bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endocrine Therapy Trials of Aromatase Inhibitors for Breast Cancer in the Adjuvant and Prevention Settings
Authors: Ingle James N. 
Published: June 2022

Abstract
The recent past has witnessed the appearance of substantial data relating to endocrine therapy of breast cancer. In the adjuvant therapy setting in early breast cancer, several large, well-conducted, randomized, double-blind clinical trials have provided evidence for the value of the third-generation aromatase inhibitors (AI) anastrozole, exemestane, and letrozole. The three major studies to date [i.e., Arimidex, tamoxifen alone, or in combination (ATAC), International Exemestane Study (IES), and letrozole after 5 years of tamoxifen (MA.17)] evaluated three different populations of women from the standpoints of duration of prior tamoxifen and thus time since the treatment of the primary breast cancer. A consistent pattern of improvement in disease-free survival was seen whether the control arm was tamoxifen (ATAC and IES) or placebo following tamoxifen (MA.17). From a toxicity standpoint, the major findings with the AIs were a decreased incidence of thromboembolic events and endometrial cancers but an increase in musculoskeletal complaints and potential for decreasing bone density. The last issue should be clarified with ongoing studies addressing the impact of the three AIs on bone density and fractures. In summary, based on ATAC, IES, and MA.17, respectively, the following conclusions can be drawn relating to postmenopausal women with hormone receptor positive early breast cancer: anastrozole is a reasonable choice for initial endocrine adjuvant therapy, exemestane should be considered for women who have received 2 to 3 years of tamoxifen, and letrozole should be considered for those who have completed about 5 years of tamoxifen.
In the prevention setting, tamoxifen has been evaluated in multiple trials involving &gt;28,000 women and, despite clear evidence of benefit, the level of acceptance of this agent by women seems to be low. Two recently developed prevention trials, IBIS 2 and MAP.3, involve the study of aromatase inhibitors against a placebo control rather than tamoxifen. Whereas the recent adjuvant trials have established the value of the third-generation aromatase inhibitors in early-stage breast cancer, the marked reductions in contralateral breast cancers seen in these trials suggest they will be of value in the prevention setting in women at increased risk of developing the disease.
TAS-108: A Novel Steroidal Antiestrogen
Authors: Buzdar Aman U. 
Published: June 2022

Abstract
TAS-108 is a novel steroidal antiestrogen compound that has a strong binding affinity to the estrogen receptor and, in preclinical studies, has antitumor activity against tamoxifen-resistant breast cancer cell lines. Its molecular mechanisms of actions are different from those of tamoxifen and fulvestrant. TAS-108 showed tissue-selective agonist activity in the bone and cardiovascular systems and, in preclinical and phase I studies, did not show any effect on the endometrium. In a phase I study, TAS-108 was well tolerated at doses ranging from 40 to 160 mg/d with no maximum tolerated dose. Toxicities included hot flashes, headache, and nausea and vomiting. The drug has linear pharmacokinetics. In the phase I study, there was evidence of biological antitumor activity, with stable disease noted in several patients. A phase II study is ongoing, and phase III studies are being planned with the drug.
Tamoxifen versus Aromatase Inhibitors for Breast Cancer Prevention
Authors: Yue Wei , Wang Ji-Ping , Li Yuebai , Bocchinfuso Wayne P. , Korach Kenneth S. , Devanesan Prabu D. , Rogan Eleanor , Cavalieri Ercole , Santen Richard J. 
Published: June 2022

Abstract
Long-term exposure to estradiol is associated with an increased risk of breast cancer, but the mechanisms responsible are not firmly established. The prevailing theory postulates that estrogens increase the rate of cell proliferation by stimulating estrogen receptor (ER)–mediated transcription, thereby increasing the number of errors occurring during DNA replication. An alternative theory suggests that estradiol is metabolized to quinone derivatives, which directly remove base pairs from DNA through a process called depurination. Error-prone DNA repair then results in point mutations. We postulate that both processes act in an additive or synergistic fashion. If correct, aromatase inhibitors would block both processes, whereas antiestrogens would only inhibit receptor-mediated effects. Accordingly, aromatase inhibitors would be more effective in preventing breast cancer than antiestrogens. Our initial studies showed that catechol-estrogen metabolites are formed in MCF-7 human breast cancer cells in culture. We then used an animal model that allows dissociation of ER-mediated function from the effects of estradiol metabolites and showed formation of genotoxic estradiol metabolites. We also examined the incidence of tumors formed in these ERα knockout mice bearing the Wnt-1 transgene. The absence of estradiol markedly reduced the incidence of tumors and delayed their onset. In aggregate, our results support the concept that metabolites of estradiol may act in concert with ER-mediated mechanisms to induce breast cancer. These findings support the possibility that aromatase inhibitors might be more effective than antiestrogens in preventing breast cancer.
Dual Role of Transforming Growth Factor β in Mammary Tumorigenesis and Metastatic Progression
Authors: Muraoka-Cook Rebecca S. , Dumont Nancy , Arteaga Carlos L. 
Published: June 2022

Abstract
It is generally accepted that transforming growth factor β (TGFβ) is both a tumor suppressor and tumor promoter. Whereas loss or attenuation of TGFβ signal transduction is permissive for transformation, introduction of dominant-negative TGFβ receptors into metastatic breast cancer cells has been shown to inhibit epithelial-to-mesenchymal transition, motility, invasiveness, survival, and metastases. In addition, there is evidence that excess production and/or activation of TGFβ by cancer cells can contribute to tumor progression by paracrine mechanisms involving neoangiogenesis, production of stroma and proteases, and subversion of immune surveillance mechanisms in tumor hosts. These data provide a rationale in favor of blockade of autocrine/paracrine TGFβ signaling in human mammary tumors with therapeutic intent. Several treatment approaches are currently in early clinical development and have been the focus of our laboratory. These include (1) ligand antibodies or receptor-containing fusion proteins aimed at blocking ligand binding to cognate receptors and (2) small-molecule inhibitors of the type I TGFβ receptor serine/threonine kinase. Many questions remain about the viability of anti-TGFβ treatment strategies, the best molecular approach (or combinations) for inhibition of TGFβ function in vivo, the biochemical surrogate markers of tumor response, the molecular profiles in tumors for selection into clinical trials, and potential toxicities, among others.
Insulin-Like Growth Factor-I and Breast Cancer Therapy
Authors: Ibrahim Yasir H. , Yee Douglas 
Published: June 2022

Abstract
Targeting hormonal and growth factor signaling pathways has proven to be useful in the treatment of breast cancer. In vitro, animal, and epidemiologic evidence provide a rationale for the relevance of the insulin-like growth factor (IGF) system to breast cancer biology. The IGF system has been implicated in promoting mitogenic, metastatic, and antiapoptotic phenotypes in breast cancer. As a consequence of the ability of IGF to promote tumorigenesis, pharmacologic interventions targeting the IGF system are being devised. Such strategies include decreasing ligand production, ligand binding, or receptor activation. In this article, directed anti-IGF strategies and the possible clinical impact of using such therapies for treating breast cancer are discussed.
Expression of Erythropoietin and Erythropoietin Receptor in Non–Small Cell Lung Carcinomas
Authors: Dagnon Koami , Pacary Emilie , Commo Frédéric , Antoine Martine , Bernaudin Myriam , Bernaudin Jean-Francois , Callard Patrice 
Published: June 2022

Abstract
Purpose: Expression of erythropoietin (Epo) and its receptor (Epo-R) has been shown in various normal and neoplastic nonhematopoietic tissues. This study, in non–small cell lung carcinoma, was designed to investigate the previously unreported expression of Epo and Epo-R as well as hypoxia-inducible factor-1α (HIF-1α), which is known to control Epo expression.
Experimental Design: Samples from lung squamous cell carcinomas (n = 17) and adenocarcinomas (n = 12) were obtained from patients undergoing curative surgery. mRNA transcripts of Epo, Epo-R, soluble Epo-R (sEpo-R), HIF-1α, and factor inhibiting HIF-1 (FIH-1) were evaluated by reverse transcription-PCR, whereas localization of Epo, Epo-R, and HIF-1α was assessed by immunohistochemistry.
Results: Epo, Epo-R, sEpo-R, HIF-1α, and FIH-1 transcripts were detected by reverse transcription-PCR in all samples tested, but with heterogeneous levels of expression for Epo, Epo-R, and sEpo-R. Coordinated levels of mRNA were observed for HIF-1α and FIH-1.
Epo was detected in carcinomatous cells by immunohistochemistry in 50% of samples and Epo-R was detected in 96% of samples. Co-expression of Epo and Epo-R was observed on contiguous sections from 50% of tumors. HIF-1α was immunolocalized in 80% of non–small cell lung carcinomas.
Conclusion: Epo-R was expressed in almost all samples and Epo was expressed in one half of samples on immunohistochemistry and in 100% of samples by mRNA detection, suggesting a potential paracrine and/or autocrine role of endogenous Epo in non–small cell lung carcinoma. The detection of stabilized HIF-1α suggests a possible role in Epo expression. Moreover, in the light of these results, the potential interactions between therapeutic recombinant Epo and the putative neoplastic Epo/Epo-R signaling pathways must be considered.
The Genotoxic Effect of Nasal Steroids on Human Nasal Septal Mucosa and Cartilage Cells In Vitro
Authors: Türkoğlu Babakurban Seda , Vural Ömer , Korkmaz Kasap Yeşim , Hızal Evren , Yurtcu Erkan , Büyüklü Adnan Fuat 
Published: June 2022

Objective: To determine whether budesonide (Bud) and triamcinolone acetate (TA) cause DNA fractures in the nasal mucosa and septal cartilage cells through examinations using the comet assay technique. Study design: Prospective, controlled experimental study. Setting: University hospital. Methods: Septal mucosal epithelial and cartilage tissue samples were taken from 9 patients. Cell cultures were prepared from these samples. Then, budesonide and triamcinolone acetate active ingredients at 2 different doses of 0.2 and 10 µM were separately applied to the cell cultures formed from both tissues of each patient, except the control cell culture, for 7 days in one group and 14 days in one group. After the applications, genotoxic damage was scored with the comet assay technique and the groups were compared. Results: In both the budesonide and triamcinolone acetate groups, the comet scores at low and high doses, on the 7th and 14th days were found to be significantly higher in both cartilage and epithelial tissue than in the control group. Conclusion: The study results showed that budesonide and triamcinolone acetate lead to a significantly high rate of genotoxic damage in both epithelial tissue and cartilage tissue.
When should palliative care be introduced for people with progressive fibrotic interstitial lung disease? A meta-ethnography of the experiences of people with end-stage interstitial lung disease and their family carers
Authors: Palmer Evelyn , Kavanagh Emily , Visram Shelina , Bourke Anne-Marie , Forrest Ian , Exley Catherine 
Published: June 2022

Background: Little is currently known about the perspectives of people with interstitial lung disease and their carers in relation to the timing of palliative care conversations. Aim: To establish patients’ and carers’ views on palliative care in interstitial lung disease and identify an optimum time to introduce the concept of palliative care. Design: Meta-ethnography of qualitative evidence. The review protocol was prospectively registered with PROSPERO (CRD42021243179). Data sources: Five electronic healthcare databases were searched (Medline, Embase, CINAHL, Scopus and Web of Science) from 1st January 1996 to 31st March 2022. Studies were included that used qualitative methodology and included patients’ or carers’ perspectives on living with end-stage disease or palliative care. Quality was assessed using the Critical Appraisal Skills Programme checklist. Results: About 1779 articles were identified by initial searches. Twelve met the inclusion criteria, providing evidence from 266 individuals across five countries. Three stages were identified in the illness journey of a person with interstitial lung disease: (1) Information seeking, (2) Grief and adjustment, (3) Fear of the future. Palliative care involvement was believed to be most appropriate in the latter two stages and should be prompted by changes in patients’ health such as respiratory infections, onset of new symptoms, hospital admission, decline in physical function and initiation of oxygen. Conclusions: Patients and carers prefer referral to palliative care services to be prompted by changes in health status. Future research should focus on supporting timely recognition of changes in patients’ health status and how to respond in a community setting.
Association of bladder trabeculation and neurogenic bladder with spinal cord injury
Authors: Won Yu Hui , Kim Da-Sol , Kim Gi-Wook , Park Sung-Hee , Ko Myoung-Hwan , Seo Jeong-Hwan 
Published: June 2022

Objective To compare clinical findings and urodynamic parameters according to trabeculation grade and analyze their correlations with trabeculation severity in neurogenic bladder caused by suprasacral spinal cord injury (SCI). Methods A retrospective chart review was performed of neurogenic bladder caused by SCI. Bladder trabeculation grade was compared with SCI-related clinical parameters and bladder-related urodynamic parameters. Results In SCI patients, factors such as disease duration, bladder capacity, detrusor pressure, peak detrusor pressure values, and compliance were significantly different between different grades of bladder trabeculation, while neurological level of injury, completeness, and detrusor sphincter dyssynergia had no clear relationship with bladder trabeculation grade. In the correlation analysis, vesicoureteral reflux was moderately correlated with trabeculation grade (correlation coefficient 0.433), while the correlation coefficients of disease duration, involuntary detrusor contraction, and bladder filling volume were between 0.3 and 0.4. Conclusion Bladder trabeculation with suprasacral-type neurogenic bladder was graded. Although disease duration was positively correlated with bladder trabeculation grade, differences in the neurological level of injury or American Spinal Injury Association Impairment Scale score were not observed. Bladder volume, peak detrusor pressure, compliance, reflex volume, and vesicoureteral reflux also showed significant differences according to trabeculation grade. Vesicoureteral reflux was moderately correlated with trabeculation grade.
Social Suffering: A New Reference Framework for Economic Analysis
Authors: ballet Jerome , Mahieu François-Regis 
Published: June 2022

Social suffering has become a recurrent theme in various disciplines (sociology, social psychology, anthropology), but remains absent from economic analysis. The aim of our article is hence to reinstate the role of social suffering in economics. We first define the scope of the concept, which should be interpreted as a form of suffering generated by economic systems, particularly the current capitalist system. We then dismiss the objections to this conception of social suffering. In particular, we dismiss the attempt to reduce social suffering to a set of categorical phenomena that can be interpreted independently of the functioning of an economic system. Finally, we point out that lowering social suffering should take precedence over the pursuit of happiness. JEL Classification: B40, P46, A13
Carrier-free prodrug nanoparticles based on lonidamine and cisplatin for synergistic treatment of breast cancer
Authors: Yang Lu , Li Junnan , Guan Zhaoyuan , Zhang Jingwen , Wang Xin , Tang Rupei 
Published: June 2022

Herein, we combined a derivative of cisplatin (CP) and the chemosensitizer lonidamine (LND) to design an amphiphilic prodrug, in which the ratio of LND to cisplatin was fixed at 2:1. Diaminedichlorodihydroxyplatinum (DH-CP) is a hydrophilic cisplatin derivative. Due to its appropriate amphiphilicity, this prodrug could self-assemble into stable nanoparticles (denoted as LNP-NPs). Under the action of excessive glutathione (GSH) in tumor cells, DH-CP could be reduced to cytotoxic cisplatin. In addition, the released LND could inhibit the metabolic process of tumor cells, and improving the sensitivity of tumor cells to cisplatin. In vitro studies demonstrated that LNP-NPs displayed significantly cytotoxicity on breast cancer cells, and the cell viability after co-incubation for 48 h (CP 16 μg/mL) were 18.77% (MCF-7) and 20.01% (EMT6), respectively. LNP-NPs could also significantly inhibit the growth of MCF-7 tumor-like spheroids, which were realized through the high coordination and cooperation between CP and LND. Therefore, the carrier-free drug delivery system based on LND and DH-CP is expected to achieve a good synergistic anti-tumor effect.
Perspectives on Engagement With Youth Physical Activity Opportunities in Low-Income, African American, Urban Neighborhoods
Authors: Suminski Richard R. , Robson Shannon M. , Kopetsky Fultz Amanda , Sundermeir Samantha M. , Jahnke Sara A. 
Published: June 2022

Purpose To identify and describe factors related to low-income, African American youth’s participation in neighborhood youth physical activity opportunities (YPAO). Approach Formative research. Setting Face-to-face focus groups in New Castle County, Delaware. Participants Fifty-five adults (parents/guardians of youth, YPAO providers, small business representatives) living and/or working in low-income, African American neighborhoods. Method Nine, 60-90 minute focus groups were conducted from December 2018 through March 2019. Focus group questions were developed a priori and included domains related to neighborhood YPAOs. The domains were awareness of YPAOs, benefits and barriers to providing YPAOs, ways to increase youth participation in YPAOs, and strategies for creating, improving, and sustaining YPAOs. Focus group recordings were transcribed, and thematic analysis was performed to identify themes related to increasing youth participation in YPAOs. Results Four major themes related to YPAOs emerged: 1) exposure/access, 2) parent buy-in/accountability (e.g., personal values and trust with YPAOs), 3) technology, and 4) increasing a sense of community. Three minor themes included liability, advertising, and schools. Small businesses desired to support YPAOs mainly through non-monetary means, while mutually benefitting from receiving local recognition. Conclusion Developing strategies to incorporate effective community partnerships, creative program ideas with advertising, and active, multisector involvement including small businesses into practice has the potential to increase engagement of low-income, African American youth in YPAOs.
Reliability of 3D planning and simulations of medial open wedge high tibial osteotomies
Authors: Jörgens Maximilian , Keppler Alexander M , Degen Nikolaus , Bachmeier Andreas T , Bergstraesser Marcel , Sass Jan , Prall Wolf Christian , Böcker Wolfgang , Fürmetz Julian 
Published: June 2022

Purpose: In medial open-wedge high tibial osteotomy (HTO) hinge axis and osteotomy plane influence the resulting anatomy, but accurate angular quantifications using 3D-planning-simulations are lacking. The objectives of this study were developing a standardized and validated 3D-planning method of an HTO and to perform several simulated realignments to explain unintended anatomy changes. Methods: The cutting direction of the main osteotomy was defined parallel to the medial tibial slope and the hinge axis 1.5 cm distal to the lateral plateau. For interobserver testing, this 3D planning was performed on 13 digital models of human tibiae by two observers. In addition, four different hinge axis positions and five differently inclined osteotomy planes each were simulated. The osteotomy direction ranged from medial 0°–30° anteromedial, while the tilt of the osteotomy plane compared to the tibial plateau was −10° to +10°. All anatomic angular changes were calculated using 3D analysis. Results: Multiple HTO plannings by two medical investigators using standardized procedures showed only minimal differences. In the 3D-simulation, each 10° rotation of the hinge axis resulted in a 1.7° significant increase in slope. Tilting the osteotomy plane by 10° resulted in significant torsional changes of 2°, in addition to minor but significant changes in the medial proximal tibial angle (MPTA). Conclusion: Standardized 3D-planning of the HTO can be performed with high reliability using two-observer planning. 3D-simulations suggest that control of the osteotomy plane is highly relevant to avoid unintended changes in the resulting anatomy, but this can be a helpful tool to modify specific angles in different pathologies in the HTO.
JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B
Authors: Gane Ed , Yuen Man-Fung , Kakuda Thomas N , Ogawa Tetsuro , Takahashi Yasushi , Goeyvaerts Nele , Lonjon-Domanec Isabelle , Vaughan Tamisha , Schluep Thomas , Hamilton James , Njumbe Ediage Emmanuel , Hillewaert Vera , Snoeys Jan , Lenz Oliver , Talloen Willem , Biermer Michael 
Published: June 2022

Background JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947). Methods Healthy participant cohorts were double-blind and randomized to receive a single subcutaneous JNJ-73763989 dose (non-Japanese participants, 35, 100, 200, 300 or 400 mg; Japanese participants, 25, 100 or 200 mg) or placebo. JNJ-73763976 and JNJ-73763924 plasma concentrations were assessed over 48 h. CHB patients received JNJ-73763989 200 mg every 4 weeks plus daily oral JNJ-56136379 250 mg and NA in an open-label fashion. Safety and tolerability were assessed through Day 28 (healthy participants) or Day 112 (patients). Results Thirty non-Japanese ( n = 4/dose; placebo, n = 10) and 24 Japanese healthy participants ( n = 6/dose; placebo, n = 6) were randomized. JNJ-73763976 and JNJ-73763924 exposure generally increased in a dose-proportional manner. Mean plasma half-life was 4–9 h. No differences between pharmacokinetic parameters were apparent between non-Japanese and Japanese healthy participants. In the 12 CHB patients, mean JNJ-73763976, JNJ-73763924 and JNJ-56136379 plasma concentrations 2 h post-dose on Day 29 were 663, 269 and 14,718 ng/mL, respectively. In both studies, all adverse events were mild/moderate. Conclusion JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.