ABSTRACT
MazF is an Escherichia coli-derived endoribonuclease that selectively cleaves ACA sequences of mRNA prevalent in HIV. We administered a single infusion of autologous CD4 T lymphocytes modified to express a Tat-dependent MazF transgene to 10 HIV-infected individuals (six remaining on antiretroviral therapy [ART]; four undergoing treatment interruption post-infusion) in order to provide a population of HIV-resistant immune cells. In participants who remained on ART, increases in CD4 and CD8 T cell counts of ~200 cells/mm3 each occurred within 2 weeks of infusion and persisted for at least 6 months. Modified cells were detectable for several months in the blood and trafficked to gastrointestinal lymph tissue. HIV-1 Tat introduced ex vivo to the modified CD4+ T cells induced MazF expression in both pre- and post-infusion samples, and MazF expression was detected in vivo post-viral-rebound during ATI. One participant experienced mild cytokine release syndrome. In sum, this study of a single infusion of MazF-modified CD4 T lymphocytes demonstrated safety of these cells, distribution to lymph tissue and maintenance of Tat-inducible MazF endoribonuclease activity, as well as sustained elevation of blood CD4 and CD8 T cell counts. Future studies to assess effects on viremia and latent proviral reservoir are warranted.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Endoribonucleases/genetics , HIV Infections/immunology , HIV Infections/virology , HIV-1/physiology , tat Gene Products, Human Immunodeficiency Virus/metabolism , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Endoribonucleases/metabolism , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Genetic Therapy , HIV Infections/metabolism , HIV Infections/therapy , Viral Load , Virus ReplicationABSTRACT
BACKGROUND: With an increasing aging population, postmenopausal osteoporosis has become a global public health problem. Previous evidence has shown that postmenopausal osteoporosis is a skeletal disease mainly caused by estrogen deficiency, generally accompanied by inflammation, and dietary isoflavones may ameliorate postmenopausal osteoporosis by anti-inflammatory activity. We have generated isoflavone-enriched soybean leaves (IESLs), but their anti-inflammatory activity and effect on attenuating osteoporosis are still obscure. Here, we determined the isoflavone profiles of IESLs and evaluated their anti-inflammatory activity in lipopolysaccharide-stimulated RAW 264.7 cells and anti-osteoporotic effects on ovariectomy-induced osteoporosis in rats. RESULTS: IESLs had a high content of total isoflavone. Hydrolysate of IESLs (HIESLs) was rich with the aglycones daidzein and genistein, and HIESLs can significantly inhibit lipopolysaccharide-induced inflammation by reducing messenger RNA expression of iNOS, COX-2, IL6, and IL1ß. Moreover, ovariectomized rats receiving aqueous extracts of IESLs (HIESLs) orally maintained more bone mass than control rats did, which was attributed to inhibition of osteoclastogenesis by downregulating the messenger RNA expression of the bone-specific genes RANKL/OPG, OC, and cathepsin K, and the inflammation-related genes IL6, NFκB, and COX-2. CONCLUSION: IESLs may attenuate postmenopausal osteoporosis by suppressing osteoclastogenesis with anti-inflammatory activity and be a potential source of functional food ingredients for the prevention of osteoporosis. © 2020 Society of Chemical Industry.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Glycine max/chemistry , Isoflavones/administration & dosage , Osteoporosis, Postmenopausal/drug therapy , Animals , Cathepsin K/genetics , Cathepsin K/metabolism , Female , Humans , Mice , Osteogenesis/drug effects , Osteoporosis, Postmenopausal/genetics , Osteoporosis, Postmenopausal/metabolism , Osteoporosis, Postmenopausal/physiopathology , Ovariectomy , Plant Leaves/chemistry , RANK Ligand/genetics , RANK Ligand/metabolism , RAW 264.7 Cells , Rats , Rats, Sprague-DawleyABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase; Subject(s)
Carcinoma, Pancreatic Ductal/pathology
, Core Binding Factor Alpha 3 Subunit/metabolism
, Kynurenine/metabolism
, Nitric Oxide Synthase Type II/metabolism
, Nitric Oxide/metabolism
, Pancreatic Neoplasms/pathology
, Carcinoma, Pancreatic Ductal/mortality
, Cell Movement
, Humans
, Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
, Neoplasm Invasiveness/pathology
, Pancreatic Neoplasms/mortality
, Receptors, Aryl Hydrocarbon/genetics
, Signal Transduction/physiology
, Spheroids, Cellular
, Tryptophan/metabolism
, Tumor Cells, Cultured
ABSTRACT
The extent to which donor multidrug-resistant organisms (MDROs) affect organ utilization remains unclear. We performed a retrospective cohort study at 4 transplant centers between 2015 and 2016 to evaluate this question. All deceased donors who donated at least one organ were included. Exposed donors had at least one MDRO on culture. Unexposed donors had no MDRO-positive cultures. Only cultures obtained during the donor's terminal hospitalization were evaluated. Multivariable regression was used to determine the association between donor MDRO and (1) number of organs transplanted per donor and (2) the match run at which each organ was accepted. Subsequently, we restricted the analysis to donors with MDR-Gram-negative (GN) organisms. Of 440 total donors, 29 (7%) donors grew MDROs and 7 (2%) grew MDR-GNs. There was no significant association between donor MDRO and either measure of organ utilization. However, donor MDR-GNs were associated with a significant reduction in the number of organs transplanted per donor (incidence rate ratio 0.43, 95% confidence interval [CI] 0.39-0.48, P < .01), and organs were accepted significantly further down the match list (relative count 5.08, 95% CI 1.64-15.68, P = .01). Though donor MDR-GNs were infrequent in our study, their growing prevalence could meaningfully reduce the donor pool over time.
Subject(s)
Tissue and Organ Procurement , Transplants , Humans , Retrospective Studies , Tissue DonorsABSTRACT
Donor infection or colonization with a multidrug-resistant organism (MDRO) affects organ utilization and recipient antibiotic management. Approaches to identifying donors at risk of carrying MDROs are unknown. We sought to determine the risk factors for MDROs among transplant donors. A multicenter retrospective cohort study was conducted at four transplant centers between 2015 and 2016. All deceased donors who donated at least one organ were included. Cultures obtained during the donor's terminal hospitalization and organ procurement were evaluated. The primary outcome was isolation of an MDRO on culture. Multivariable Cox regression was used to determine risk factors associated with time to donor MDRO. Of 440 total donors, 64 (15%) donors grew an MDRO on culture. Predictors of an MDRO on donor culture included hepatitis C viremia (hazard ratio [HR] 4.09, 95% confidence interval [CI] 1.71-9.78, P = .002), need for dialysis (HR 4.59, 95% CI 1.09-19.21, P = .037), prior hematopoietic cell transplant (HR 7.57, 95% CI 1.03-55.75, P = .047), and exposure to antibiotics with a narrow gram-negative spectrum (HR 1.13, 95% CI 1.00-1.27, P = .045). This is the first study to determine risk factors for MDROs among deceased donors and will be important for risk stratifying potential donors and informing transplant recipient prophylaxis.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Drug Resistance, Multiple, Bacterial , Tissue Donors , Adult , Anti-Bacterial Agents/adverse effects , Cross Infection , Female , Hematopoietic Stem Cell Transplantation , Hepatitis C/complications , Hospitalization , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Proportional Hazards Models , Renal Dialysis , Retrospective Studies , Risk Factors , Tissue and Organ Procurement , Transplant Recipients , Treatment OutcomeABSTRACT
Hahnemann University Hospital has performed 120 kidney transplantations in human immunodeficiency virus (HIV)-positive individuals during the last 16 years. Our patient population represents â¼10% of the entire US population of HIV-positive kidney recipients. In our earlier years of HIV transplantation, we noted increased rejection rates, often leading to graft failure. We have established a multidisciplinary team and over the years have made substantial protocol modifications based on lessons learned. These modifications affected our approach to candidate evaluation, donor selection, perioperative immunosuppression, and posttransplantation monitoring and resulted in excellent posttransplantation outcomes, including 100% patient and graft survival at 1 year and patient and graft survival at 3 years of 100% and 96%, respectively. We present key clinical data, including a granular patient-level analysis of the associations of antiretroviral therapy regimens with long-term survival, cellular and antibody-mediated rejection rates, and the causes of allograft failures. In summary, we provide details on the evolution of our approach to HIV transplantation during the last 16 years, including strategies that may improve outcomes among HIV-positive kidney transplantation candidates throughout the United States.
Subject(s)
HIV Seropositivity/complications , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/surgery , Kidney Transplantation , Aged , Female , Hospitals, University , Humans , Male , Retrospective Studies , Time FactorsABSTRACT
These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of HSV in the pre- and post-transplant period. A majority of transplant recipients are seropositive for HSV-1 or 2. Compared with immunocompetent persons, SOT recipients shed HSV more frequently, have more severe clinical manifestations, and are slower to respond to therapy. Most HSV infection is diagnosed on clinical grounds, but patients may present with atypical lesions and/or other clinical manifestations. Acquisition from the donor is rare. Polymerase chain reaction is the preferred diagnostic test unless culture is needed for resistance testing. For limited mucocutaneous lesions, oral therapy can be used; however, in severe, disseminated, visceral or CNS involvement, acyclovir doses of up to 10 mg/kg every 8 hours intravenously should be initiated. Acyclovir-resistant HSV is less common in SOT patients than in HSCT and can be treated with foscarnet, though other novel therapies are currently under investigation. HSV-specific prophylaxis should be considered for all HSV-1 and HSV-2-seropositive organ recipients who are not receiving antiviral medication for CMV prevention that has activity against HSV.
Subject(s)
Antiviral Agents/therapeutic use , Herpes Simplex/diagnosis , Herpes Simplex/drug therapy , Organ Transplantation/adverse effects , Practice Guidelines as Topic/standards , Simplexvirus/isolation & purification , Herpes Simplex/etiology , Humans , Societies, Medical , Transplant RecipientsABSTRACT
BACKGROUND: The eradication rate of Helicobacter pylori has declined, mainly due to antimicrobial resistance. To overcome resistance-associated treatment failure, the efficacy of culture-based, susceptibility-guided therapy was demonstrated as the first-line eradication therapy for H pylori infection. AIMS: To evaluate the efficacy of culture-based therapy as the first-line eradication therapy in regions with high levels of antimicrobial resistance. METHODS: Helicobacter pylori-positive patients without previous eradication treatment history were recommended to undergo culture to determine the minimal inhibitory concentration (MIC). If they consented, 7-day clarithromycin-containing PPI triple; 7-day esomeprazole, moxifloxacin, and amoxicillin (MEA) therapy; or 7- or 14-day esomeprazole, bismuth, metronidazole, and tetracycline (quadruple) therapy were administered based on the agar dilution-determined MIC. Eradication, treatment compliance, and adverse events were examined. RESULTS: In total, 74 patients were enrolled, and 69 patients completed the protocols. The overall resistance rates to amoxicillin, clarithromycin, metronidazole, and moxifloxacin were 6.7%, 31.0%, 41.8%, and 39.2%, respectively. The patients were allocated to the PPI triple (n = 50), MEA (n = 8) or quadruple (n = 16) therapy. The eradication rate in the intention-to-treat analysis was 93.1% (69 of 74 patients). The eradication rates in the per-protocol analysis were 100.0% (69 of 69 patients). Epigastric pain, nausea, and vomiting were less common than those of other empirical therapies. CONCLUSIONS: Culture-based, susceptibility-guided therapy is effective first-line eradication therapy, especially in regions with high levels of antimicrobial resistance.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Bacterial , Helicobacter Infections/drug therapy , Helicobacter pylori/drug effects , Adult , Aged , Drug Therapy, Combination , Female , Helicobacter Infections/epidemiology , Helicobacter Infections/microbiology , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Prospective Studies , Republic of Korea/epidemiology , Treatment OutcomeABSTRACT
Antiretroviral therapy has significantly reduced mortality due to HIV infection, but the aging HIV-positive patient population now faces a growing burden of comorbidity. This review describes the changing epidemiology of chronic kidney disease and end-stage renal disease in this population, and highlights recent advances in antiretroviral therapy and kidney transplantation that directly impact the care of patients with HIV infection and end-stage renal disease.
Subject(s)
Anti-Retroviral Agents/administration & dosage , HIV Infections/complications , Kidney Failure, Chronic/etiology , Kidney Transplantation/methods , Renal Dialysis/adverse effects , HIV Infections/drug therapy , Humans , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/therapy , Renal Dialysis/methodsABSTRACT
BACKGROUND: Tenofovir disoproxil fumarate (TDF) is an antiretroviral agent frequently used to treat human immunodeficiency virus (HIV). There are concerns regarding its potential to cause acute kidney injury, chronic kidney disease, and proximal tubulopathy. Although TDF can effectively suppress HIV after kidney transplantation, it is unknown whether use of TDF-based antiretroviral therapy (ART) after kidney transplantation adversely affects allograft survival. METHODS: We examined 104 HIV+ kidney transplant (KT) recipients at our center between 2001 and 2014. We generated a propensity score for TDF treatment using recipient and donor characteristics. We then fit Cox proportional hazards models to investigate the association between TDF treatment and 3-year, death-censored primary allograft failure, adjusting for the propensity score and delayed graft function (DGF). RESULTS: Of the 104 HIV+ KT candidates who underwent transplantation during the study period, 23 (22%) were maintained on TDF-based ART at the time of transplantation, and 81 (78%) were on non-TDF-based ART. Median age of the cohort was 48 years; 87% were male; 88% were black; and median CD4 count at transplantation was 450 cells/mm3 . Median kidney donor risk index was 1.2. At 3 years post transplantation, primary allograft failure occurred in 26% of patients on TDF-based ART and in 28% of patients on non-TDF-based ART (P=.5). TDF treatment was not associated with primary allograft failure at 3 years post transplant after adjusting for DGF and a propensity score for TDF use (hazard ratio 2.12, 95% confidence interval 0.41-10.9). CONCLUSIONS: In a large single-center experience of HIV+ kidney transplantation, TDF use following kidney transplantation was not significantly associated with primary allograft failure. These results may help inform management for HIV+ KT recipients in need of TDF therapy for adequate viral suppression.
Subject(s)
Graft Survival/drug effects , HIV Infections/drug therapy , Kidney Transplantation/mortality , Tenofovir/therapeutic use , Adult , Allografts , Cohort Studies , Female , HIV Seropositivity , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
Our research team investigated the elemental composition and the presence of various toxic organic compounds, such as polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs), in estuary surface sediments to trace the spatial distribution of the sources of pollution deposited in Nakdong River, Busan, South Korea. The spatial patterns of elemental composition and toxic organic compounds were determined from the measurements of total organic carbon (TOC), total nitrogen, total sulfur, PAHs, and PCBs. The sediments had TOC contents of between 0.02 and 1.80 wt% (avg. 0.34 wt%), depending on the amount of clay-sized particles. The concentrations of PAHs and PCBs (10.8-167.7 ng g-1 dry wt and 197.0-754.0 pg g-1 dry wt, respectively) in surface sediments revealed different spatial patterns for these compounds, suggesting that they partially originated from the combustion of fossil fuels and from the use of commercial PCB products at adjacent industrial complexes. Although these concentrations were far below the Sediment Quality Guideline (SQG) of the National Oceanic and Atmospheric Administration (NOAA), the sediments at one site contained PCBs at concentrations close to the response level (754.0 pg g-1 dry wt), and were dominated by low-molecular-weight PAHs. The PAHs and PCBs in Nakdong River Estuary sediments were likely to have originated from the combustion of fossil fuels and biomass at the adjacent industrial complexes. The primarily analyzed results determined that PAHs originated from the combustion of fossil fuels and biomass, and overall concentrations were related to the contributions of individual PAHs in most sediment samples. Based on the SQG of the NOAA, our results indicate that the anthropogenic activity should be considered on the future-sustainable management of this estuary system.
Subject(s)
Environmental Monitoring/methods , Polychlorinated Biphenyls/analysis , Polycyclic Aromatic Hydrocarbons/analysis , Rivers/chemistry , Water Pollutants, Chemical/analysis , Estuaries , Geologic Sediments/chemistry , Republic of KoreaABSTRACT
BACKGROUND AND AIMS: Resistance rates of Helicobacter pylori to clarithromycin, metronidazole, and quinolone are over 30% in South Korea. The aim of this prospective study was to evaluate the ultimate eradication rate of H. pylori after first, second, or third-line therapy in Korea. METHODS: A cohort of 2202 patients with H. pylori was treated with proton pump inhibitor (PPI)-based triple therapy for seven days. In case of treatment failure or recurrence, moxifloxacin-based triple therapy (MA) or bismuth-based quadruple therapy (QUAD) was randomly given. When the second-line treatment failed or H. pylori recurred, the unused MA or QUAD was used as a third-line treatment. RESULTS: Eighty-six patients had recurrence at least once during consecutive lines of treatments. Among 2116 patients (intention-to-treat [ITT]) without recurrence, 1644 (77.7%, per-protocol [PP]) completely followed our treatment flow. The ITT and PP rates of first-line treatment were 69.8% and 89.3%. After second line, they reached 78.4% (ITT) and 98.4% (PP). The "final" eradication rate up to third line treatment were 80.0% (1692/2116) and 99.8% (1641/1644), respectively. Resistance to clarithromycin showed significantly lower eradication rate (OR 0.358, P < 0.001) than those with susceptible strains in multivariate analysis. However in PP analysis, there was no significant difference in ultimate success rate regarding resistance pattern. CONCLUSION: Final success rate of PP was high, 99.8% in Korea in spite of high antibiotic resistance rates. However, high rate of refusal of further treatment and follow-up loss made ITT eradication rate low. Proper strategy to improve the treatment adherence is needed.
Subject(s)
Gastritis/drug therapy , Gastritis/microbiology , Helicobacter Infections , Helicobacter pylori , Adult , Aged , Amoxicillin/administration & dosage , Clarithromycin/administration & dosage , Cohort Studies , Drug Resistance, Bacterial , Drug Therapy, Combination , Female , Gastritis/diagnosis , Gastritis/epidemiology , Humans , Korea/epidemiology , Logistic Models , Male , Middle Aged , Patient Compliance/statistics & numerical data , Proton Pump Inhibitors/administration & dosage , Recurrence , Treatment OutcomeABSTRACT
PURPOSE: To report short-term surgical outcomes of single-stage simultaneous rescue and sutureless intrascleral fixation of dislocated intraocular lens (IOLs). METHODS: Sixteen eyes of 16 patients who underwent simultaneous rescue and intrascleral fixation of dislocated 3-piece IOLs were retrospectively evaluated. Partial thickness limbal-based scleral flaps (2.0 × 2.0 mm) were created, and a 22-gauge round needle was used to create a sclerotomy at 1.5 mm from the limbus under the previously created scleral flap, and a 23-gauge trans pars plana vitrectomy was performed. Bimanual maneuvers using two 23-gauge end-grasping forceps under chandelier illumination and a wide-angle viewing system enabled 1 step rescue of IOLs from the posterior vitreous cavity with 1 hand and simultaneous haptic externalization through sclerotomy with the other hand. An externalized haptic was placed into the 3-mm intrascleral tunnel created using a bent 26-gauge needle. Fibrin glue was used to fixate haptics and close the scleral flaps. RESULTS: Intraocular lenses were successfully rescued and sclera-fixated through intrascleral tunnels in all 16 eyes (mean age, 56.56 ± 19.89 years). The mean preoperative logarithm of the minimum angle of resolution best-corrected visual acuity was 0.92 ± 0.68, and this significantly improved at 6 months to 0.289 ± 0.36 (P = 0.003). During the follow-up period (10.1 ± 3.21 months), no significant change of endothelial cell count or central foveal thickness was noted postoperatively (P = 0.203 and P = 0.979, respectively). There were no significant postoperative complications such as IOL dislocation, IOL decentration, retinal detachment, endophthalmitis, or postoperative hypotony. CONCLUSION: Simultaneous rescue and sutureless intrascleral haptic fixation of dislocated 3-piece IOLs using bimanual maneuvers is an effective, safe, and minimally invasive surgical method to rescue and fixate the dislocated IOL without further explant.
Subject(s)
Artificial Lens Implant Migration/surgery , Lenses, Intraocular , Sclera/surgery , Surgical Flaps , Suture Techniques , Adult , Aged , Aged, 80 and over , Cell Count , Endothelium, Corneal/pathology , Female , Fibrin Tissue Adhesive/therapeutic use , Humans , Male , Middle Aged , Reoperation , Retrospective Studies , Sclerostomy , Tissue Adhesives/therapeutic use , Tomography, Optical Coherence , Visual Acuity/physiology , VitrectomyABSTRACT
Carotid blowout is a rare fatal complication most commonly observed in head and neck cancer patients, especially after radiation therapy. Traditional surgical approaches carry extremely high morbidity and mortality rates. We present a case of acute hemorrhage from extracranial carotid artery in a 64-year-old man with history of total laryngectomy, tracheostomy, and chemoradiotherapy for laryngeal cancer. Tumor was noted to be encasing and eroding into the internal and common carotid artery with a large soft tissue neck defect. Hemorrhage was successfully controlled employing 3 Viabahn covered stents of increasing diameter in the internal and common carotid artery in an overlapping fashion under local anesthesia. Deployment of tapering overlapped covered stents in common and internal carotid artery may safely be performed to obtain endovascular control of active hemorrhage in a hostile neck.
Subject(s)
Carotid Artery Diseases/therapy , Carotid Artery, Internal/radiation effects , Endovascular Procedures/instrumentation , Hemorrhage/therapy , Laryngeal Neoplasms/radiotherapy , Radiation Injuries/therapy , Stents , Acute Disease , Carotid Artery Diseases/diagnosis , Carotid Artery Diseases/etiology , Carotid Artery, Internal/diagnostic imaging , Hemorrhage/diagnosis , Hemorrhage/etiology , Humans , Male , Middle Aged , Prosthesis Design , Radiation Injuries/diagnosis , Radiation Injuries/etiology , Radiotherapy/adverse effects , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent data set and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a candidate predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair and actin dynamics. This observation was further corroborated with protein expression analysis and 3'-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that the miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters the cellular organization of F-actin and inhibits tumor cell invasion and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility.
Subject(s)
Biomarkers, Tumor/metabolism , MicroRNAs/metabolism , Prostatic Neoplasms/genetics , Biomarkers, Tumor/genetics , Cell Cycle/genetics , Cell Line, Tumor , Cell Movement , Cell Proliferation , DNA Repair/genetics , Epigenesis, Genetic , Genes, Tumor Suppressor , Histone Deacetylase Inhibitors/pharmacology , Humans , Male , MicroRNAs/genetics , Mitosis , Neoplasm Metastasis , Neoplasm Recurrence, Local/diagnosis , Prognosis , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
Reference genome assemblies have been created from multiple lineages within the Canidae family; however, despite its phylogenetic relevance as a basal genus within the clade, there is currently no reference genome for the gray fox (Urocyon cinereoargenteus). Here, we present a chromosome-level assembly for the gray fox (U. cinereoargenteus), which represents the most contiguous, non-domestic canid reference genome available to date, with 90% of the genome contained in just 34 scaffolds and a contig N50 and scaffold N50 of 59.4 and 72.9 Megabases, respectively. Repeat analyses identified an increased number of simple repeats relative to other canids. Based on mitochondrial DNA, our Vermont sample clusters with other gray fox samples from the northeastern United States and contains slightly lower levels of heterozygosity than gray foxes on the west coast of California. This new assembly lays the groundwork for future studies to describe past and present population dynamics, including the delineation of evolutionarily significant units of management relevance. Importantly, the phylogenetic position of Urocyon allows us to verify the loss of PRDM9 functionality in the basal canid lineage, confirming that pseudogenization occurred at least 10 million years ago.
Subject(s)
Chromosomes , Foxes , Animals , Foxes/genetics , Phylogeny , Chromosomes/genetics , DNA, Mitochondrial/genetics , GenomeABSTRACT
MIF is a proinflammatory cytokine and is implicated in cancer. A higher MIF level is found in many human cancer and cancer-prone inflammatory diseases, including chronic pancreatitis and pancreatic cancer. We tested the hypothesis that MIF contributes to pancreatic cancer aggressiveness and predicts disease outcome in resected cases. Consistent with our hypothesis we found that an elevated MIF mRNA expression in tumors was significantly associated with poor outcome in resected cases. Multivariate Cox-regression analysis further showed that MIF is independently associated with patients' survival (HR = 2.26, 95% CI = 1.17-4.37, p = 0.015). Mechanistic analyses revealed that MIF overexpression decreased E-cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with the features of epithelial-to-mesenchymal transition (EMT). Furthermore, MIF-overexpression significantly increased ZEB1/2 and decreased miR-200b expression, while shRNA-mediated inhibition of MIF increased E-cadherin and miR-200b expression, and reduced the expression of ZEB1/2 in Panc1 cells. Re-expression of miR-200b in MIF overexpressing cells restored the epithelial characteristics, as indicated by an increase in E-cadherin and decrease in ZEB1/2 and vimentin expression. A reduced sensitivity to the chemotherapeutic drug, gemcitabine, occurred in MIF-overexpressing cells. Indicative of an increased malignant potential, MIF over-expressing cells showed significant increase in their invasion ability in vitro, and tumor growth and metastasis in an orthotopic xenograft mouse model. These results support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate target for designing improved treatment in pancreatic cancer.
Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Epithelial-Mesenchymal Transition/genetics , Macrophage Migration-Inhibitory Factors/genetics , Pancreatic Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Animals , Antimetabolites, Antineoplastic/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Female , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Macrophage Migration-Inhibitory Factors/metabolism , Male , Mice, Nude , MicroRNAs/genetics , Middle Aged , Neoplasm Invasiveness , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Prognosis , RNA Interference , Transplantation, Heterologous , GemcitabineABSTRACT
INTRODUCTION: The immunosuppressive enzyme, indoleamine 2,3 dioxygenase (IDO), is overexpressed in many different tumor types including breast cancer. IDO inhibitors synergize with chemotherapy in breast cancer murine models. Characterizing IDO expression in breast cancer could define which patients receive IDO inhibitors. This study analyzed IDO protein expression in 203 breast cancer cases. The relationship between IDO, overall survival (OS), disease-specific survival (DSS), clinicopathologic, molecular, and immune tumor infiltrate factors was evaluated. METHODS: Expression of IDO, estrogen receptor (ER), progesterone receptor (PR), human epithelial receptor 2, cytokeratin 5/6, epithelial growth factor receptor, phosphorylated AKT, neoangiogenesis, nitrogen oxide synthetase 2 (NOS2), cyclooxygenase 2 (COX2), FoxP3, CD8, and CD11b on archival breast cancer tissue sections was evaluated by immunohistochemistry. Associations between IDO and these markers were explored by a univariate and multivariate analysis. Survival was analyzed using Kaplan-Meier (OS) and Wilcoxon two-sample (DSS) tests. RESULTS: IDO expression was higher in ER+ tumors compared to ER- tumors. IDO was lower in those with higher neoangiogenesis. OS was better in ER+ patients with high IDO expression. DSS was better in node-positive patients with high IDO expression. IDO activity positively correlates with NOS2. COX2 as positively correlated with IDO on univariate but not multivariate analysis. There was a trend toward greater numbers of CD11b+ cells in IDO-low tumors. CONCLUSIONS: IDO protein expression is lower in ER- breast tumors with greater neoangiogenesis. Future clinical trials evaluating the synergy between IDO inhibitors and chemotherapy should take this finding into account and stratify for ER status in the trial design.
Subject(s)
Breast Neoplasms/enzymology , Immunohistochemistry/methods , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Cyclooxygenase 2/metabolism , Enzyme Inhibitors/pharmacology , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Models, Statistical , Multivariate Analysis , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Regression Analysis , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: A new botulinum toxin type A (NBoNT) produced from the same strain of Clostridium botulinum as onabotulinumtoxinA (OBoNT) is widely used in Asia. OBJECTIVES: To compare the efficacy and safety of NBoNT and OBoNT for moderate to severe glabellar wrinkles. METHODS: A double-blind, randomized, active-controlled, phase III study was performed. Three hundred fourteen patients were randomized at a 1:1 ratio to receive 20 U of toxin. The primary end point was the responder rate according to investigator live assessment at maximum frown at week 4. Secondary end points were responder rates according to investigator live assessment with frowning and at rest at weeks 8, 12, and 16, with additional photographic assessment by a panel of blinded raters 4 weeks after injection. Subjective satisfaction scores were also evaluated. RESULTS: Four weeks after treatment, responder rates for maximum frown were 93.7% (133/142) in the NBoNT group and 94.5% (138/146) in the OBoNT group. For secondary end points, there was no significant difference between the two groups for any variable at any time point. Noninferiority of NBoNT was confirmed. There were no serious adverse effects with either toxin. CONCLUSION: NBoNT is equally as effective as OBoNT for the treatment of glabellar frown lines. Both toxins were well tolerated.
Subject(s)
Botulinum Toxins, Type A/therapeutic use , Neurotoxins/therapeutic use , Skin Aging/drug effects , Adult , Botulinum Toxins, Type A/adverse effects , Double-Blind Method , Eyebrows , Female , Forehead , Humans , Male , Middle Aged , Neurotoxins/adverse effects , Patient Satisfaction , Photography , Time FactorsABSTRACT
BACKGROUND AND AIMS: To assess the validity of biopsy-based tests (histology, culture, and urease test) and serology in detecting current H. pylori infection for the peptic ulcer patients who had gastric bleeding. METHODS: A total of 398 peptic ulcer patients were enrolled and divided into two groups, according to the presence or absence of bleeding. The diagnosis for current H. pylori infection was verified using the gold standard combining individual H. pylori tests. Sensitivity, specificity, and positive and negative predictive values of the culture, Campylobacter-like organism (CLO) test (urease test), histology, and serology were compared. RESULTS: Of the total study population (N = 398), 157 (39.4%) patients were categorized into the bleeding group. The sensitivities of the culture (40.0%) and CLO (85.0%) in the bleeding group were significantly lower than culture (58.1%) and CLO (96.4%) in the nonbleeding group (p = .012 and p < .001, respectively). In the bleeding group, the sensitivity of CLO (85.0%) was significantly lower than histology (92.5%) and serology (97.4%) (p = .013 and p = .002, respectively), which was not found in the nonbleeding group. The specificity of serology in the bleeding group (56.3%) was significantly lower than that of nonbleeding group (74.2%) (p = .038). Similarly, the specificity of serology was significantly lower than the other H. pylori tests in the bleeders. CONCLUSIONS: Bleeding decreased the sensitivity of H. pylori tests in patients with peptic ulcer, especially in urease test or culture. In contrast, histology was found to be a quite reliable test, regardless of the presence of bleeding.