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1.
Front Cell Dev Biol ; 12: 1342872, 2024.
Article in English | MEDLINE | ID: mdl-38510176

ABSTRACT

MYC is a pleiotropic transcription factor involved in multiple cellular processes. While its mechanism of action and targets are not completely elucidated, it has a fundamental role in cellular proliferation, differentiation, metabolism, ribogenesis, and bone and vascular development. Over 4 decades of research and some 10,000 publications linking it to tumorigenesis (by searching PubMed for "MYC oncogene") have led to MYC becoming a most-wanted target for the treatment of cancer, where many of MYC's physiological functions become co-opted for tumour initiation and maintenance. In this context, an abundance of reviews describes strategies for potentially targeting MYC in the oncology field. However, its multiple roles in different aspects of cellular biology suggest that it may also play a role in many additional diseases, and other publications are indeed linking MYC to pathologies beyond cancer. Here, we review these physiological functions and the current literature linking MYC to non-oncological diseases. The intense efforts towards developing MYC inhibitors as a cancer therapy will potentially have huge implications for the treatment of other diseases. In addition, with a complementary approach, we discuss some diseases and conditions where MYC appears to play a protective role and hence its increased expression or activation could be therapeutic.

2.
Nat Med ; 30(3): 762-771, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38321218

ABSTRACT

Among the 'most wanted' targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg-1).ClinicalTrials.gov identifier: NCT04808362 .


Subject(s)
Neoplasms , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology
3.
Cytokine Growth Factor Rev ; 75: 119-125, 2024 02.
Article in English | MEDLINE | ID: mdl-38296759

ABSTRACT

The involvement of interferons (IFNs) in various diseases, including breast cancer, has sparked controversy due to their diverse roles in immunity and significant impact on pathological mechanisms. In the context of breast cancer, the heightened expression of endogenous IFNs has been linked to anti-tumor activity and a favorable prognosis for patients. Within the tumor tissue and microenvironment, IFNs initiate a cascade of molecular events involving numerous factors, which can lead to either cooperative or repressive interactions. The specific functions of IFNs in breast cancer vary depending on the two major disease phenotypes: hormone dependent (or responsive) and hormone independent (or unresponsive) breast cancer. Hormone dependence is determined by the presence of estrogen receptors (ERs). The interplay between the IFN and ER signaling pathways, and the involvement of intermediate factors such as NFκB, are areas that have been somewhat under-researched, but that hold potential importance for the understanding and treatment of breast cancer. This review aims to provide a comprehensive overview of the actions of IFNs in breast cancer, particularly in relation to the different breast cancer phenotypes and the significance of comprehending the underlying mechanisms. Furthermore, the use of IFN-based therapies in cancer treatment remains a topic of debate and has not yet gained widespread acceptance. However, emerging discoveries may redirect focus towards the potential of IFN-based therapies.


Subject(s)
Breast Neoplasms , Interferons , Humans , Female , Interferons/therapeutic use , Interferons/metabolism , Breast Neoplasms/drug therapy , Signal Transduction , Hormones/therapeutic use , Tumor Microenvironment
4.
Genes Dev ; 37(7-8): 303-320, 2023 04 01.
Article in English | MEDLINE | ID: mdl-37024284

ABSTRACT

MYC's key role in oncogenesis and tumor progression has long been established for most human cancers. In melanoma, its deregulated activity by amplification of 8q24 chromosome or by upstream signaling coming from activating mutations in the RAS/RAF/MAPK pathway-the most predominantly mutated pathway in this disease-turns MYC into not only a driver but also a facilitator of melanoma progression, with documented effects leading to an aggressive clinical course and resistance to targeted therapy. Here, by making use of Omomyc, the most characterized MYC inhibitor to date that has just successfully completed a phase I clinical trial, we show for the first time that MYC inhibition in melanoma induces remarkable transcriptional modulation, resulting in severely compromised tumor growth and a clear abrogation of metastatic capacity independently of the driver mutation. By reducing MYC's transcriptional footprint in melanoma, Omomyc elicits gene expression profiles remarkably similar to those of patients with good prognosis, underlining the therapeutic potential that such an approach could eventually have in the clinic in this dismal disease.


Subject(s)
Melanoma , Humans , Prognosis , Melanoma/genetics , Signal Transduction , Carcinogenesis , Cell Transformation, Neoplastic , Proto-Oncogene Proteins c-myc/metabolism
5.
Br J Hosp Med (Lond) ; 83(5): 1-10, 2022 May 02.
Article in English | MEDLINE | ID: mdl-35653316

ABSTRACT

BACKGROUND/AIMS: Abdominal X-rays are frequently requested by clinicians in the Aberdeen Royal Infirmary acute medical initial assessment unit. METHOD: The proportion of indicated abdominal X-rays requested within 24 hours of admission was retrospectively examined. This process was repeated after displaying an educational poster with the Royal College of Radiologists guidelines (cycle 2) and a graded assertive communication poster (cycles 3 and 4); a tool to enable junior doctors to challenge inappropriate requests for abdominal X-rays from seniors. RESULTS: Only 47.2% of abdominal X-ray requests were deemed appropriate in cycle 1. A 1.54% reduction in abdominal X-ray requests and an 11.5% increase in indicated abdominal X-rays were noted after cycle 2. Cycle 3 led to a statistically significant improvement with 2.6% fewer patients undergoing an abdominal X-ray and a 24.6% increase in indicated abdominal X-rays. This improvement was sustained in cycle 4. CONCLUSIONS: Promoting graded assertive communication is an effective means of helping junior doctors to challenge seniors requesting non-indicated abdominal X-rays.


Subject(s)
Hospitalization , Radiography, Abdominal , Humans , Medical Staff, Hospital , Retrospective Studies , X-Rays
6.
Cancer Res Commun ; 2(2): 110-130, 2022 02.
Article in English | MEDLINE | ID: mdl-36860495

ABSTRACT

MYC's role in promoting tumorigenesis is beyond doubt, but its function in the metastatic process is still controversial. Omomyc is a MYC dominant negative that has shown potent antitumor activity in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, by impacting on several of the hallmarks of cancer. However, its therapeutic efficacy against metastasis has not been elucidated yet. Here we demonstrate for the first time that MYC inhibition by transgenic Omomyc is efficacious against all breast cancer molecular subtypes, including triple-negative breast cancer, where it displays potent antimetastatic properties both in vitro and in vivo. Importantly, pharmacologic treatment with the recombinantly produced Omomyc miniprotein, recently entering a clinical trial in solid tumors, recapitulates several key features of expression of the Omomyc transgene, confirming its clinical applicability to metastatic breast cancer, including advanced triple-negative breast cancer, a disease in urgent need of better therapeutic options. Significance: While MYC role in metastasis has been long controversial, this manuscript demonstrates that MYC inhibition by either transgenic expression or pharmacologic use of the recombinantly produced Omomyc miniprotein exerts antitumor and antimetastatic activity in breast cancer models in vitro and in vivo, suggesting its clinical applicability.


Subject(s)
Triple Negative Breast Neoplasms , Animals , Humans , Mice , Cell Line , Protein Binding , Triple Negative Breast Neoplasms/drug therapy , Proto-Oncogene Proteins c-myc
7.
J Card Fail ; 28(12): 1692-1702, 2022 12.
Article in English | MEDLINE | ID: mdl-34555524

ABSTRACT

BACKGROUND: Heart failure is the leading cause of hospitalization in the elderly and readmission is common. Clinical indicators of congestion may not precede acute congestion with enough time to prevent hospital admission for heart failure. Thus, there is a large and unmet need for accurate, noninvasive assessment of congestion. Noninvasive venous waveform analysis in heart failure (NIVAHF) is a novel, noninvasive technology that monitors intravascular volume status and hemodynamic congestion. The objective of this study was to determine the correlation of NIVAHF with pulmonary capillary wedge pressure (PCWP) and the ability of NIVAHF to predict 30-day admission after right heart catheterization. METHODS AND RESULTS: The prototype NIVAHF device was compared with the PCWP in 106 patients undergoing right heart catheterization. The NIVAHF algorithm was developed and trained to estimate the PCWP. NIVA scores and central hemodynamic parameters (PCWP, pulmonary artery diastolic pressure, and cardiac output) were evaluated in 84 patients undergoing outpatient right heart catheterization. Receiver operating characteristic curves were used to determine whether a NIVA score predicted 30-day hospital admission. The NIVA score demonstrated a positive correlation with PCWP (r = 0.92, n = 106, P < .0001). The NIVA score at the time of hospital discharge predicted 30-day admission with an AUC of 0.84, a NIVA score of more than 18 predicted admission with a sensitivity of 91% and specificity of 56%. Residual analysis suggested that no single patient demographic confounded the predictive accuracy of the NIVA score. CONCLUSIONS: The NIVAHF score is a noninvasive monitoring technology that is designed to provide an estimate of PCWP. A NIVA score of more than 18 indicated an increased risk for 30-day hospital admission. This noninvasive measurement has the potential for guiding decongestive therapy and the prevention of hospital admission in patients with heart failure.


Subject(s)
Heart Failure , Humans , Aged , Pulmonary Wedge Pressure , Heart Failure/diagnosis , Heart Failure/therapy , Predictive Value of Tests , Cardiac Catheterization , Hospitalization
8.
Blood Adv ; 5(23): 5239-5257, 2021 12 14.
Article in English | MEDLINE | ID: mdl-34625792

ABSTRACT

The expression of BCL6 in B-cell lymphoma can be deregulated by chromosomal translocations, somatic mutations in the promoter regulatory regions, or reduced proteasome-mediated degradation. FBXO11 was recently identified as a ubiquitin ligase that is involved in the degradation of BCL6, and it is frequently inactivated in lymphoma or other tumors. Here, we show that FBXO11 mutations are found in 23% of patients with Burkitt lymphoma (BL). FBXO11 mutations impaired BCL6 degradation, and the deletion of FBXO11 protein completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of 1 or 2 copies of the FBXO11 gene in mice cooperated with oncogenic MYC and accelerated B-cell lymphoma onset, providing experimental evidence that FBXO11 is a haploinsufficient oncosuppressor in B-cell lymphoma. In wild-type and FBXO11-deficient BL mouse and human cell lines, targeting BCL6 via specific degraders or inhibitors partially impaired lymphoma growth in vitro and in vivo. Inhibition of MYC by the Omomyc mini-protein blocked cell proliferation and increased apoptosis, effects further increased by combined BCL6 targeting. Thus, by validating the functional role of FBXO11 mutations in BL, we further highlight the key role of BCL6 in BL biology and provide evidence that innovative therapeutic approaches, such as BCL6 degraders and direct MYC inhibition, could be exploited as a targeted therapy for BL.


Subject(s)
Burkitt Lymphoma , F-Box Proteins , Lymphoma, B-Cell , Animals , Burkitt Lymphoma/drug therapy , Burkitt Lymphoma/genetics , F-Box Proteins/genetics , Genes, myc , Humans , Lymphoma, B-Cell/genetics , Mice , Mutation , Protein-Arginine N-Methyltransferases/genetics , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-bcl-6/metabolism
9.
Cytokine ; 146: 155637, 2021 10.
Article in English | MEDLINE | ID: mdl-34242899

ABSTRACT

Interferons have prominent roles in various pathophysiological conditions, mostly related to inflammation. Interferon-gamma (IFNγ) was, initially discovered as a potent antiviral agent, over 50 years ago, and has recently garnered renewed interest as a promising factor involved in both innate and adaptive immunity. When new disease epidemics appear such as SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), IAV (Influenza A virus), and in particular the current SARS-CoV-2 pandemic, it is especially timely to review the complexity of immune system responses to viral infections. Here we consider the controversial roles of effectors like IFNγ, discussing its actions in immunomodulation and immunotolerance. We explore the possibility that modulation of IFNγ could be used to influence the course of such infections. Importantly, not only could endogenous expression of IFNγ influence the outcome, there are existing IFNγ therapeutics that can readily be applied in the clinic. However, our understanding of the molecular mechanisms controlled by IFNγ suggests that the exact timing for application of IFNγ-based therapeutics could be crucial: it should be earlier to significantly reduce the viral load and thus decrease the overall severity of the disease.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Immune Tolerance/immunology , Immunity, Innate/immunology , Interferon-gamma/immunology , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , COVID-19/virology , Humans , Interferon-gamma/therapeutic use , Receptors, Interferon/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Signal Transduction/immunology , COVID-19 Drug Treatment
10.
J Cell Biol ; 220(8)2021 08 02.
Article in English | MEDLINE | ID: mdl-34160558

ABSTRACT

The oncogene Myc is deregulated in the majority of human tumors and drives numerous hallmarks of cancer. Despite its indisputable role in cancer development and maintenance, Myc is still undrugged. Developing a clinical inhibitor for Myc has been particularly challenging owing to its intrinsically disordered nature and lack of a binding pocket, coupled with concerns regarding potentially deleterious side effects in normal proliferating tissues. However, major breakthroughs in the development of Myc inhibitors have arisen in the last couple of years. Notably, the direct Myc inhibitor that we developed has just entered clinical trials. Celebrating this milestone, with this Perspective, we pay homage to the different strategies developed so far against Myc and all of the researchers focused on developing treatments for a target long deemed undruggable.


Subject(s)
Antineoplastic Agents/therapeutic use , Cell Proliferation/drug effects , Drug Design , Neoplasms/drug therapy , Proto-Oncogene Proteins c-myc/antagonists & inhibitors , Animals , Antineoplastic Agents/adverse effects , Diffusion of Innovation , Gene Expression Regulation, Neoplastic , Humans , Molecular Targeted Therapy , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Signal Transduction
11.
Methods Mol Biol ; 2318: 1-11, 2021.
Article in English | MEDLINE | ID: mdl-34019283

ABSTRACT

The MYC transcription factor coordinates a wide range of intra- and extracellular processes associated with tissue proliferation and regeneration. While these processes are typically tightly regulated in physiological conditions, they become deregulated in cancer, where MYC is oncogenically activated.The last decade has seen MYC progress from a renowned undruggable target to a hot topic in the cancer therapy field, as proof emerged from mouse models that its inhibition constitutes an effective and broadly applicable approach to fight cancer. However, there are several aspects of MYC biology that still appear to be elusive and maintain the interest in further studying this intriguing protein. Since MYC's discovery, more than four decades ago, multiple strategies have been developed to study it, related to the many and varied facets of its biology. This new version of The Myc gene: Methods and Protocols provides valuable tips from key "inhabitants of the MYC world," which significantly increase the reach of our investigative tools to shed light on the mysteries still surrounding MYC.


Subject(s)
Proto-Oncogene Proteins c-myc/physiology , Animals , Genes, myc , Humans , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/physiopathology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism
12.
Life Sci Alliance ; 4(5)2021 05.
Article in English | MEDLINE | ID: mdl-33653688

ABSTRACT

The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and ß-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation. Together, our results indicate that the Wnt signaling receptor Fzd9 is essential for Myc-induced tumorigenesis in pancreatic islets.


Subject(s)
Adenoma, Islet Cell/physiopathology , Carcinogenesis/metabolism , Frizzled Receptors/metabolism , Adenoma, Islet Cell/metabolism , Animals , Cell Movement , Cell Proliferation , Female , Frizzled Receptors/genetics , Frizzled Receptors/physiology , Genes, myc/genetics , Genes, myc/physiology , Islets of Langerhans/metabolism , Male , Mice , Wnt Signaling Pathway/genetics , Wnt Signaling Pathway/physiology , beta Catenin/metabolism
14.
Sci Transl Med ; 11(484)2019 03 20.
Article in English | MEDLINE | ID: mdl-30894502

ABSTRACT

Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non-small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.


Subject(s)
Cell-Penetrating Peptides/pharmacology , Peptide Fragments/pharmacology , Proto-Oncogene Proteins c-myc/antagonists & inhibitors , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Animals , Basic-Leucine Zipper Transcription Factors/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell-Penetrating Peptides/pharmacokinetics , Cell-Penetrating Peptides/therapeutic use , DNA/metabolism , Disease Models, Animal , E-Box Elements/genetics , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mice, Inbred C57BL , Peptide Fragments/administration & dosage , Peptide Fragments/pharmacokinetics , Peptide Fragments/therapeutic use , Promoter Regions, Genetic/genetics , Protein Binding/drug effects , Protein Multimerization/drug effects , Proto-Oncogene Proteins c-myc/administration & dosage , Proto-Oncogene Proteins c-myc/metabolism , Proto-Oncogene Proteins c-myc/pharmacokinetics , Proto-Oncogene Proteins c-myc/pharmacology , Proto-Oncogene Proteins c-myc/therapeutic use
15.
Oncotarget ; 9(27): 18734-18746, 2018 Apr 10.
Article in English | MEDLINE | ID: mdl-29721157

ABSTRACT

Effectively treating KRAS-driven tumors remains an unsolved challenge. The inhibition of downstream signaling effectors is a way of overcoming the issue of direct targeting of mutant KRAS, which has shown limited efficacy so far. Bromodomain and Extra-Terminal (BET) protein inhibition has displayed anti-tumor activity in a wide range of cancers, including KRAS-driven malignancies. Here, we preclinically evaluate the effect of BET inhibition making use of a new BET inhibitor, BAY 1238097, against Pancreatic Ductal Adenocarcinoma (PDAC) and Non-Small Cell Lung Cancer (NSCLC) models harboring RAS mutations both in vivo and in vitro. Our results demonstrate that BET inhibition displays significant therapeutic impact in genetic mouse models of KRAS-driven PDAC and NSCLC, reducing both tumor area and tumor grade. The same approach also causes a significant reduction in cell number of a panel of RAS-mutated human cancer cell lines (8 PDAC and 6 NSCLC). In this context, we demonstrate that while BET inhibition by BAY 1238097 decreases MYC expression in some cell lines, at least in PDAC cells its anti-tumorigenic effect is independent of MYC regulation. Together, these studies reinforce the use of BET inhibition and prompt the optimization of more efficient and less toxic BET inhibitors for the treatment of KRAS-driven malignancies, which are in urgent therapeutic need.

16.
Front Cell Dev Biol ; 5: 10, 2017.
Article in English | MEDLINE | ID: mdl-28280720

ABSTRACT

Myc is an oncogene deregulated in most-perhaps all-human cancers. Each Myc family member, c-, L-, and N-Myc, has been connected to tumor progression and maintenance. Myc is recognized as a "most wanted" target for cancer therapy, but has for many years been considered undruggable, mainly due to its nuclear localization, lack of a defined ligand binding site, and physiological function essential to the maintenance of normal tissues. The challenge of identifying a pharmacophore capable of overcoming these hurdles is reflected in the current absence of a clinically-viable Myc inhibitor. The first attempts to inhibit Myc used antisense technology some three decades ago, followed by small molecule inhibitors discovered through "classical" compound library screens. Notable breakthroughs proving the feasibility of systemic Myc inhibition were made with the Myc dominant negative mutant Omomyc, showing both the great promise in targeting this infamous oncogene for cancer treatment as well as allaying fears about the deleterious side effects that Myc inhibition might have on normal proliferating tissues. During this time many other strategies have appeared in an attempt to drug the undruggable, including direct and indirect targeting, knockdown, protein/protein and DNA interaction inhibitors, and translation and expression regulation. The inhibitors range from traditional small molecules to natural chemicals, to RNA and antisense, to peptides and miniproteins. Here, we briefly describe the many approaches taken so far, with a particular focus on their potential clinical applicability.

17.
Hypertension ; 68(2): 418-26, 2016 08.
Article in English | MEDLINE | ID: mdl-27271310

ABSTRACT

UNLABELLED: Splanchnic venous pooling is a major hemodynamic determinant of orthostatic hypotension, but is not specifically targeted by pressor agents, the mainstay of treatment. We developed an automated inflatable abdominal binder that provides sustained servo-controlled venous compression (40 mm Hg) and can be activated only on standing. We tested the efficacy of this device against placebo and compared it to midodrine in 19 autonomic failure patients randomized to receive either placebo, midodrine (2.5-10 mg), or placebo combined with binder on separate days in a single-blind, crossover study. Systolic blood pressure (SBP) was measured seated and standing before and 1-hour post medication; the binder was inflated immediately before standing. Only midodrine increased seated SBP (31±5 versus 9±4 placebo and 7±5 binder, P=0.003), whereas orthostatic tolerance (defined as area under the curve of upright SBP [AUCSBP]) improved similarly with binder and midodrine (AUCSBP, 195±35 and 197±41 versus 19±38 mm Hg×minute for placebo; P=0.003). Orthostatic symptom burden decreased with the binder (from 21.9±3.6 to 16.3±3.1, P=0.032) and midodrine (from 25.6±3.4 to 14.2±3.3, P<0.001), but not with placebo (from 19.6±3.5 to 20.1±3.3, P=0.756). We also compared the combination of midodrine and binder with midodrine alone. The combination produced a greater increase in orthostatic tolerance (AUCSBP, 326±65 versus 140±53 mm Hg×minute for midodrine alone; P=0.028, n=21) and decreased orthostatic symptoms (from 21.8±3.2 to 12.9±2.9, P<0.001). In conclusion, servo-controlled abdominal venous compression with an automated inflatable binder is as effective as midodrine, the standard of care, in the management of orthostatic hypotension. Combining both therapies produces greater improvement in orthostatic tolerance. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00223691.


Subject(s)
Hypotension, Orthostatic , Intermittent Pneumatic Compression Devices , Midodrine , Splanchnic Circulation , Aged , Autonomic Nervous System/drug effects , Autonomic Nervous System/physiopathology , Blood Pressure/drug effects , Blood Pressure/physiology , Blood Pressure Determination/methods , Female , Humans , Hypotension, Orthostatic/diagnosis , Hypotension, Orthostatic/physiopathology , Hypotension, Orthostatic/therapy , Male , Midodrine/administration & dosage , Midodrine/adverse effects , Monitoring, Physiologic/methods , Splanchnic Circulation/drug effects , Splanchnic Circulation/physiology , Treatment Outcome , Vasoconstrictor Agents/administration & dosage , Vasoconstrictor Agents/adverse effects
18.
IEEE Trans Biomed Circuits Syst ; 10(4): 912-9, 2016 08.
Article in English | MEDLINE | ID: mdl-26863670

ABSTRACT

Bioelectrical impedance analysis (BIA) is a noninvasive and commonly used method for the assessment of body composition including body water. We designed a small, portable and wireless multi-frequency impedance spectrometer based on the 12 bit impedance network analyzer AD5933 and a precision wide-band constant current source for tetrapolar whole body impedance measurements. The impedance spectrometer communicates via Bluetooth with mobile devices (smart phone or tablet computer) that provide user interface for patient management and data visualization. The export of patient measurement results into a clinical research database facilitates the aggregation of bioelectrical impedance analysis and biolectrical impedance vector analysis (BIVA) data across multiple subjects and/or studies. The performance of the spectrometer was evaluated using a passive tissue equivalent circuit model as well as a comparison of body composition changes assessed with bioelectrical impedance and dual-energy X-ray absorptiometry (DXA) in healthy volunteers. Our results show an absolute error of 1% for resistance and 5% for reactance measurements in the frequency range of 3 kHz to 150 kHz. A linear regression of BIA and DXA fat mass estimations showed a strong correlation (r(2)=0.985) between measures with a maximum absolute error of 6.5%. The simplicity of BIA measurements, a cost effective design and the simple visual representation of impedance data enables patients to compare and determine body composition during the time course of a specific treatment plan in a clinical or home environment.


Subject(s)
Body Composition/physiology , Dielectric Spectroscopy/methods , Absorptiometry, Photon , Adult , Aged , Body Height , Body Weight , Cell Phone , Dielectric Spectroscopy/instrumentation , Female , Humans , Linear Models , Male , Middle Aged , Wireless Technology
19.
Carcinogenesis ; 36 Suppl 1: S160-83, 2015 Jun.
Article in English | MEDLINE | ID: mdl-26106136

ABSTRACT

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.


Subject(s)
Environmental Exposure/adverse effects , Hazardous Substances/adverse effects , Tumor Microenvironment/drug effects , Animals , Carcinogenesis/chemically induced , Humans , Neoplasms/chemically induced
20.
Cancer Res ; 75(8): 1675-81, 2015 Apr 15.
Article in English | MEDLINE | ID: mdl-25878147

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal fibroinflammatory reaction that is a major obstacle to effective therapy. The desmoplastic stroma comprises many inflammatory cells, in particular mast cells as key components of the PDAC microenvironment, and such infiltration correlates with poor patient outcome. Indeed, it has been hypothesized that stromal ablation is critical to improve clinical response in patients with PDAC. Ibrutinib is a clinically approved Bruton's tyrosine kinase inhibitor that inhibits mast cells and tumor progression in a mouse model of ß-cell tumorigenesis. Here, we show that ibrutinib is highly effective at limiting the growth of PDAC in both transgenic mouse and patient-derived xenograft models of the disease. In these various experimental settings, ibrutinib effectively diminished fibrosis, extended survival, and improved the response to clinical standard-of-care therapy. Our results offer a preclinical rationale to immediately evaluate the clinical efficacy of ibrutinib in patients with PDAC.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Pancreatic Neoplasms/drug therapy , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Adenocarcinoma/pathology , Animals , Antineoplastic Agents/pharmacology , Female , Fibrosis/prevention & control , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Pancreatic Neoplasms/pathology , Piperidines , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Tumor Cells, Cultured , Tumor Microenvironment/drug effects , Xenograft Model Antitumor Assays
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