Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 70
Filter
1.
Radiography (Lond) ; 29 Suppl 1: S46-S51, 2023 05.
Article in English | MEDLINE | ID: mdl-36922325

ABSTRACT

INTRODUCTION: Dementia is a global health priority, which requires the healthcare workforce to have the necessary attitudes and skills to deliver person-centred care to people with dementia. Radiographers have frequent contact with people with dementia, and undergraduate training is potentially an optimal time to deliver dementia education. Time for Dementia is an education programme in which undergraduate healthcare students visit a person with dementia and their carer over a two-year period to gain an in-depth understanding of the condition. The aim of this study was to understand undergraduate radiography students' experiences of undertaking the Time for Dementia (TFD) programme. METHODS: Two focus groups were undertaken with 14 radiography students who were half-way through the TFD programme. Data was analysed using thematic analysis. RESULTS: Three key themes were constructed from the analysis: A Holistic Learning Experience, Transferring Learning into Practice and Preparedness & Expectations. Participants discussed the value from learning directly from people with dementia and their carers, reporting an increase in their awareness and understanding of dementia as well as the impact of caring for somebody with the condition. Participants were able to identify learning to take into practice such as person-centred care, compassion, and patience. Challenges to learning were also identified. CONCLUSIONS: This study suggests that a longitudinal, experiential education programme provides radiography students with the opportunity to develop a more holistic understanding of dementia and the impact it may have on the individual and their family members. IMPLICATIONS FOR PRACTICE: Experiential dementia teaching is of value to radiography students, however preparation and learning support should fit with previous personal and teaching experience.


Subject(s)
Delivery of Health Care , Dementia , Humans , Students , Health Personnel/education , Radiography , Dementia/diagnostic imaging
2.
Cancer Cell Int ; 22(1): 421, 2022 Dec 29.
Article in English | MEDLINE | ID: mdl-36581895

ABSTRACT

BACKGROUND: Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. METHODS: We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. RESULTS: RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. CONCLUSION: HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6-1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.

3.
J Proteome Res ; 21(12): 2920-2935, 2022 12 02.
Article in English | MEDLINE | ID: mdl-36356215

ABSTRACT

Many of the diseases that plague society today are driven by a loss of protein quality. One method to quantify protein quality is to measure the protein folding stability (PFS). Here, we present a novel mass spectrometry (MS)-based approach for PFS measurement, iodination protein stability assay (IPSA). IPSA quantifies the PFS by tracking the surface-accessibility differences of tyrosine, histidine, methionine, and cysteine under denaturing conditions. Relative to current methods, IPSA increases protein coverage and granularity to track the PFS changes of a protein along its sequence. To our knowledge, this study is the first time the PFS of human serum proteins has been measured in the context of the blood serum (in situ). We show that IPSA can quantify the PFS differences between different transferrin iron-binding states in near in vivo conditions. We also show that the direction of the denaturation curve reflects the in vivo surface accessibility of the amino acid residue and reproducibly reports a residue-specific PFS. Along with IPSA, we introduce an analysis tool Chalf that provides a simple workflow to calculate the residue-specific PFS. The introduction of IPSA increases the potential to use protein structural stability as a structural quality metric in understanding the etiology and progression of human disease. Data is openly available at Chorusproject.org (project ID 1771).


Subject(s)
Halogenation , Protein Folding , Humans , Protein Stability , Transferrin/metabolism , Mass Spectrometry
4.
Cancers (Basel) ; 14(11)2022 May 24.
Article in English | MEDLINE | ID: mdl-35681556

ABSTRACT

Within the last forty years, seminal contributions have been made in the areas of bladder cancer (BC) biology, driver genes, molecular profiling, biomarkers, and therapeutic targets for improving personalized patient care. This overview includes seminal discoveries and advances in the molecular oncology of BC. Starting with the concept of divergent molecular pathways for the development of low- and high-grade bladder tumors, field cancerization versus clonality of bladder tumors, cancer driver genes/mutations, genetic polymorphisms, and bacillus Calmette-Guérin (BCG) as an early form of immunotherapy are some of the conceptual contributions towards improving patient care. Although beginning with a promise of predicting prognosis and individualizing treatments, "-omic" approaches and molecular subtypes have revealed the importance of BC stem cells, lineage plasticity, and intra-tumor heterogeneity as the next frontiers for realizing individualized patient care. Along with urine as the optimal non-invasive liquid biopsy, BC is at the forefront of the biomarker field. If the goal is to reduce the number of cystoscopies but not to replace them for monitoring recurrence and asymptomatic microscopic hematuria, a BC marker may reach clinical acceptance. As advances in the molecular oncology of BC continue, the next twenty-five years should significantly advance personalized care for BC patients.

5.
Lymphology ; 54(1): 23-40, 2021.
Article in English | MEDLINE | ID: mdl-34506085

ABSTRACT

To determine the historical use and utility of various lymphatic imaging modalities in Noonan syndrome (NS) patients, we performed a comprehensive literature review by collecting the published medical imaging of NS lymphatic dysplasias. We correlated imaging findings with clinical phenotypes and treatment. Our analysis of lymphatic imaging modalities provides an algorithmic approach to imaging and patient care across the spectrum of NS developmental defects. A total of 54 NS cases have been published since 1975. Using the observations reported in 15 reviewed publications, an association was made between disruptions in central lymphatic flow and poor clinical presentations/outcomes in NS patients.


Subject(s)
Lymphatic Vessels , Noonan Syndrome , Diagnostic Imaging , Humans , Lymphatic Vessels/diagnostic imaging , Noonan Syndrome/diagnostic imaging , Noonan Syndrome/genetics , Phenotype
6.
Mol Cancer Res ; 19(9): 1486-1497, 2021 09.
Article in English | MEDLINE | ID: mdl-34099522

ABSTRACT

DNA damage, induced by either chemical carcinogens or environmental pollutants, plays an important role in the initiation of colorectal cancer. DNA repair processes, however, are involved in both protecting against cancer formation, and also contributing to cancer development, by ensuring genomic integrity and promoting the efficient DNA repair in tumor cells, respectively. Although DNA repair pathways have been well exploited in the treatment of breast and ovarian cancers, the role of DNA repair processes and their therapeutic efficacy in colorectal cancer is yet to be appreciably explored. To understand the role of DNA repair, especially homologous recombination (HR), in chemical carcinogen-induced colorectal cancer growth, we unraveled the role of RAD51AP1 (RAD51-associated protein 1), a protein involved in HR, in genotoxic carcinogen (azoxymethane, AOM)-induced colorectal cancer. Although AOM treatment alone significantly increased RAD51AP1 expression, the combination of AOM and dextran sulfate sodium (DSS) treatment dramatically increased by several folds. RAD51AP1 expression is found in mouse colonic crypt and proliferating cells. RAD51AP1 expression is significantly increased in majority of human colorectal cancer tissues, including BRAF/KRAS mutant colorectal cancer, and associated with reduced treatment response and poor prognosis. Rad51ap1-deficient mice were protected against AOM/DSS-induced colorectal cancer. These observations were recapitulated in a genetically engineered mouse model of colorectal cancer (ApcMin /+ ). Furthermore, chemotherapy-resistant colorectal cancer is associated with increased RAD51AP1 expression. This phenomenon is associated with reduced cell proliferation and colorectal cancer stem cell (CRCSC) self-renewal. Overall, our studies provide evidence that RAD51AP1 could be a novel diagnostic marker for colorectal cancer and a potential therapeutic target for colorectal cancer prevention and treatment. IMPLICATIONS: This study provides first in vivo evidence that RAD51AP1 plays a critical role in colorectal cancer growth and drug resistance by regulating CRCSC self-renewal.


Subject(s)
Cell Self Renewal , Colorectal Neoplasms/drug therapy , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/physiology , Drug Resistance, Neoplasm , Fluorouracil/pharmacology , Neoplastic Stem Cells/drug effects , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/physiology , Animals , Antimetabolites, Antineoplastic/pharmacology , Apoptosis , Case-Control Studies , Cell Proliferation , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , DNA-Binding Proteins/genetics , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Prognosis , RNA-Binding Proteins/genetics , Survival Rate , Tumor Cells, Cultured
7.
Clin Cancer Res ; 27(15): 4410-4421, 2021 08 01.
Article in English | MEDLINE | ID: mdl-34031055

ABSTRACT

PURPOSE: Gemcitabine-based chemotherapy regimens are first-line for several advanced cancers. Because of better tolerability, gemcitabine + cisplatin is a preferred neoadjuvant, adjuvant, and/or palliative chemotherapy regimen for advanced bladder cancer. Nevertheless, predicting treatment failure and overcoming resistance remain unmet clinical needs. We discovered that splice variant (V1) of HYAL-4 is a first-in-class eukaryotic chondroitinase (Chase), and CD44 is its major substrate. V1 is upregulated in bladder cancer and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance. EXPERIMENTAL DESIGN: V1 expression was measured in muscle-invasive bladder cancer (MIBC) specimens by qRT-PCR and IHC. HYAL-4 wild-type (Wt) and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for chemoresistance and associated mechanism in preclinical models. RESULTS: V1 levels in MIBC specimens of patients who developed metastasis, predicted response to gemcitabine + cisplatin adjuvant/salvage treatment and disease-specific mortality. V1-expressing bladder cells were resistant to gemcitabine but not to cisplatin. V1 expression neither affected gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression through increased CD44-JAK2/STAT3 signaling. CDA inhibitor tetrahydrouridine resensitized V1-expressing cells to gemcitabine. While gemcitabine (25-50 mg/kg) inhibited bladder cancer xenograft growth, V1-expressing tumors were resistant. Low-dose combination of gemcitabine and tetrahydrouridine abrogated the growth of V1 tumors with minimal toxicity. CONCLUSIONS: V1/Chase drives gemcitabine resistance and potentially predicts gemcitabine + cisplatin failure. CDA inhibition resensitizes V1-expressing tumors to gemcitabine. Because several chemotherapy regimens include gemcitabine, our study could have broad significance.


Subject(s)
Antigens, Neoplasm/physiology , Antimetabolites, Antineoplastic/therapeutic use , Chondroitinases and Chondroitin Lyases/physiology , Deoxycytidine/analogs & derivatives , Drug Resistance, Neoplasm/physiology , Histone Acetyltransferases/physiology , Hyaluronoglucosaminidase/physiology , Urinary Bladder Neoplasms/drug therapy , Animals , Deoxycytidine/therapeutic use , Humans , Mice , Prognosis , Treatment Failure , Gemcitabine
9.
Lymphology ; 53(3): 97-98, 2020.
Article in English | MEDLINE | ID: mdl-33350283

ABSTRACT

[Editorial] Lymphatic vessels and lymph are a missing link in SARS-CoV-2/COVID-19 pathophysiology and therapeutic strategies. Based on well-established principles of lymphatic function and dysfunction and a neglected literature, this article highlights promising directions for future research and clinical exploration.


Subject(s)
COVID-19/physiopathology , Lymph/physiology , Lymphatic Vessels/physiology , SARS-CoV-2 , Drainage , Humans
10.
Cancer Res ; 80(18): 3855-3866, 2020 09 15.
Article in English | MEDLINE | ID: mdl-32665355

ABSTRACT

RAD51-associated protein 1 (RAD51AP1) plays an integral role in homologous recombination by activating RAD51 recombinase. Homologous recombination is essential for preserving genome integrity and RAD51AP1 is critical for D-loop formation, a key step in homologous recombination. Although RAD51AP1 is involved in maintaining genomic stability, recent studies have shown that RAD51AP1 expression is significantly upregulated in human cancers. However, the functional role of RAD51AP1 in tumor growth and the underlying molecular mechanism(s) by which RAD51AP1 regulates tumorigenesis have not been fully understood. Here, we use Rad51ap1-knockout mice in genetically engineered mouse models of breast cancer to unravel the role of RAD51AP1 in tumor growth and metastasis. RAD51AP1 gene transcript was increased in both luminal estrogen receptor-positive breast cancer and basal triple-negative breast cancer, which is associated with poor prognosis. Conversely, knockdown of RAD51AP1 (RADP51AP1 KD) in breast cancer cell lines reduced tumor growth. Rad51ap1-deficient mice were protected from oncogene-driven spontaneous mouse mammary tumor growth and associated lung metastasis. In vivo, limiting dilution studies provided evidence that Rad51ap1 plays a critical role in breast cancer stem cell (BCSC) self-renewal. RAD51AP1 KD improved chemotherapy and radiotherapy response by inhibiting BCSC self-renewal and associated pluripotency. Overall, our study provides genetic and biochemical evidences that RAD51AP1 is critical for tumor growth and metastasis by increasing BCSC self-renewal and may serve as a novel target for chemotherapy- and radiotherapy-resistant breast cancer. SIGNIFICANCE: This study provides in vivo evidence that RAD51AP1 plays a critical role in breast cancer growth and metastasis by regulating breast cancer stem cell self-renewal.


Subject(s)
Breast Neoplasms/pathology , Cell Self Renewal/genetics , DNA-Binding Proteins/deficiency , Mammary Neoplasms, Animal/pathology , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/therapy , DNA-Binding Proteins/genetics , Disease Models, Animal , Enzyme Activation , Female , Humans , Lung Neoplasms/secondary , Mammary Neoplasms, Animal/metabolism , Mammary Neoplasms, Animal/therapy , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplastic Stem Cells , RNA-Binding Proteins/genetics , Rad51 Recombinase/metabolism , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Up-Regulation
11.
Prostate ; 80(12): 938-949, 2020 09.
Article in English | MEDLINE | ID: mdl-32542667

ABSTRACT

BACKGROUND: The clinical manifestation of benign prostatic hyperplasia (BPH) is causally linked to the inflammatory microenvironment and proliferation of epithelial and stromal cells in the prostate transitional zone. The CXC-chemokine interleukin-8 (IL-8) contributes to inflammation. We evaluated the expression of inflammatory cytokines in clinical specimens, primary cultures, and prostatic lineage cell lines. We investigated whether IL-8 via its receptor system (IL-8 axis) promotes BPH. METHODS: The messenger RNA and protein expression of chemokines, including components of the IL-8 axis, were measured in normal prostate (NP; n = 7) and BPH (n = 21), urine (n = 24) specimens, primary cultures, prostatic lineage epithelial cell lines (NHPrE1, BHPrE1, BPH-1), and normal prostate cells (RWPE-1). The functional role of the IL-8 axis in prostate epithelial cell growth was evaluated by CRISPR/Cas9 gene editing. The effect of a combination with two natural compounds, oleanolic acid (OA) and ursolic acid (UA), was evaluated on the expression of the IL-8 axis and epithelial cell growth. RESULTS: Among the 19 inflammatory chemokines and chemokine receptors we analyzed, levels of IL-8 and its receptors (CXCR1, CXCR2), as well as, of CXCR7, a receptor for CXCL12, were 5- to 25-fold elevated in BPH tissues when compared to NP tissues (P ≤ .001). Urinary IL-8 levels were threefold to sixfold elevated in BPH patients, but not in asymptomatic males and females with lower urinary tract symptoms (P ≤ .004). The expression of the IL-8 axis components was confined to the prostate luminal epithelial cells in both normal and BPH tissues. However, these components were elevated in BPH-1 and primary explant cultures as compared to RWPE-1, NHPrE1, and BHPrE1 cells. Knockout of CXCR7 reduced IL-8, and CXCR1 expression by 4- to 10-fold and caused greater than or equal to 50% growth inhibition in BPH-1 cells. Low-dose OA + UA combination synergistically inhibited the growth of BPH-1 and BPH primary cultures. In the combination, the drug reduction indices for UA and OA were 16.4 and 7852, respectively, demonstrating that the combination was effective in inhibiting BPH-1 growth at significantly reduced doses of UA or OA alone. CONCLUSION: The IL-8 axis is a promotor of BPH pathogenesis. Low-dose OA + UA combination inhibits BPH cell growth by inducing autophagy and reducing IL-8 axis expression in BPH-epithelial cells.


Subject(s)
Interleukin-8/metabolism , Prostate/metabolism , Prostate/pathology , Prostatic Hyperplasia/metabolism , Prostatic Hyperplasia/pathology , Receptors, CXCR/metabolism , Cell Growth Processes/drug effects , Cell Line , Cells, Cultured , Epithelium/drug effects , Epithelium/metabolism , Epithelium/pathology , Humans , Interleukin-8/biosynthesis , Interleukin-8/genetics , Male , Oleanolic Acid/pharmacology , Prostate/drug effects , Prostatic Hyperplasia/drug therapy , Prostatic Hyperplasia/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, CXCR/biosynthesis , Receptors, CXCR/genetics , Signal Transduction/drug effects , Triterpenes/pharmacology , Ursolic Acid
12.
Oncogenesis ; 9(5): 52, 2020 May 19.
Article in English | MEDLINE | ID: mdl-32427869

ABSTRACT

The 5-year survival rate of patients with metastatic renal cell carcinoma (mRCC) is <12% due to treatment failure. Therapeutic strategies that overcome resistance to modestly effective drugs for mRCC, such as sorafenib (SF), could improve outcome in mRCC patients. SF is terminally biotransformed by UDP-glucuronosyltransferase-1A9 (A9) mediated glucuronidation, which inactivates SF. In a clinical-cohort and the TCGA-dataset, A9 transcript and/or protein levels were highly elevated in RCC specimens and predicted metastasis and overall-survival. This suggested that elevated A9 levels even in primary tumors of patients who eventually develop mRCC could be a mechanism for SF failure. 4-methylumbelliferone (MU), a choleretic and antispasmodic drug, downregulated A9 and inhibited SF-glucuronidation in RCC cells. Low-dose SF and MU combinations inhibited growth, motility, invasion and downregulated an invasive signature in RCC cells, patient-derived tumor explants and/or endothelial-RCC cell co-cultures; however, both agents individually were ineffective. A9 overexpression made RCC cells resistant to the combination, while its downregulation sensitized them to SF treatment alone. The combination inhibited kidney tumor growth, angiogenesis and distant metastasis, with no detectable toxicity; A9-overexpressing tumors were resistant to treatment. With effective primary tumor control and abrogation of metastasis in preclinical models, the low-dose SF and MU combinations could be an effective treatment option for mRCC patients. Broadly, our study highlights how targeting specific mechanisms that cause the failure of "old" modestly effective FDA-approved drugs could improve treatment response with minimal alteration in toxicity profile.

13.
Clin Cancer Res ; 26(13): 3455-3467, 2020 07 01.
Article in English | MEDLINE | ID: mdl-32094233

ABSTRACT

PURPOSE: Poor prognosis of patients with muscle-invasive bladder cancer that often metastasizes drives the need for discovery of molecular determinants of bladder cancer progression. Chondroitin sulfate proteoglycans, including CD44, regulate cancer progression; however, the identity of a chondroitinase (Chase) that cleaves chondroitin sulfate from proteoglycans is unknown. HYAL-4 is an understudied gene suspected to encode a Chase, with no known biological function. We evaluated HYAL-4 expression and its role in bladder cancer. EXPERIMENTAL DESIGN: In clinical specimens, HYAL-4 wild-type (Wt) and V1 expression was evaluated by RT-qPCR, IHC, and/or immunoblotting; a novel assay measured Chase activity. Wt and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for stem cell phenotype, invasive signature and tumorigenesis, and metastasis in four xenograft models, including orthotopic bladder. RESULTS: HYAL-4 expression, specifically a novel splice variant (V1), was elevated in bladder tumors; Wt expression was barely detectable. V1 encoded a truncated 349 amino acid protein that was secreted. In bladder cancer tissues, V1 levels associated with metastasis and cancer-specific survival with high efficacy and encoded Chase activity. V1 cleaved chondroitin-6-sulfate from CD44, increasing CD44 secretion. V1 induced stem cell phenotype, motility/invasion, and an invasive signature. CD44 knockdown abrogated these phenotypes. V1-expressing urothelial cells developed angiogenic, muscle-invasive tumors. V1-expressing bladder cancer cells formed tumors at low density and formed metastatic bladder tumors when implanted orthotopically. CONCLUSIONS: Our study discovered the first naturally-occurring eukaryotic/human Chase and connected it to disease pathology, specifically cancer. V1-Chase is a driver of malignant bladder cancer and potential predictor of outcome in patients with bladder cancer.


Subject(s)
Alternative Splicing , Biomarkers, Tumor , Cell Transformation, Neoplastic/genetics , Hyaluronoglucosaminidase/genetics , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/mortality , Animals , Apoptosis/genetics , Cell Line, Tumor , Cell Transformation, Neoplastic/metabolism , Disease Models, Animal , Disease Progression , Gene Expression Regulation, Neoplastic , Heterografts , Humans , Hyaluronoglucosaminidase/chemistry , Hyaluronoglucosaminidase/metabolism , Immunohistochemistry , Mice , Neoplasm Invasiveness , Prognosis , Tumor Cells, Cultured , Urinary Bladder Neoplasms/pathology
14.
J Urol ; 203(1): 62-72, 2020 01.
Article in English | MEDLINE | ID: mdl-31112107

ABSTRACT

PURPOSE: Studies indicate that molecular subtypes in muscle invasive bladder cancer predict the clinical outcome. We evaluated whether subtyping by a simplified method and established classifications could predict the clinical outcome. MATERIALS AND METHODS: We subtyped institutional cohort 1 of 52 patients, including 39 with muscle invasive bladder cancer, an Oncomine™ data set of 151 with muscle invasive bladder cancer and TCGA (The Cancer Genome Atlas) data set of 402 with muscle invasive bladder cancer. Subtyping was done using simplified panels (MCG-1 and MCG-Ext) which included only transcripts common in published studies and were analyzed for predicting metastasis, and cancer specific, overall and recurrence-free survival. TCGA data set was further analyzed using the Lund taxonomy, the Bladder Cancer Molecular Taxonomy Group Consensus and TCGA 2017 mRNA subtype classifications. RESULTS: Muscle invasive bladder cancer specimens from cohort 1 and the Oncomine data set showed intratumor heterogeneity for transcript and protein expression. MCG-1 subtypes did not predict the outcome on univariate or Kaplan-Meier analysis. On multivariate analysis N stage (p ≤0.007), T stage (p ≤0.04), M stage (p=0.007) and/or patient age (p=0.01) predicted metastasis, cancer specific and overall survival, and/or the cisplatin based adjuvant chemotherapy response. In TCGA data set publications showed that subtypes risk stratified patients for overall survival. Consistently the MCG-1 and MCG-Ext subtypes were associated with overall but not recurrence-free survival on univariate and Kaplan-Meier analyses. TCGA data set included 21 low grade specimens of the total of 402 and subtypes associated with tumor grade (p=0.005). However, less than 1% of muscle invasive bladder cancer cases are low grade. In only high grade specimens the MCG-1 and MCG-Ext subtypes could not predict overall survival. On univariate analysis subtypes according to the Bladder Cancer Molecular Taxonomy Group Consensus, TCGA 2017 and the Lund taxonomy were associated with tumor grade (p <0.0001) and overall survival (p=0.01 to <0.0001). Regardless of classification, subtypes had about 50% to 60% sensitivity and specificity to predict overall and recurrence-free survival. On multivariate analyses N stage and lymphovascular invasion consistently predicted recurrence-free and overall survival (p=0.039 and 0.003, respectively). CONCLUSIONS: Molecular subtypes reflect bladder tumor heterogeneity and are associated with tumor grade. In multiple cohorts and subtyping classifications the clinical parameters outperformed subtypes for predicting the outcome.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Transitional Cell/genetics , Carcinoma, Transitional Cell/pathology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Female , Humans , Kaplan-Meier Estimate , Male , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Staging , Phenotype , Predictive Value of Tests , Prognosis , Risk Assessment , Risk Factors , Transcriptome
15.
Sci Immunol ; 4(41)2019 11 22.
Article in English | MEDLINE | ID: mdl-31757835

ABSTRACT

MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing-based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 "mature" MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ-producing MAIT1 cells and interleukin-17-producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)-deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.


Subject(s)
Mucosal-Associated Invariant T Cells/immunology , Signaling Lymphocytic Activation Molecule Family/genetics , Transcription, Genetic/genetics , Adult , Animals , Cell Differentiation/immunology , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Signaling Lymphocytic Activation Molecule Family/immunology
16.
Cancer Biomark ; 26(3): 291-301, 2019.
Article in English | MEDLINE | ID: mdl-31524146

ABSTRACT

BACKGROUND: Differential expression of chemokines/chemokine receptors in colorectal cancer (CRC) may enable molecular characterization of patients' tumors for predicting clinical outcome. OBJECTIVE: To evaluate the prognostic ability of these molecules in a CRC cohort and the CRC TCGA-dataset. METHODS: Chemokine (CXCL-12α, CXCL-12ß, IL-17A, CXCL-8, GM-CSF) and chemokine receptor (CXCR-4, CXCR-7) transcripts were analyzed by RT-qPCR in 76 CRC specimens (normal: 27, tumor: 49; clinical cohort). RNA-Seq data was analyzed from the TCGA-dataset (n= 375). Transcript levels were correlated with outcome; analyses: univariate, multivariable, Kaplan-Meier. RESULTS: In the clinical cohort, chemokine/chemokine receptor levels were elevated 3-10-fold in CRC specimens (P⩽ 0.004) and were higher in patients who developed metastasis (P= 0.03 - < 0.0001). CXCR-4, CXCR-7, CXCL-12α, CXCL-8, IL-17 and GM-CSF levels predicted metastasis (P⩽ 0.0421) and/or overall survival (OS; P⩽ 0.0373). The CXCR-4+CXCR-7+CXCL-12 marker (CXCR-4/7+CXCL-12 (α/b) signature) stratified patients into risk for metastasis (P= 0.0014; OR, 2.72) and OS (P= 0.0442; OR, 2.7); sensitivity: 86.67%, specificity: 97.06%. In the TCGA-dataset, the CXCR-4/7+CXCL-12 signature predicted metastasis (P= 0.011; OR, 2.72) and OS (P= 0.0006; OR: 4.04). In both datasets, the signature was an independent predictor of clinical outcome. CONCLUSIONS: Results of 451 specimens from both cohorts reveal that the CXCR-4/7+CXCL-12 signature potentially predicts outcome in CRC patients and may allow earlier intervention.


Subject(s)
Biomarkers, Tumor/metabolism , Chemokine CXCL12/metabolism , Colorectal Neoplasms/pathology , Receptors, CXCR4/metabolism , Receptors, CXCR/metabolism , Aged , Colon/pathology , Colorectal Neoplasms/mortality , Datasets as Topic , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Prognosis , RNA-Seq , Real-Time Polymerase Chain Reaction
17.
Sex Med ; 7(3): 337-344, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31327724

ABSTRACT

BACKGROUND: In an effort to reduce dependence on opioids following inflatable penile prosthesis placement, intra-operative soaking of the implant in Bupivacaine (BUP) has been proposed as part of a multimodal approach to pain control. However, no study has shown if the addition of BUP affects the antimicrobial properties of InhibiZone on AMS700 (Boston Scientific, Marlborough, MA) and/or of antibiotic soaked Titan Coloplast (Coloplast Corporation, Minneapolis, MN). AIM: To determine if BUP alters the zone of inhibition (ZOI) against Staphylococcus epidermidis (S epidermidis) and Escherichia coli (E coli), common gram-positive and gram-negative bacterial causes of infection, respectively, created by InhibiZone coated AMS and/or by antibiotic-soaked Coloplast implant. METHODS: S epidermidis and E coli were spread on agar plates. After a 30-minute incubation, four AMS with InhibiZone strips treated with sterile saline or BUP (1.25 mg/mL) were placed on a plate. 4 Coloplast strips were dipped in varying routinely used concentrations of Rifampin (0-10 mg/mL) plus Gentamicin (0-1 mg/mL; rifampin and gentamicin (R+G)) solution with or without BUP. The ZOI for AMS with InhibiZone and Coloplast dipped in antibiotic solution was measured using ImageJ software. Normalized ZOI was calculated as (ZOI area/plate area) × 100. Unpaired t-test compared the mean ± SD ZOI between BUP and no BUP groups (n = 4/group). OUTCOMES: The primary outcome of the study was the ZOI against E coli and S epidermidis at 24 and 48 hours. RESULTS: Growth of both S epidermidis and E coli at 24 and 48 hours of incubation was inhibited in both implants and the addition of BUP did not alter the ZOI. Coloplast strips dipped in R+G produced a ZOI in a dose-dependent manner. Interestingly, the ZOI against S epidermidis compared to that of E coli was much wider for both implants. CLINICAL IMPLICATIONS: This suggests that the use of BUP does not affect the protective effects of antibiotic dips and can potentially be used during penile prosthesis surgery pending clinical trials. STRENGTHS AND LIMITATIONS: This is the first study to evaluate the effect of BUP on anti-bacterial dips. As with all in vitro analysis, further research must be done to see if these findings hold true in the clinical setting. CONCLUSIONS: The addition of BUP does not impede the in vitro antibacterial activity of InhibiZone-coated AMS or R+G-soaked Coloplast. Whether these in vitro findings translate to surgical outcomes needs to be evaluated in future preclinical trials. Lokeshwar SD, Horodyski L, Lahorewala SS, et al. The Effect of Bupivacaine on the Efficacy of Antibiotic Coating on Penile Implants in Preventing Infection. J Sex Med 2019;7:337-344.

18.
J Acoust Soc Am ; 145(6): 3488, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31255095

ABSTRACT

Acoustic black holes (ABHs) are geometric structural features that provide a potential lightweight damping solution for flexural vibrations. In this article, a parametric study of an ABH on a beam has been carried out to assess how practical design constraints affect its behaviour, thus providing detailed insight into design trade-offs. The reflection coefficient of the ABH has been calculated for each taper profile, parameterised via the tip-height, taper-length, and power-law, and it has been shown to exhibit spectral bands of low reflection. These bands have been related to the modes of the ABH cell and become more closely spaced in frequency as the ABH parameters are suitably varied. This suggests that ABH design should maximise the modal density to minimise the broadband reflection coefficient; however, the minimum level of reflection is also dependent on the power-law and tip-height. Consequently, broadband reflection values have been used to show that optimum power-law and tip-height settings exist that achieve a balance between maximum modal density and minimum level of reflection. Additionally, at discrete frequencies, in cases where tip-height and taper-length are practically constrained, the power law can be tuned to maximise performance. Finally, an experimental study is used to validate the results.

19.
Mol Cancer Ther ; 18(4): 801-811, 2019 04.
Article in English | MEDLINE | ID: mdl-30787175

ABSTRACT

ß-Arrestins are classic attenuators of G-protein-coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. This work shows for the first time that ß-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer. ß-Arrestin-1 (ARRB1) and ß-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n = 63 and 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated. The consequence of forced expression of ARRBs on tumor growth and response to Gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared with normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, disease-specific-mortality, and failure to Gemcitabine + Cisplatin (G+C) chemotherapy; ∼80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity toward Gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. CRISPR-Cas9-mediated gene-knockout of ARRB1 resulted in the reversal of this aggressive phenotype. ARRBs regulate cancer stem cell-like properties in bladder cancer and are potential prognostic indicators for tumor progression and chemotherapy response.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Phenotype , Stem Cells/drug effects , Stem Cells/metabolism , Urinary Bladder Neoplasms/drug therapy , beta-Arrestin 1/genetics , beta-Arrestin 2/genetics , Animals , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/pharmacology , Antimetabolites, Antineoplastic/therapeutic use , Cell Line, Tumor , Cisplatin/administration & dosage , Cisplatin/pharmacology , Cisplatin/therapeutic use , Cohort Studies , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Drug Resistance, Neoplasm/genetics , Female , Humans , Male , Mice , Mice, Nude , Prognosis , Transfection , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , beta-Arrestin 1/metabolism , beta-Arrestin 2/metabolism , Gemcitabine
20.
Opt Express ; 26(19): 24487-24496, 2018 Sep 17.
Article in English | MEDLINE | ID: mdl-30469565

ABSTRACT

We analyze the degree of entanglement measurable from a quantum dot via the biexciton-exciton cascade as a function of the exciton fine-structure splitting and the detection time resolution. We show that the time-energy uncertainty relation provides means to measure a high entanglement even in presence of a finite fine-structure splitting when a detection system with high temporal resolution is employed. Still, in many applications it would be beneficial if the fine-structure splitting could be compensated to zero. To solve this problem, we propose an all-optical approach with rotating waveplates to erase this fine-structure splitting completely which should allow obtaining a high degree of entanglement with near-unity efficiency. Our optical approach is possible with current technology and is also compatible with any quantum dot showing fine-structure splitting. This bears the advantage that for example the fine-structure splitting of quantum dots in nanowires and micropillars can be directly compensated without the need for further sample processing.

SELECTION OF CITATIONS
SEARCH DETAIL
...