abstract
In previous studies using a xenograft model with tumors of human estrogen receptor (ER)–positive breast cancer cells transfected with aromatase (MCF-7Ca), we explored the antitumor efficacy of treatment combining the nonsteroidal aromatase inhibitor letrozole with tamoxifen. However, treatment with this combination resulted in tumor suppression similar to tamoxifen alone but was less effective than letrozole alone. Clinical findings with the nonsteroidal inhibitor anastrozole in combination with tamoxifen (ATAC trial) were consistent with our results. Although letrozole was the most effective single agent in the model, tumors ultimately began to grow during continued treatment. To investigate the mechanisms by which tumors adapted to growth during letrozole treatment, we determined the expression of proteins in tumors during letrozole treatment compared with the tumors of control mice. We found that tumors initially up-regulated the ER, but subsequently receptor levels decreased in tumors unresponsive to letrozole. Adapter proteins (p-Shc and Grb-2) as well as all of the signaling proteins in the mitogen-activated protein kinase cascade (p-Raf, p-MEK1/2, and p-MAPK) but not Akt were increased in tumors no longer responsive to letrozole. The results suggest that tumor cells adapt to estrogen deprivation during letrozole treatment by activation of alternate signaling pathways. When letrozole was combined with the pure antiestrogen fulvestrant, which down-regulates ER, the combination was extremely effective. Tumors regressed by 45% and were maintained without growth for the duration of the experiment (29 weeks). Thus, achieving more complete estrogen blockade may delay development of hormone-independent signaling pathways regulating proliferation.
Estrogen, Estrogen Plus Progestin Therapy, and Risk of Breast Cancer
Authors: Colditz Graham A. 
Published: June 2022

Abstract
Epidemiologic evidence relating use of postmenopausal hormones to risk of breast cancer by nature relies on trends in prescribing practices. Data on the adverse effect of combination estrogen plus progestin used for long durations has only become available over the past decade. Evidence is reviewed relating estrogen alone and estrogen plus progestin to increased risk of breast cancer. Whereas current evidence indicates that longer duration of use increases risk of invasive breast cancer regardless of formulation, the rate of increase in risk is greater for combination estrogen plus progestin therapy. Although data are limited, continuous combined therapy and sequential therapy seem to have comparable impact on breast cancer risk. Combination therapy is more strongly related to lobular breast cancer than is estrogen alone. Unresolved issues remain about dose of estrogen and progestin in relation to risk, and about identification of women for whom short-term use to relieve menopausal symptoms may be safe and effective.
Exemestane for Breast Cancer Prevention: A Feasible Strategy?
Authors: Lønning Per E. 
Published: June 2022

Abstract
Third-generation aromatase inhibitors and inactivators have been successfully implemented in therapy of metastatic breast cancer, and three large phase III trials have revealed superiority compared with tamoxifen monotherapy in the adjuvant setting. Notably, each of these trials recorded a substantial reduction in contralateral breast cancer among patients exposed to the aromatase inhibitor/inactivator. A major concern in implementing use of these compounds in the preventive setting relates to potential detrimental effects of estrogen suppression on bone and lipid metabolism. Recent data from a placebo-controlled study now reveal 2 years of treatment with exemestane compared with placebo to have moderate effects on bone metabolism and plasma lipid profile, supporting further evaluation of exemestane as a potential preventive agent for breast cancer in postmenopausal women.
Pemetrexed in Malignant Pleural Mesothelioma
Authors: Hazarika Maitreyee , White Robert M. , Booth Brian P. , Wang Yong-Cheng , Lee Ham Doo Y. , Liang Cheng Yi , Rahman Atiqur , Gobburu Jogarao V.S. , Li Ning , Sridhara Rajeshwari , Morse David E. , Lostritto Richard , Garvey Patricia , Johnson John R. , Pazdur Richard 
Published: June 2022

Abstract
Purpose: This report describes the data and analysis leading to the approval of pemetrexed (LY 231514, MTA, Alimta, Eli Lilly and Co., Indianapolis, IN) by the U.S. Food and Drug Administration (FDA) of a New Drug Application for the treatment of malignant pleural mesothelioma (MPM).
Experimental Design: The FDA review of the efficacy and safety of pemetrexed assessed in a randomized clinical trial of 448 patients with unresectable MPM comparing pemetrexed plus cisplatin with cisplatin alone, as well as preclinical pharmacology and chemistry data, are described. The basis for marketing approval is discussed.
Results: In one randomized, single-blind, multicenter international trial, 226 patients were randomized to the pemetrexed and cisplatin arm and 222 patients were randomized to cisplatin alone. Median survival times were 12.1 months for pemetrexed and cisplatin and 9.3 months for cisplatin (P = 0.021; hazard ratio, 0.766; 95% confidence interval, 0.61-0.96). Myelosuppression, predominantly neutropenia, was the most common toxicity of pemetrexed plus cisplatin. Other common adverse events were fatigue, leucopenia, nausea, dyspnea, vomiting, chest pain, anemia, thrombocytopenia, and anorexia.
Conclusions: Pemetrexed in combination with cisplatin was approved by the FDA on February 4, 2004 for the treatment of patients with MPM whose disease is either unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m2 intra venous infusion over 10 minutes on day 1 of each 21-day cycle in combination with 75 mg/m2 cisplatin infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B12 injections before the start and during therapy to reduce severe toxicities. Patients should also receive corticosteroids with the chemotherapy to decrease the incidence of skin rash. Approval was based on a demonstration of survival improvement in a single randomized trial. Response rates and time to tumor progression were not included in product labeling because of inconsistencies in assessments among the investigators, independent radiologic reviewers, and the FDA, reflecting the difficulty of radiographic assessments in malignant mesothelioma. Complete prescribing information is available on the FDA Web site at http://www.fda.gov/cder/approval/index.htm.
Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis: A Multicenter Randomized Phase II Trial
Authors: Uphaus Timo , Richards Toby , Weimar Christian , Neugebauer Hermann , Poli Sven , Weissenborn Karin , Imray Christopher , Michalski Dominik , Rashid Hisham , Loftus Ian , Rummey Christian , Ritter Martin , Hauser Till-Karsten , Münch Götz , Gröschel Klaus , Poppert Holger 
Published: June 2022

Background:
Patients with symptomatic internal carotid artery (ICA) stenosis are at high risk of recurrent ischemic stroke and require early interventional treatment and antiplatelet therapy. Increased bleeding rates might counterbalance the periprocedural efficacy of intensified platelet inhibition. We aim to investigate, whether Revacept, a competitive antagonist of glycoprotein VI, adjunct to standard antiplatelet therapy reduces the occurrence of ischemic lesions in patients with symptomatic ICA stenosis.

Methods:
International, multicenter (16 sites), 3-arm, randomized (1:1:1), double-blind, and placebo-controlled study with parallel groups, including patients with symptomatic ICA stenosis. A single infusion over 20 minutes of either placebo, 40 mg or 120 mg Revacept in addition to guideline-conform antiplatelet therapy was evaluated with regard to the exploratory efficacy end point: Number of new ischemic lesions on diffusion-weighted magnetic resonance imaging after treatment initiation. Main clinical outcome was the combined safety and efficacy end point including any stroke or death, transient ischemic attack, myocardial infarction, coronary intervention, and bleeding complications during follow-up.

Results:

Out of 160 randomized patients, 158 patients (68±10.1 years, 24% female) received study medication (51 patients placebo, 54 patients 40 mg Revacept and 53 patients 120 mg Revacept) and were followed for 11.2±2.3 months. A total of 1.16 (95% CI, 0.88–1.53)/1.05 (95% CI, 0.78–1.42;
P
=0.629)/0.63 (95% CI, 0.43–0.93) new diffusion-weighted magnetic resonance imaging lesions per patient were detected in the placebo/40 mg/120 mg Revacept groups, without statistical evidence of a difference. A reduction of the combined safety and efficacy end point during the study period was observed in patients who received 120 mg (HR, 0.46 [95% CI, 0.21–0.99];
P
=0.047), but not 40 mg Revacept compared with placebo (HR, 0.72 [95% CI, 0.37–1.42];
P
=0.343).

Conclusions:
Revacept 120 mg reduced the combined safety and efficacy end point in patients with symptomatic ICA stenosis.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique Identifier: NCT01645306.
The prevalence of self-reported mental illness among those imprisoned in New South Wales across three health surveys, from 2001 to 2015
Authors: Browne Christie C , Korobanova Daria , Yee Natalia , Spencer Sarah-Jane , Ma Trevor , Butler Tony , Dean Kimberlie 
Published: June 2022

Objective: The prevalence of mental illness among those in prison is much higher than in the community; however, very few studies have examined whether rates have changed over time, in line with increasing self-reported rates in the community. Methods: This study compares the prevalence of self-reported mental illness, self-harm and suicidal thoughts/behaviours, and drug and alcohol use across three waves (2001, 2009 and 2015) of health surveys involving men and women in New South Wales prisons and compared these rates with published community-level findings. Results: The prevalence of those reporting any mental health diagnosis increased significantly across the three surveys, even after adjustment for socio-demographic and criminal justice variables that also changed over time. Individuals surveyed in 2015 were more likely to report a mental health diagnosis than those surveyed in 2001 (adjusted odds ratio = 2.66, 95% confidence interval = [2.16, 3.27]). The prevalence of self-harm and suicidal thoughts and behaviours remained stable across the three surveys, while self-reported regular drug use decreased over the period. Women experienced a far greater burden of mental illness than men across all three surveys and experienced more growth in the prevalence of most psychiatric disorders. Conclusion: These findings have important implications for public and prison health systems given the poor social, health and criminal justice outcomes of those imprisoned with mental illness, both in custody and post-release.
The Effect of Safety Claims on Consumer Chemical Product Perceptions and the Role of Warnings
Authors: Kim Soyun 
Published: June 2022

Objective To assess the effect of safety claims and warnings on perceptions of consumer chemical products. Background Manufacturers have two contradictory objectives: to increase sales by emphasizing the positive aspects of a product and to protect consumers from hazards of the product. One of the strategies that some manufactures have devised to achieve these goals is to use anti-warnings. Safety claims placed on consumer chemical products were examined to determine if anti-warnings influenced product perceptions. Method Two experiments were conducted. In Experiment 1, three consumer chemical products with manipulated safety claims were presented to 300 participants, who completed a survey to rate their perceptions of the products. In Experiment 2, the same products with the safety claims and added warnings were presented to 600 participants and were rated using the same measurements as Experiment 1. Results Safety claims on product labels decreased perceived hazards compared to no safety claims on products in both Experiments 1 and 2. In Experiment 2, added warnings raised the perceived hazards. Conclusion The use of safety claims on consumer chemical products had an effect on product perceptions by decreasing hazard perceptions. The addition of strong warnings on product labels mitigated this effect. Application This research provides empirical evidence suggesting that the use of safety claims decreased hazard perceptions of potentially hazardous consumer chemical products and can serve as a possible form of anti-warnings.
How much information is ‘reasonable’? A qualitative interview study of the prescribing practices of palliative care professionals
Authors: Dumble Katie , Driessen Annelieke , Borgstrom Erica , Martin Jonathan , Yardley Sarah , Cohn Simon 
Published: June 2022

Background: Prescribing clinicians have to negotiate ambiguities around information provision and consent for medications on a daily basis, despite the availability of professional guidance. Aim: This study aims to explore some of the many factors prescribing clinicians in the United Kingdom take into account when deciding what information to give to patients about medication choices, and when. Design: In depth face-to-face interviews, utilising both a hypothetical scenario and semi-structured prompts, were conducted in order to elicit extended reflections on how clinicians individually work through such dilemmas and make decisions. Setting/participants: Ten prescribing clinicians (doctors and nurses) from a large combined team of National Health Service (NHS) secondary and community palliative care providers in England. Results: Palliative care staff regularly face choices about information provision in prescribing discussions, in particular when considering whether information might increase distress. Participants presented three overlapping framings that helped them assess the range of factors that could potentially be taken into account; (1) assessing the individual patient, (2) tailoring the provision of information and (3) jointly forming a plan. Conclusions: Information provision about medication choices and effects is a demanding, ongoing process, requiring nuanced judgements that constitute an unacknowledged yet significant aspect of clinical workload. Although current medical guidelines allow clinical discretion about information provision, this can leave individual clinicians feeling vulnerable. Further evolution of guidelines needs to establish a more sophisticated way to acknowledge professional and legal requirements, whilst also promoting professional autonomy and judgement.
A scoping review of online international student collaboration in occupational therapy education
Authors: Hynes Sinéad M. , Hills Caroline , Orban Kristina 
Published: June 2022

Introduction For occupational therapy students, international experiences and access to a global curriculum develops understanding of broad cultural and contextual determinants of health and wellbeing. International placements or study abroad opportunities are not possible for many students and many universities are developing alternative internationalisation opportunities. The aim of this review was to determine what is known from the existing literature on the use of online international student collaboration in occupational therapy curricula. Method A scoping review design was used to search relevant literature on online international student collaboration in occupational therapy education, following a methodological framework for conducting scoping reviews. Seven databases were searched. Search included all articles published up until November 2020. Findings The database searches yielded a total of 2011 results. Following screening and review of articles ten papers met the inclusion criteria and were included in the review. The studies were charted and discussed in the areas of format of the online interactions, reported outcomes of the online interactions, barriers and facilitators in implementation. Conclusion Findings inform curricula designers establishing online international learning and those conducting research in this area. Outcomes indicate the breadth of student learning including culture, diversity, as well as the social determinants of occupational engagement and participation. Registration Protocol Registered: 2020-07-06, available on Open Science Framework (OSF) at https://osf.io/wfkjy
Understanding Domestic Food Safety: An Investigation into Self-Reported Food Safety Practice and Associated Factors in Southern Ethiopian Households
Authors: Yemane Bethlehem , Tamene Aiggan 
Published: June 2022

Background: According to available studies, 12%-20% of reported foodborne outbreaks start in the household. It is projected that 1 out of every 10 persons will become ill as a result of consuming tainted food. Poor food handling practices cause 600 million foodborne illnesses each year. In a given year, this leads to 420 000 deaths. In Ethiopia, there is a scarcity of studies on home-food-safety practices and the factors that affect them. This has resulted in a shortage of relevant information on the status of home-food-related illnesses in the country. Methods: A community-based cross-sectional study was carried out from May to June 23, 2021. A standardized and pre-tested questionnaire was used to collect data from 622 households. The total plate count method was used to analyze bacteria on cleaned plates. Epi data version 3.1 was used to enter data, while SPSS version 25 was used to analyze the data. Descriptive statistics and multivariable regression were used to characterize the data and identify factors associated with food safety practices. Result: 51.1% of the study participants had a safe food handling practice. The mean total plate count was 2.34 CFU/cm2. In the multivariable regression, Household wealth (AOR = 2.05, 95% CI [1.01-3.16]), Education (AOR = 3.33, 95% CI [1.41-6.31]), Training (AOR = 2.85, 95% CI: [1.31–3.19]), Knowledge of safe practices (AOR = 1.95, 95% CI [1.23-3.08], and Attitude (AOR = 2.04, 95% CI [1.09, 3.82]) were associated with safe food handling practices. Conclusion: Although data gathering systems for food-borne diseases typically overlook a large number of home-based outbreaks of sporadic infection, it is now widely understood that many episodes of food-borne sicknesses are caused by individuals’ inappropriate food handling and preparation in their kitchens. In the current study, educational status, household wealth, food safety training, attitude, and knowledge about FBDs were found to be strongly associated with safe practices. This implies that public education is a key factor in improving food safety practices at home.