Download or read book Targeting Molecular Resistance in Castration Resistant Prostate Cancer written by Legnica Legnica Press and published by . This book was released on 2016-01-21 with total page 38 pages. Available in PDF, EPUB and Kindle. Book excerpt: Multiple mechanisms of resistance contribute to the inevitable progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly. Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment. Understanding the mechanisms of resistance resulting in progression as well as identifying new targetable pathways remains the focus of current prostate cancer research. We review current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes.

Download or read book Hormone Therapy and Castration Resistance of Prostate Cancer written by Yoichi Arai and published by Springer. This book was released on 2018-05-11 with total page 420 pages. Available in PDF, EPUB and Kindle. Book excerpt: This comprehensive reference expounds the current state of hormone therapy and castration resistance of prostate cancer (PCa). Previously, the incidence of PCa in Asian countries was relatively low, but it has been increasing dramatically in recent years. Although most of the new cases are diagnosed in early stages, a significant proportion of patients receive hormone therapy for metastatic disease or for relapse after local treatment. Thus the situation has gradually changed toward earlier and longer use of hormone therapy. The malignancy finally forms castration-resistant prostate cancer (CRPC) despite the lack of testicular androgen. With advances in understanding of the molecular basis of hormone dependence and CRPC, many new androgen receptor-targeted agents have emerged. During the last decade, much evidence on hormone therapy has been accumulated in Japan. Interestingly, some of these findings are different from those reported from Western countries, suggesting ethnic variation in the outcome of hormone therapy. In the chapters of this book, expert authors provide exhaustive interpretations of the evidence recently reported from Japan and provide important Asian perspectives on hormone therapy for PCa. This work benefits not only Asian urologists but also their Western counterparts and all physicians and medical personnel who are involved in the treatment of PCa.

Download or read book Response and Resistance in Castration Resistant Prostate Cancer written by Hung-Ming Lam and published by Frontiers Media SA. This book was released on 2020-12-24 with total page 99 pages. Available in PDF, EPUB and Kindle. Book excerpt: This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.

Download or read book Therapy Resistance in Prostate Cancer written by Hisham Bahmad and published by Elsevier. This book was released on 2023-10-24 with total page 342 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer (PCa) is among the most diagnosed cancers in men worldwide as well as one of the most common causes of cancer-related deaths. Despite the advances in treatment, the disease remains associated with poor survival and resistance to cytotoxic and targeted therapies. Therapy Resistance in Prostate Cancer: Mechanisms and Insights highlights the main mechanisms that are responsible for therapy resistance in PCa allowing researchers and clinicians to have a synopsis of current options and new therapies that can be proposed to overcome this resistance. Understanding the mechanisms responsible for chemotherapy resistance helps researchers all over the world to delve deeper into the pathways behind this resistance and potentially discover new therapeutic targets for PCa. Tackles the topic of resistance from a broader perspective, including, but not limited to, the role of the extracellular matrix and cancer stem cells in therapy resistance Creates understanding on how to develop novel therapies that specifically target CSCs to eliminate the regenerating capacity of the tumor and overcome therapy resistance Helps in identifying novel molecular biomarkers and potential therapeutic targets pertaining to the tumor microenvironment to overcome therapy resistance Provides a general view of the main pathways involved in PCa progression that will aid in understanding the mechanisms responsible for chemotherapy resistance

Download or read book Management of Castration Resistant Prostate Cancer written by Fred Saad and published by Springer. This book was released on 2014-08-20 with total page 336 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume provides new data about the molecular biology of CRPC and a review of the definition, staging and prognostic factors that define CRPC. The book features an in depth review of proven therapeutic options, including bone targeted therapies, immunotherapy, chemotherapy and hormonal based therapies. Combination therapy as well as novel targeted approaches presently under investigations are also reviewed. The text provides up to date guidelines and algorithms for the management of CRPC based on international guidelines presently available as well as evidence based medicine. As a concise yet comprehensive summary of the current status of the field, Management of Castration Resistant Prostate Cancer serves as a very useful resource for physicians and researchers dealing with this challenging malignancy.

Download or read book Molecular Targeting of Prostate Cancer During Androgen Ablation Inhibition of CHES1 FOXN3 written by and published by . This book was released on 2010 with total page 51 pages. Available in PDF, EPUB and Kindle. Book excerpt: Our operating hypothesis is that checkpoint suppressor 1 (CHES1)/FOXN3 is an androgen withdrawal-induced gene that promotes prostate cancer resistance to apoptosis. The purposes of this research are two-fold. The first is to define the mechanisms of CHES1 gene expression regulation and function, particularly in mediating apoptosis resistance during androgen ablation. Secondly, the tools yielded from our functional studies will be utilized to test the efficacy of CHES1-silencing therapy (CST) in preventing castration-resistant prostate cancer and to develop a mechanism-based noninvasive imaging strategy for monitoring the success of CST. Several significant findings were made. Of major clinical importance, CHES1 expression was elevated substantially during combined androgen blockade and was associated with enhanced PI3K/Akt activation and suppression of pro-apoptotic BNIP3 expression. Conversely, CHES1 down-regulation is potentially necessary for genotoxic stress to trigger apoptosis. To test the hypothesis that CHES1 could be exploited as a therapeutic target, we developed and validated several LNCaP sublines in which we can conditionally silence CHES1 expression, thereby providing us with the necessary models to easily test the value of potential CST. In the coming year, we will test the efficacy of CST to heighten cell killing during androgen ablation and in response to chemotherapy.

Download or read book Inhibiting Castration resistant Prostate Cancer Via Targeting Transcriptional Coregulators written by and published by . This book was released on 2017 with total page 390 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Molecular Mechanisms of Prostate Cancer Progression and Treatment Resistance written by Yezi Zhu and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer is the most common type of cancer in American men and ranks second to lung cancer in cancer-related deaths. The growth and survival of primary prostate tumors requires physiological level of androgen. Thus hormone therapy has been used for treatment of primary prostate cancer. However, prostate cancer eventually progresses to a castration-resistant state. Understanding the molecular mechanisms leading to castration resistance is very critical for combat this lethal disease. The first part of this thesis will discuss the loss of Rho-GDP dissociation inhibitor [alpha] (RhoGDI[alpha]) as one of the molecular mechanisms leading to prostate cancer castration-resistant progression. My study demonstrated that RhoGDI[alpha] suppresses growth and survival of prostate cancer cells. In this part, I utilized the previously generated LNCaP-IL6+ cells which were able to grow in androgen-deprived condition. The protein expression profiles of LNCaP and LNCaP-IL6+ cells were compared using two-dimensional gel electrophoresis. Expression of RhoGDI[alpha] was reduced in LNCaP-IL6+ cells and was down-regulated in more aggressive prostate cancer cells compared to LNCaP cells. The effects of RhoGDI[alpha] in prostate cancer cells growth and survival were examined both in vitro and in vivo. Overexpression of RhoGDI[alpha] inhibited the growth and induced apoptosis of prostate cancer cells. RhoGDI[alpha] caused LNCaP-IL6+ cells reversal to androgen-sensitive state, and downregulation of RhoGDI[alpha] enhanced growth of androgen-sensitive LNCaP cells in androgen-deprived condition. In addition, RhoGDI[alpha] suppressed the tumorigenic ability and prostate-specific antigen (PSA) production of prostate tumor xenografts in vivo. The aberrant activation of androgen receptor (AR) is responsible for castration-resistant prostate cancer (CRPC) progression and regulation of AR-target genes such as PSA. My in vivo study showed RhoGDI[alpha] inhibited PSA production in the mice sera bearing tumors, indicating RhoGDI[alpha] inhibits AR signaling in prostate cancer cells. The effects of RhoGDI[alpha] on AR signaling will be further discussed. RhoGDI[alpha] was transiently or stably transfected into several prostate cancer cell lines including LNCaP, C4-2, CWR22Rv1 and DU145. The regulation of AR expression by RhoGDI[alpha] was analyzed by qRT-PCR and Western blot. Overexpression of RhoGDI[alpha] downregulated AR expression at both mRNA and protein levels. AR activity was measured by luciferase reporter assays and electrophoretic mobility shift analysis (EMSA). RhoGDI[alpha] was able to inhibit transactivation of AR target genes and prevent AR binding to androgen response element. Immunofluorescence assay was performed and overexpression of RhoGDI[alpha] prevented AR nuclear translocation induced by androgens. The interaction between RhoGDI[alpha] and AR was examined by co-immunoprecipitation assays. RhoGDI[alpha] was found to physically interact with the N-terminal domain of AR. Neuroendocrine differentiation (NED) is associated with castration-resistance of prostate cancer. It has been suggested as a marker of poor prognosis for prostate cancer. Paracrine interleukin-6 (IL-6) can mediate NED features in prostate cancer. The second part of this thesis will discuss the mechanism underlying IL-6-induced NED. RE1-silencing transcription factor (REST) is a main negative regulator of neurogenesis and represses expression of NED genes. I confirmed the IL-6-induced NED by cell morphological changes as well as the induction of NE markers such as neuron-specific enolase (NSE), chromogranin A (ChgA) and synaptophysin. The expression of REST was suppressed in IL-6-induced NED in LNCaP cells. To further study the impact of REST-mediated repression on NED in LNCaP cells, either wild-type REST or a dominant-positive form of REST, REST-VP16, in which both repressor domains of REST were replaced with the activation domain of the herpes simplex virus protein VP16, was introduced into LNCaP cells. Overexpression of exogenous wild type REST abrogated IL-6-induced NED in prostate cancer cells. Expression of the recombinant REST-VP16 fusion protein activated REST target genes and other neuronal differentiation genes and produced neuronal physiological properties. In addition, REST protein turnover was accelerated in IL-6 induced NE differentiated LNCaP cells via the ubiquitin-proteasome pathway, accompanied by a decrease in the expression of the deubiquitylase HAUSP, indicating that pathway(s) priming REST degradation may be involved in IL-6 induced NE differentiation. Docetaxel is the first-line standard treatment for CRPC. However, once tumors develop resistance to docetaxel, the treatment options are again limited. In the last part of this thesis, I will discuss the docetaxel resistance mechanisms and potential therapeutic strategies for docetaxel-resistant CRPC. I established a docetaxel resistant cell line, TaxR, by culturing C4-2B cells in docetaxel in a dose-escalation manner until cells were able to divide freely in 5 nM docetaxel. Global gene expression analysis by cDNA microarrays (approximately 28000 genes) was performed using mRNA from parental C4-2B and TaxR cells. ABCB1, which belongs to the ATP-binding cassette (ABC) transporter family, was identified among the top upregulated genes in TaxR cells. Overexpression of ABCB1 in TaxR cells has been validated by both real-time PCR and Western blot analysis. Downregulation of ABCB1 by specific shRNA or inhibiting ABCB1 activity by ABCB1 inhibitor elacridar restored docetaxel sensitivity in TaxR cells. Apigenin (4', 5, 7-trihydroxyflavone), a natural product belonging to the flavone family, downregulated ABCB1 protein expression in ubiquitin-proteasome pathway and overcame docetaxel resistance in TaxR cells. The effects of different anti-androgens like enzalutamide, abiraterone and bicalutamide on ABCB1 efflux activity were tested using rhodamine123 efflux assay. These antiandrogens inhibited ABCB1 efflux activity and reversed docetaxel resistance in TaxR cells in vitro. The reversal effect of bicalutamide was further confirmed in TaxR xenograft tumors, suggesting targeting ABCB1 could be a potential approach to resensitize docetaxel-resistant prostate cancer cells to docetaxel treatment.

Download or read book Targeting the Androgen Receptor DNA Binding Domain in in Vitro Models of Castration resistant Prostate Cancer written by Elisabeth Ashlyn Messner and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer remains a leading contributor to overall cancer incidence and mortality worldwide. The androgen receptor (AR) plays a predominant role in prostate cancer pathology on the cellular level by driving a pro-tumorigenic transcriptional program. Androgen deprivation therapy (ADT) and AR signaling inhibitors (ASIs) can halt disease progression by inhibiting AR function through indirect or direct ligand binding domain (LBD) inhibition. These remedies are temporary, and upon relapse, the disease progresses into an incurable state of castration resistance that has limited therapeutic options. Mechanisms driving ADT and ASI treatment relapse and advancement to castration resistance can include the cellular production of alternatively spliced AR variants (AR-Vs), often translated into low molecular weight AR isoforms, or alternative oncogenic pathways that interact with the AR. AR-Vs often lack the LBD of the AR, rendering AR LBD-specific clinical therapies ineffective. To date, no small molecule that targets alternative AR domains is used in clinical practice. The DNA binding domain (DBD) is a prime target for inhibition as it performs necessary roles in AR transcriptional activity and is less susceptible to AR alternative splicing compared to the LBD. DBD inhibition would hinder AR-DNA interaction, AR-AR interaction, and AR localization to the nucleus to halt AR and AR-V tumorigenic activity and disease progression. This study examines the role of a series of novel compounds designed to inhibit AR-DNA interaction and induce cell death in castration-resistant prostate cancer cells. From 11 compounds, 4 are selected for further study on the basis of specificity and the ability to induce cell death. Two of these, C08 and C15, induce cell death, reduce PSA promoter activity and mRNA expression, reduce Akt and ERK phosphorylation, and bind to the AR DBD. Of the 11 compounds, C15, with limited off-target mechanisms of action, induces cell death in AR-positive prostate cells by physically binding the AR DBD and inhibiting both AR genomic and non-genomic activity to overcome common mechanisms of resistance.

Download or read book Nanostructures for Cancer Therapy written by Alexandru Mihai Grumezescu and published by Elsevier. This book was released on 2017-04-11 with total page 922 pages. Available in PDF, EPUB and Kindle. Book excerpt: Nanostructures for Cancer Therapy discusses the available preclinical and clinical nanoparticle technology platforms and their impact on cancer therapy, including current trends and developments in the use of nanostructured materials in chemotherapy and chemotherapeutics. In particular, coverage is given to the applications of gold nanoparticles and quantum dots in cancer therapies. In addition to the multifunctional nanomaterials involved in the treatment of cancer, other topics covered include nanocomposites that can target tumoral cells and the release of antitumoral therapeutic agents. The book is an up-to-date overview that covers the inorganic and organic nanostructures involved in the diagnostics and treatment of cancer. Provides an examination of nanoparticle delivery systems for cancer treatment, illustrating how the use of nanotechnology can help provide more effective chemotherapeutic treatments Examines, in detail, the different types of nanomaterials used in cancer therapy, also explaining the effect of each Provides a cogent overview of recent developments in the use of nanostructured materials in chemotherapeutics, allowing readers to quickly familiarize themselves with this area

Download or read book Investigation of the Transcription Factor GATA2 as a Potential Therapeutic Target for Castration resistance Prostate Cancer written by Qianhui Yi and published by . This book was released on 2016 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The androgen receptor (AR) serves as a key driver of the proliferation and survival of prostate cancer (PCa) cells. Current mainstay treatment is to block the AR signaling by androgen deprivation therapy and antiandrogens. Despite the short-term efficacy of suppressing AR signaling, the tumor eventually adapts resistance via constitutive activation of the AR axis and manifests in the form of castration-resistant prostate cancer (CRPC). So far, multiple molecular mechanisms behind castration-resistance have been reported, including persisted androgen synthesis, AR amplification, AR point mutation, AR splice variants and AR transcriptional co-regulators. Unfortunately, current AR-targeting agents are unable to prevent AR reactivation, and as a result, there is urgent need for alternative approaches to block AR signaling. Our study has provided several lines of evidence that the transcription factor GATA-binding protein 2 (GATA2) is a critical regulator of the development of resistance in androgen ablation and antiandrogen therapy, suggesting that GATA2 could be a valuable therapeutic target against CRPC. We initially observed rapid induction of GATA2 expression after androgen deprivation or antiandrogen treatment in PCa cell line. Moreover, this overexpression exclusively occurs in AR positive PCa cells and is especially greater in CRPC cells compared to androgen-dependent cells. Stable overexpression of GATA2 in androgen-dependent LNCaP cells (referred to as LNCaP-GATA2) consequently caused the cells to adopt multiple CRPC features. AR signaling in LNCaP-GATA2 cells is constitutively active in the absence of androgen, exhibited hypersensitivity to low level of androgen stimulation, and resistance to antiandrogen inhibition. Finally, castration resistant survival and proliferation was observed in LNCaP-GATA2 cells thus demonstrated GATA2's critical role in CRPC development.Our preliminary data demonstrated that androgen-deprivation and antiandrogen treatments substantially and rapidly induce GATA2 expression, which sustain AR signaling and in turn, result in resistance to those treatments. Collectively, our results suggest a critical feedback loop between AR and GATA2 that can be targeted to inhibit progression towards CRPC. Our effort to develop chemical inhibitors of GATA2 is in progress and initial results will be briefly discussed." --

Download or read book The Role of Src Family Kinases in the Development and Progression of Prostate Cancer written by Oleg Tatarov and published by . This book was released on 2010 with total page 191 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer is the most common cancer in men and the second leading cause of cancer-related death in the western world. Typically, the treatment of advanced and metastatic prostate cancer consists of castration therapy, which suppresses the development of the disease for 2 years on average. Virtually all patients undergoing androgen deprivation therapy eventually develop castration-resistant prostate cancer. Currently, only the taxane class of drugs has been proven to provide short survival advantage in patients with castration-resistant prostate cancer. This form of the disease is the cause of significant morbidity, resulting in long periods of gradual deterioration of the patients' condition, pain related to local extension of the tumour and distant metastases, renal failure due to the invasion into the ureters, etc. Castration resistance allows prostate tumours to progress despite androgen deprivation. Several mechanisms have been described outlining the nature of molecular pathways employed by prostate cancer cells in order to proliferate and migrate in a low androgen environment. Hormone-sensitive prostate cancer cells rely on androgens for their growth needs with androgens acting through the androgen receptor (AR). In castration-resistant prostate cancer AR can be activated by reduced concentrations of androgens, AR antagonists, protein kinases or bypassed altogether. Detailed knowledge of these processes should allow better understanding of molecular patterns, driving the progression of prostate cancer and, ultimately, could lead to the development of novel molecular targeted therapies. Molecular pathways implicated in the development of castration-resistant prostate cancer frequently show cross-talk, resulting in the ability of cancer cells to adapt to a changing microenvironment. Inhibiting the proteins, facilitating these cross-talks provides an attractive targeting mechanism. The Src family of non-receptor tyrosine kinases (SFK) represent proteins involved in the development of various solid malignancies, including prostate cancer. These proteins are often found on the cross-roads of intracellular pathways, integrating molecular systems into complex signalling networks. SFK interact with receptor tyrosine kinases, G-protein coupled receptors, motility and adhesion factors and, thus, influence multiple cell functions. In prostate cancer, SFK have been demonstrated to form complexes with AR, activating AR by means of tyrosine phosphorylation. SFK inhibitory compounds have been developed and are now in Phase II clinical trial in patients with castration-resistant prostate cancer. However, there is considerable lack of data regarding the role of SFK expression and activation in prostate cancer in clinical settings. In this thesis, we studied the role of SFK in prostate cancer using matched paired prostate cancer samples, taken from patients prior to castration therapy being administered and following the development of castration resistance. Using paired tissue specimens allows following molecular changes through the natural history of the disease and correlating these changes with various clinical parameters. We also conducted in vitro experiments, employing hormone-sensitive LNCaP cell line and its counterpart, castration-resistant LNCaP-SDM cell line, developed by gradual withdrawal of androgens from the culture medium. Our main finding is that in a subgroup of prostate cancer patients, the increase in SFK activity in the transition of prostate cancer from hormone-sensitive to castration-resistant state is associated with significant decrease in survival (p

Download or read book Handbook of Cancer Chemotherapy written by Roland T. Skeel and published by Lippincott Williams & Wilkins. This book was released on 2011 with total page 896 pages. Available in PDF, EPUB and Kindle. Book excerpt: Skeel's Handbook of Cancer Chemotherapy combines in one place the most current rationale and specific details necessary to safely administer chemotherapy for most adult cancers. The handbook is a practical, diseased-focused pocket reference that emphasizes the best current medical practice as it relates to the delivery of chemotherapeutic drugs. By focusing on specific plans for treatment, the book is an invaluable resource for the daily care of cancer patients.

Download or read book Molecular Analysis of Anti androgenic Effects of Atraric Acid on Human Prostate Cancer in Vivo and Androgen Receptor mediated Negative Regulation of the TERT Gene written by and published by . This book was released on 2014 with total page 77 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book PIM1 A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer written by and published by . This book was released on 2008 with total page 47 pages. Available in PDF, EPUB and Kindle. Book excerpt: The contract supports studies to define the role of the PIM1 kinase in acquired resistance to chemotherapy by prostate cancer cells. Data to date for specific aim #1 define a signaling pathway induced by docetaxel, involving sequential steps of STAT3 phosphorylation, expression of PIM1, and activation of NFkB signaling. Blockade of this pathway prevents drug-induced upregulation of NFkB activity, and sensitizes cells to docetaxel. Other studies (specific aim #2)focus on identifying a mechanism through which PIM1 activates NFkB. We have unambiguously identified S937 as the major PIM1 phosphorylation site on the NFKB1/p105 precursor protein, through use of LCM/MS/MS analysis. We have now shown that phosphorylation at S937 potentiates NFkB transcriptional activity. Additional data (specific aim #3) have been published to describe a small molecule inhibitor of PIM1. This molecule can sensitize prostate cancer cells to the cytotoxic effects of docetaxel in an additive or synergistic manner. Pharmacophore analysis has identified future modifications of the inhibitor.

Download or read book Successful Drug Discovery Volume 5 written by Janos Fischer and published by John Wiley & Sons. This book was released on 2021-02-12 with total page 340 pages. Available in PDF, EPUB and Kindle. Book excerpt: Filled with unique insights into current drugs that have made it to the marketplace In the fifth volume of Successful Drug Discovery, the inventors and primary developers of drugs that made it to the market tell the story of the drugs discovery and development. Case studies of drugs from different therapeutic fields reveal the all-too-often unpredictable path from the first drug candidate molecule to the successfully marketed drug. In addition, this new volume addresses overarching topics for drug discovery, such as drug discovery in academia, and discusses currently important classes of small molecule as well as biological drugs. Comprehensive in scope, the books nine chapters provide a representative cross-section of the present-day drug development effort. The authoritative fifth volume is filled with relevant data and chemical information, as well as the insight and experience of the best contemporary drug creators. This important volume: - Puts the focus on recently introduced drugs that have not yet made it into standard textbooks or general references - Contains information and insight that is new and often not even available from the primary literature - Reveals what it takes to successfully develop a drug molecule that has made it all the way to the market - Is endorsed and supported by the International Union of Pure and Applied Chemistry (IUPAC) Written for medicinal chemists, pharmaceutical chemists, organic chemists, Successful Drug Discovery, Volume Five reveals the most recent techniques used by drug innovators in the drug development process.

Download or read book Advances in Molecular Targeted Therapies of Urologic Cancers written by Bianca Nitzsche and published by Frontiers Media SA. This book was released on 2022-11-24 with total page 134 pages. Available in PDF, EPUB and Kindle. Book excerpt: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.