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1.
J Hosp Infect ; 116: 53-59, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34252477

ABSTRACT

BACKGROUND: Conflicting results have been published on the impact of contact precautions (CPs) on reduction of transmission of multi-drug-resistant micro-organisms (MDROs) in the endemic setting. Ambiguous definitions coupled with low adherence partly explain these differences. AIM: We prospectively monitored the level of adherence to CPs and aimed to relate it to in-hospital transmission of MDROs. METHODS: Between January 2016 and March 2018, all patients under CPs underwent continuous monitoring of adherence to CPs by routine on-site visits on days 0, 3 and 7 after initiating CPs using a standardized checklist. The protocol included 10 interventions that were routinely checked such as CP sign at the door as well as wearing of gowns and gloves upon entry to the patient room. Patients requiring CPs were defined as colonized or infected with MDROs (meticillin-resistant Staphylococcus aureus (MRSA), non-Escherichia coli extended-spectrum beta lactamase (ESBL) Enterobacterales, vancomycin-resistant enterococci (VRE) and carbapenem-resistant Gram-negative micro-organisms (CRGN)) as well as patients infected with respiratory viruses, norovirus, scabies and hypervirulent strains of Clostridioides difficile. FINDINGS: Overall, data from 13,756 CP records from 1378 visits of 812 patients were analysed. Adherence varied between 93% and 100% for each intervention, except for "separate space for contaminated material" with an adherence of 5.3-6.1%. The incidence of in-hospital transmission during the study period was extremely low for MRSA, VRE, non-E.coli ESBL Enterobacterales and CRGN with 0.00-0.064 cases/1000 patient days. CONCLUSION: High adherence coupled with continuous monitoring of CPs correlated with a very low in-hospital transmission rate. These results indicate that CPs are highly effective if routine monitoring of adherence is implemented.


Subject(s)
Cross Infection , Methicillin-Resistant Staphylococcus aureus , Pharmaceutical Preparations , Staphylococcal Infections , Vancomycin-Resistant Enterococci , Cross Infection/epidemiology , Cross Infection/prevention & control , Hospitals , Humans , Infection Control
2.
Br J Surg ; 108(10): 1207-1215, 2021 10 23.
Article in English | MEDLINE | ID: mdl-34095952

ABSTRACT

BACKGROUND: Long-term survival outcomes of trimodal therapy (TMT; chemoradiation plus surgery) and bimodal therapy (BMT; chemoradiation) have seldom been analysed. In a selective-surgery paradigm, the benefit of TMT in patients with a complete clinical response is controversial. Factors associated with survival in patients with a clinical complete response to chemoradiation were evaluated. METHODS: Patients with stage II-III oesophageal squamous cell carcinoma treated with TMT or BMT from 2002 to 2017 were evaluated. The BMT group consisted of patients who were otherwise eligible for surgery but underwent chemoradiation alone followed by observation. This group included patients who later had salvage oesophagectomy. Survival was evaluated and compared between TMT and BMT groups. Elastic net regularization was performed to select co-variables for Cox multivariable survival analysis in patients with a clinical complete response. RESULTS: Of 143 patients, 60 (41.9 per cent) underwent TMT and 83 (58.0 per cent) BMT. Patients who underwent TMT had longer median overall survival than those who had BMT (77 versus 33 months; P = 0.019). For patients with a clinical complete response, TMT achieved longer median overall survival than BMT (123 versus 55 months; P = 0.04). BMT had a high locoregional recurrence rate (48 versus 6 per cent; P < 0.001); 26 of 29 patients with locoregional recurrence in the BMT groupunderwent salvage resection. Cox multivariable analysis demonstrated that upper-mid oesophageal tumour location (hazard ratio (HR) 2.04; P = 0.024) and tumour length (HR 1.18; P = 0.046) were associated with worse survival. Although TMT was not associated with survival, it was a predictor of reduced recurrence (HR 0.28; P = 0.028). The maximum standardized uptake value after chemoradiation also predicted recurrence (HR 1.33; P < 0.001). CONCLUSION: In patients who achieve a clinical complete response, TMT reduces locoregional recurrence but may not prolong survival. The differences in survival outcomes may be due to patient selection; therefore, a selective-surgery strategy in oesophageal squamous cell carcinoma is a reasonable approach.


Subject(s)
Esophageal Neoplasms/therapy , Esophageal Squamous Cell Carcinoma/therapy , Aged , Chemoradiotherapy, Adjuvant , Disease-Free Survival , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophageal Neoplasms/surgery , Esophageal Squamous Cell Carcinoma/mortality , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/surgery , Esophagectomy , Female , Humans , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Metastasis , Neoplasm Recurrence, Local , Neoplasm Staging , Proportional Hazards Models , Salvage Therapy
3.
Ann Oncol ; 31(3): 404-411, 2020 03.
Article in English | MEDLINE | ID: mdl-32067682

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined. PATIENTS AND METHODS: To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB. RESULTS: We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different [PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141]. CONCLUSIONS: PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Phospholipase D/metabolism , Apoptosis , B7-H1 Antigen/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Programmed Cell Death 1 Receptor , Retrospective Studies , Smokers
4.
Dis Esophagus ; 33(3)2020 Mar 16.
Article in English | MEDLINE | ID: mdl-31313820

ABSTRACT

The survival advantage associated with the addition of surgical therapy in esophageal squamous cell carcinoma (ESCC) patients who demonstrate a complete clinical response to chemoradiotherapy is unclear, and many institutions have adopted an organ-preserving strategy of selective surgery in this population. We sought to characterize our institutional experience of salvage esophagectomy (for failure of definitive bimodality therapy) and planned esophagectomy (as a component of trimodality therapy) by retrospectively analyzing patients with ESCC of the thoracic esophagus and GEJ who underwent esophagectomy following chemoradiotherapy between 2004 and 2016. Of 76 patients who met inclusion criteria, 46.1% (35) underwent salvage esophagectomy. Major postoperative complications (major cardiovascular and pulmonary events, anastomotic leak [grade ≥ 2], and 90-day mortality) were frequent and occurred in 52.6% of the cohort (planned resection: 36.6% [15/41]; salvage esophagectomy: 71.4% [25/35]). Observed rates of 30- and 90-day mortality for the entire cohort were 7.9% (planned: 7.3% [3/41]; salvage: 8.6% [3/35]) and 13.2% (planned: 9.8% [4/41]; salvage: 17.1% [6/35]), respectively. In summary, esophagectomy following chemoradiotherapy for ESCC at our institution has been associated with frequent postoperative morbidity and considerable rates of mortality in both planned and salvage settings. Although a selective approach to surgery may permit organ preservation in many patients with ESCC, these results highlight that salvage esophagectomy for failure of definitive-intent treatment of ESCC may also constitute a difficult clinical undertaking in some cases.


Subject(s)
Chemoradiotherapy , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Esophagectomy , Postoperative Complications , Chemoradiotherapy/adverse effects , Chemoradiotherapy/methods , Combined Modality Therapy/methods , Combined Modality Therapy/statistics & numerical data , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophageal Neoplasms/surgery , Esophageal Squamous Cell Carcinoma/mortality , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/surgery , Esophagectomy/adverse effects , Esophagectomy/methods , Female , Humans , Male , Middle Aged , Neoplasm Staging , Outcome and Process Assessment, Health Care , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Salvage Therapy/methods , Salvage Therapy/statistics & numerical data
5.
Ann Oncol ; 28(5): 1124-1129, 2017 05 01.
Article in English | MEDLINE | ID: mdl-28453699

ABSTRACT

Background: Genetic variations in MicroRNA (miRNA) binding sites may alter structural accessibility of miRNA binding sites to modulate risk of cancer. This large-scale integrative multistage study was aimed to evaluate the interplay of genetic variations in miRNA binding sites of iron regulatory pathway, dietary iron intake and lung cancer (LC) risk. Patients and methods: The interplay of genetic variant, dietary iron intake and LC risk was assessed in large-scale case-control study. Functional characterization of the validated SNP and analysis of target miRNAs were performed. Results: We found that the miRNA binding site SNP rs1062980 in 3' UTR of Iron-Responsive Element Binding protein 2 gene (IREB2) was associated with a 14% reduced LC risk (P value = 4.9×10 - 9). Comparing to AA genotype, GG genotype was associated with a 27% reduced LC risk. This association was evident in males and ever-smokers but not in females and never-smokers. Higher level of dietary iron intake was significantly associated with 39% reduced LC risk (P value = 2.0×10 - 8). This association was only present in individuals with AG + AA genotypes with a 46% reduced risk (P value = 1.0×10 - 10), but not in GG genotype. The eQTL-analysis showed that rs1062980 significantly alters IREB2 expression level. Rs1062980 is predicted to alter a miR-29 binding site on IREB2 and indeed the expression of miR-29 is inversely correlated with IREB2 expression. Further, we found that higher circulating miR-29a level was significantly associated with 78% increased LC risk. Conclusion: The miRNA binding site SNP rs1062980 in iron regulatory pathway, which may alter the expression of IREB2 potentially through modulating the binding of miR-29a, together with dietary iron intake may modify risk of LC both individually and jointly. These discoveries reveal novel pathway for understanding lung cancer tumorigenesis and risk stratification.


Subject(s)
Iron, Dietary/metabolism , Lung Neoplasms/genetics , MicroRNAs/genetics , Polymorphism, Single Nucleotide , Genetic Association Studies , Genetic Loci , Genetic Predisposition to Disease , Humans , Lung Neoplasms/metabolism , Metabolic Networks and Pathways/genetics , Risk Factors
6.
Ann Oncol ; 28(7): 1625-1630, 2017 Jul 01.
Article in English | MEDLINE | ID: mdl-28383694

ABSTRACT

BACKGROUND: Cancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatic analyses, The Cancer Genome Atlas (TCGA) project has identified panels of somatic mutations that contributed to the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these significantly mutated genes (SMGs) and lung cancer susceptibility. PATIENTS AND METHODS: We comprehensively evaluated 1655 tagged single nucleotide polymorphisms (SNPs) located in 127 SMGs identified by TCGA, and test their association with lung cancer risk in large-scale case-control study. Functional effect of the validated SNPs, gene mutation frequency and pathways were analyzed. RESULTS: We found 11 SNPs in 8 genes showed consistent association (P < 0.1) and 8 SNPs significantly associated with lung cancer risk (P < 0.05) in both discovery and validation phases. The most significant association was rs10412613 in PPP2R1A, with the minor G allele associated with a decreased risk of lung cancer [odds ratio = 0.91, 95% confidence interval (CI): 0.87-0.96, P = 2.3 × 10-4]. Cumulative analysis of risk score built as a weight sum of the 11 SNPs showed consistently elevated risk with increasing risk score (P for trend = 9.5 × 10-9). In stratified analyses, the association of PPP2R1A:rs10412613 and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The expression quantitative trait loci analysis indicated that rs10412613, rs10804682, rs635469 and rs6742399 genotypes significantly correlated with the expression of PPP2R1A, ATR, SETBP1 and ERBB4, respectively. From TCGA data, expression of the identified genes was significantly different in lung tumors compared with normal tissues, and the genes' highest mutation frequency was found in lung cancers. Integrative pathway analysis indicated the identified genes were mainly involved in AKT/NF-κB regulatory pathway suggesting the underlying biological processes. CONCLUSION: This study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development.


Subject(s)
Biomarkers, Tumor/genetics , Cell Transformation, Neoplastic/genetics , Lung Neoplasms/genetics , Mutation , Polymorphism, Single Nucleotide , Aged , Case-Control Studies , Chi-Square Distribution , Female , Gene Frequency , Gene Regulatory Networks , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Logistic Models , Lung Neoplasms/diagnosis , Male , Middle Aged , Molecular Diagnostic Techniques , Multivariate Analysis , Odds Ratio , Phenotype , Predictive Value of Tests , Quantitative Trait Loci , Reproducibility of Results , Risk Factors
7.
Vet Immunol Immunopathol ; 175: 42-50, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27269791

ABSTRACT

The objective of this study was to investigate the impact of oral meloxicam (MEL) and long-distance transportation on cell-mediated immunity (CMI) in preconditioned steers receiving a booster vaccination on arrival. We hypothesized that steers treated with MEL at 1mg/kg body weight, 6h before night-time transport, would be less immunocompromised on arrival (day 0) and after 7days, and that CMI following vaccination with a modified live bovine viral diarrhea virus (BVDV) recall antigen would be increased. Brahman crossbreed steers, 13-17 months of age (n=87), were randomly assigned to one of four treatment groups: MEL, transported (MTR) (n=22), MEL, non-transported (MNT) (n=22), lactose placebo, transported (CTR) (n=21), and lactose placebo, non-transported (CNT) (n=22). MTR and CTR steers were transported for approximately 16h non-stop on a truck from Mississippi to Iowa (approximately 1300km), whereas steers in the MNT and CNT groups remained in Mississippi as non-transported controls. Body weight was measured and jugular blood was collected at -1, 0, and 7days from all steers at the same time, regardless of location. Multi-parameter flow cytometry (MP-FCM) was used to identify T-cell subsets and detect the expression of three activation markers (CD25 [interleukin (IL)-2 receptor], intracellular interferon-gamma [IFNγ], and IL-4) after in vitro stimulation with BVDV recall antigen. Plasma cortisol concentration was measured on day -1, 0, and 7 as a marker of transport-associated stress. Serum antibody titer to BVDV was assessed on day -1 and day 7 post-booster vaccination. Whole-blood samples were analyzed using MP-FCM on days 0 and 7. Results were log transformed and analyzed using repeated measures of analysis of variance. Compared with non-transported controls, transport led to an increase in BVDV-induced expression of CD25, IFNγ, and IL-4 in CD4(+), CD8(+), and γδ(+) T-cell subsets (P<0.05). MEL treatment mitigated the transportation-associated increase in CD25 expression by peripheral blood mononuclear cells (PBMCs), CD4(+), and γδ(+) T cells. CMI outputs for the MTR group were less than those of the CTR group (P<0.05); however, the MTR and NT groups did not differ (P>0.10). A treatment*transport interaction was noted for the increase in IL-4 expression by CD8(+) T cells after transport, with a significant difference between the CTR and MTR groups at day 7. In conclusion, the use of oral MEL prior to transport appears to have inhibitory or homeostatic effects, but further research is needed to validate the effect of MEL treatment on specific T-cell subsets in transported cattle.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Cattle/immunology , Diarrhea Viruses, Bovine Viral/immunology , Thiazines/administration & dosage , Thiazoles/administration & dosage , Viral Vaccines/administration & dosage , Animals , Anti-Inflammatory Agents, Non-Steroidal/blood , Antibodies, Viral/blood , Bovine Virus Diarrhea-Mucosal Disease/immunology , Bovine Virus Diarrhea-Mucosal Disease/prevention & control , Cattle/blood , Cattle/virology , Hydrocortisone/blood , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Immunization, Secondary , Immunocompromised Host/drug effects , Immunocompromised Host/immunology , Male , Meloxicam , Stress, Physiological/drug effects , Stress, Physiological/immunology , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , Thiazines/blood , Thiazoles/blood , Transportation , Vaccines, Attenuated/administration & dosage
8.
Clin Pharmacol Ther ; 96(5): 609-15, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25054431

ABSTRACT

Definitive radiotherapy improves locoregional control and survival in inoperable non-small cell lung cancer patients. However, radiation-induced toxicities (pneumonitis/esophagitis) are common dose-limiting inflammatory conditions. We therefore conducted a pathway-based analysis to identify inflammation-related single-nucleotide polymorphisms associated with radiation-induced pneumonitis or esophagitis. A total of 11,930 single-nucleotide polymorphisms were genotyped in 201 stage I-III non-small cell lung cancer patients treated with definitive radiotherapy. Validation was performed in an additional 220 non-small cell lung cancer cases. After validation, 19 single-nucleotide polymorphisms remained significant. A polygenic risk score was generated to summarize the effect from validated single-nucleotide polymorphisms. Significant improvements in discriminative ability were observed when the polygenic risk score was added into the clinical/epidemiological variable-based model. We then used 277 lymphoblastoid cell lines to assess radiation sensitivity and expression quantitative trait loci (eQTL) relationships of the identified single-nucleotide polymorphisms. Three genes (PRKCE, DDX58, and TNFSF7) were associated with radiation sensitivity. We concluded that inflammation-related genetic variants could contribute to the development of radiation-induced toxicities.


Subject(s)
Carcinoma, Non-Small-Cell Lung/radiotherapy , Inflammation/complications , Lung Neoplasms/radiotherapy , Polymorphism, Single Nucleotide , Aged , Carcinoma, Non-Small-Cell Lung/genetics , Female , Genetic Variation , Humans , Inflammation/genetics , Lung Neoplasms/genetics , Male , Middle Aged , Radiation Tolerance , Radiotherapy/adverse effects
9.
Clin Pharmacol Ther ; 95(6): 636-43, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24503627

ABSTRACT

The influence of warfarin pharmacogenomics on major bleeding risk has been little studied in long-term users and non-specialist care settings. We conducted a case-control study to evaluate associations between CYP2C9*2/*3, VKORC1(1173), and CYP4F2*3 variants and major bleeding among patients treated with warfarin in a community setting. We calculated major bleeding odds ratios, adjusting for race, duration of warfarin use, age, gender, and body mass index. In 265 cases and 305 controls with 3.4 and 3.7 mean years of warfarin use, respectively, CYP4F2*3 was associated with decreased major bleeding risk (odds ratio: 0.62; 95% confidence interval: 0.43-0.91). CYP2C9*2/*3 and VKORC1(1173) had null associations overall, but there was a nonsignificant increase in major bleeding risk in patients with duration <6 months (odds ratio: 1.30; 95% confidence interval: 0.60-2.83; odds ratio: 1.23; 95% confidence interval: 0.57-2.64, respectively). In summary, in the largest study of warfarin pharmacogenomics and major bleeding to date, we found a 38% lower risk in patients with CYP4F2*3, potentially reflecting interaction with warfarin and dietary vitamin K intake and warranting additional evaluation.


Subject(s)
Anticoagulants/adverse effects , Hemorrhage/chemically induced , Hemorrhage/genetics , Warfarin/adverse effects , Aged , Aryl Hydrocarbon Hydroxylases/genetics , Aryl Hydrocarbon Hydroxylases/metabolism , Case-Control Studies , Cytochrome P-450 CYP2C9 , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 4 , Diet , Drug Interactions , Ethnicity , Female , Genetic Association Studies , Hemorrhage/epidemiology , Humans , International Normalized Ratio , Male , Risk Factors , Sex Characteristics , Washington/epidemiology
10.
Ann Oncol ; 24(11): 2844-9, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23975663

ABSTRACT

BACKGROUND: The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR). METHODS: Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5-6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used. RESULTS: One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63-NA], with median OS 45.62 months (95% CI 25.56-NA) in Arm A and 43.68 months (95% CI 27.63-NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms. CONCLUSIONS: These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial. Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov).


Subject(s)
Chemoradiotherapy , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/radiotherapy , Induction Chemotherapy , Adult , Aged , Bayes Theorem , Cisplatin/administration & dosage , Combined Modality Therapy , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophageal Neoplasms/surgery , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Preoperative Period , Remission Induction
11.
Vet Pathol ; 49(6): 900-12, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22461226

ABSTRACT

The objective of this report was to characterize the enhanced clinical disease and lung lesions observed in pigs vaccinated with inactivated H1N2 swine δ-cluster influenza A virus and challenged with pandemic 2009 A/H1N1 human influenza virus. Eighty-four, 6-week-old, cross-bred pigs were randomly allocated into 3 groups of 28 pigs to represent vaccinated/challenged (V/C), non-vaccinated/challenged (NV/C), and non-vaccinated/non-challenged (NV/NC) control groups. Pigs were intratracheally inoculated with pH1N1 and euthanized at 1, 2, 5, and 21 days post inoculation (dpi). Macroscopically, V/C pigs demonstrated greater percentages of pneumonia compared to NV/C pigs. Histologically, V/C pigs demonstrated severe bronchointerstitial pneumonia with necrotizing bronchiolitis accompanied by interlobular and alveolar edema and hemorrhage at 1 and 2 dpi. The magnitude of peribronchiolar lymphocytic cuffing was greater in V/C pigs by 5 dpi. Microscopic lung lesion scores were significantly higher in the V/C pigs at 2 and 5 dpi compared to NV/C and NV/NC pigs. Elevated TNF-α, IL-1ß, IL-6, and IL-8 were detected in bronchoalveolar lavage fluid at all time points in V/C pigs compared to NV/C pigs. These data suggest H1 inactivated vaccines followed by heterologous challenge resulted in potentiated clinical signs and enhanced pulmonary lesions and correlated with an elevated proinflammatory cytokine response in the lung. The lung alterations and host immune response are consistent with the vaccine-associated enhanced respiratory disease (VAERD) clinical outcome observed reproducibly in this swine model.


Subject(s)
Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H1N2 Subtype/immunology , Influenza Vaccines/adverse effects , Orthomyxoviridae Infections/veterinary , Pneumonia, Viral/veterinary , Swine Diseases/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antibodies, Viral/immunology , Bronchoalveolar Lavage Fluid , Cytokines/analysis , Cytokines/metabolism , Disease Models, Animal , Influenza A Virus, H1N1 Subtype/pathogenicity , Influenza Vaccines/administration & dosage , Kinetics , Lung/pathology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Severity of Illness Index , Swine , Swine Diseases/pathology , Swine Diseases/prevention & control , Swine Diseases/virology , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/adverse effects , Virus Replication , Virus Shedding
12.
Vet Pathol ; 48(3): 584-92, 2011 May.
Article in English | MEDLINE | ID: mdl-20930105

ABSTRACT

The objective of this study was to develop an intestinal model of Mycobacterium avium subspecies paratuberculosis (Map) infection in the calf for evaluation of mucosal pathology and local and systemic immunologic responses. Map was inoculated into Peyer's patches of young calves using a right flank surgical approach in standing calves to exteriorize the ileocecal junction. Inoculum doses ranging from 10(3) to 10(9) colony-forming units of strain K10 Map were injected through the serosal surface into Peyer's patches of the distal ileum near the ileocecal valve. Fecal samples were collected for culture from each calf weekly until termination of the study. Calves were necropsied at 7, 30, 60, and 90 days after infection, when inoculation sites, lymph nodes, spleen, and peripheral blood were collected for evaluation. Ileocecal lymph nodes were consistently colonized by Map in the 10(5) to 10(9) groups. The ileocecal valve was also colonized in 10(7) and 10(9) groups. This correlated with fecal culture results as infected calves intermittently shed Map in their feces throughout the study. Granulomatous lesions with giant cells and acid-fast bacilli at the ileocecal junction, ileocecal lymph nodes, and lamina propria of high-dose animals (10(7) and 10(9)) were identified from each time point. Flow cytometry was used to detect antigen-specific production of interferon-γ and interleukin-4 locally (ileocecal lymph node) and systemically (peripheral blood mononuclear cells), which defined distinct immunologic profiles in low-dose and high-dose calves. This study demonstrates intestinal Map infection via Peyer's patch inoculation, a novel model with many shared features of natural Map infection.


Subject(s)
Cattle Diseases/microbiology , Intestines/microbiology , Mycobacterium avium subsp. paratuberculosis , Paratuberculosis/microbiology , Peyer's Patches/microbiology , Animals , Cattle , Cattle Diseases/immunology , Immunity, Humoral , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-2 Receptor alpha Subunit/genetics , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-4/genetics , Interleukin-4/metabolism , Intestines/immunology , Male , Paratuberculosis/pathology , Peyer's Patches/immunology , T-Lymphocyte Subsets
13.
J Laryngol Otol ; 123(10): 1082-6, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19575841

ABSTRACT

OBJECTIVE: Ossicular chain damage from chronic ear disease is a significant problem in the Australian population. The ideal ossicular chain reconstruction prosthesis has yet to be defined. This paper examines, for the first time, the use of a titanium prosthesis for ossicular chain reconstruction in Australian patients. STUDY DESIGN: Retrospective chart review. SUBJECTS AND METHODS: All patients undergoing ossicular chain reconstruction with a titanium prosthesis between 1 February 2002 and 31 March 2007. RESULTS: Results showed a low complication rate, with only one extrusion out of 55 cases (1.8 per cent). Successful rehabilitation of conductive hearing loss (i.e. to < or =20 dB air-bone gap) was obtained in 85 per cent of the partial ossicular chain reconstruction group and 77 per cent of the total ossicular chain reconstruction group. Pure tone thresholds improved by an average 18 dB in the partial reconstruction group and 25 dB in the total reconstruction group. CONCLUSION: Titanium is an ideal material for ossicular chain reconstruction due to its ease of insertion, low rate of extrusion and good functional results.


Subject(s)
Ear Ossicles/surgery , Hearing Loss, Conductive/surgery , Ossicular Prosthesis , Ossicular Replacement/methods , Titanium/therapeutic use , Adolescent , Adult , Aged , Australia , Child , Female , Humans , Male , Middle Aged , Recovery of Function , Retrospective Studies , Treatment Outcome , Young Adult
14.
Cancer Gene Ther ; 15(1): 29-39, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17828283

ABSTRACT

FUS1 is a novel tumor suppressor gene located in the human chromosome 3p21.3 region. We previously showed that restoration of FUS1 function in 3p21.3-deficient human non-small-cell lung cancer (NSCLC) cells significantly inhibited tumor cell growth in vitro and in vivo. In this study, we evaluated the combined effects of the tumor suppressor FUS1 and the chemotherapeutic drug cisplatin on tumor cell growth and apoptosis induction in NSCLC cells, and explored the molecular mechanism of their mutual action. Exogenous expression of FUS1 by nanoparticle-mediated gene transfer sensitized the response of NSCLC cells to cisplatin, resulting in a 4- to 6-fold increase in tumor-suppressing activity. A systemic treatment with a combination of FUS1-nanoparticles and cisplatin in a human H322 lung cancer orthotopic xenograft mouse model dramatically enhanced the therapeutic efficacy of cisplatin. We also found that the FUS1-enhanced chemosensitivity is associated with the downregulation of MDM2, accumulation of p53 and activation of the Apaf-1-dependent apoptosis pathway. Our results demonstrated an important role of FUS1 in modulating chemosensitivity of lung cancer cells, and suggested that a proper combination of molecular therapeutics such as the proapoptotic tumor suppressor FUS1 and the conventional chemotherapeutic drugs such as cisplatin may be an efficient treatment strategy for human lung cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/therapy , Cisplatin/pharmacology , Genetic Therapy , Lung Neoplasms/therapy , Tumor Suppressor Proteins/biosynthesis , Animals , Apoptotic Protease-Activating Factor 1/biosynthesis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Chromosomes, Human, Pair 3/genetics , Chromosomes, Human, Pair 3/metabolism , Down-Regulation , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Gene Transfer Techniques , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mice , Nanoparticles , Proto-Oncogene Proteins c-mdm2/biosynthesis , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Proteins/genetics , Xenograft Model Antitumor Assays
15.
Cancer Gene Ther ; 14(1): 12-8, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17024233

ABSTRACT

Our previous studies demonstrated that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7 (Ad-mda7) leads to rapid induction of double-stranded RNA-dependent protein kinase (PKR) and activation of its downstream targets, resulting in apoptosis induction in human lung cancer cells. Here, we report that Ad-mda7 and the benzoquinone ansamycin geldanamycin (GA) interact in a highly synergistic manner to induce cell death in human lung cancer cells. Co-administration of Ad-mda7 and GA did not modify expression of MDA-7, and was not associated with further PKR induction and activation; instead the enhanced cytotoxicity of this combination was associated with inactivation of AKT by GA. By surface staining using anti-E-cadherin monoclonal antibody and flow cytometry, we found that treatment with the combination of Ad-mda7 and GA increased E-cadherin levels in these cancer cells. Ad-mda7 and GA cotreatment also inhibited lung cancer cell motility by increasing the beta-catenin/E-cadherin association. Moreover, combination of GA derivative 17-allyl-amino, 17-demethoxygeldanamycin (17AAG), with Ad-mda7 resulted in enhancement of cell death in A549 and H460 human lung cancer cells.


Subject(s)
Adenoviridae/genetics , Benzoquinones/pharmacology , Cell Survival/drug effects , Lactams, Macrocyclic/pharmacology , Lung Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Benzoquinones/chemistry , Blotting, Western , Cell Line, Tumor , Flow Cytometry , Fluorescent Antibody Technique , Genetic Vectors , Humans , Lactams, Macrocyclic/chemistry
16.
Dis Esophagus ; 19(3): 152-7, 2006.
Article in English | MEDLINE | ID: mdl-16722991

ABSTRACT

The purpose of this study was to identify gender-dependent differences in presentation at baseline and therapy outcome in esophageal carcinoma patients treated with preoperative chemoradiotherapy (CTRT). We stratified patients according to gender and statistically compared pretreatment clinical stage, post-CTRT effect on carcinoma in the resected specimen, overall survival (OS), and patterns of failure. Of the 235 patients who underwent preoperative CTRT, 203 were men and 32 were women. Carcinomas in women correlated significantly with clinical stage II classification (78%vs. 55%) while cancers in men correlated significantly with clinical stage III classification (39%vs. 16%; P = 0.02). Carcinomas in women also correlated significantly with lower clinical N classification; more women had cN0 (52%) compared to men (28%; P = 0.01). Similarly, in the surgical specimens, more women had pN0 (78%) compared to men (64%; P = 0.06). At a median follow-up of 37 months, 10% more women than men remain alive (63%vs. 53%; P = 0.3). Distant metastases-free survival time was longer for women than men. Our results suggest that localized esophageal carcinoma is diagnosed in more advanced stages in men than in women. The reasons for these differences remain unclear and further expansion of these observations and study of biologic differences that might exist are warranted.


Subject(s)
Chemotherapy, Adjuvant , Esophageal Neoplasms/epidemiology , Esophageal Neoplasms/therapy , Neoadjuvant Therapy , Radiotherapy, Adjuvant , Disease Progression , Disease-Free Survival , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/pathology , Female , Humans , Male , Neoplasm Recurrence, Local/epidemiology , Neoplasm Staging , Prognosis , Retrospective Studies , Sex Factors , Treatment Outcome
17.
Cancer Gene Ther ; 13(8): 806-14, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16628227

ABSTRACT

Adenoviral delivery of the p53 gene is a potential therapeutic approach for the treatment of lung cancer. Furthermore, amifostine is a cytoprotective agent and recent reports have described its potentiation of chemotherapy's antitumor activity in lung cancer. Therefore, we wished to investigate the ability of amifostine both alone and in combination with p53-based therapy to induce apoptosis, and to understand the mechanisms by which this apoptosis occurs. Using p53 null and wild-type p53 human lung cancer cells and normal human bronchial epithelial cells, we evaluated the effects of amifostine on proliferation and apoptosis. We then analyzed Adp53 in combination with amifostine and performed isobologram analysis. Expression of p53, p21(WAF1), Bax, Bak, bcl-2, as well as total and phosphorylated Cdc2 in the absence and presence of olomoucine, a phosphorylated Cdc2 kinase inhibitor, was then determined. Amifostine-induced apoptosis in human lung cancer cells in a dose-dependent fashion. The combination of amifostine and Adp53 significantly enhanced, with a supra-additive effect, the inhibition of proliferation of lung cancer cells. This enhancement of apoptosis by amifostine was associated with activation of p53 and dephosphorylation of Cdc2 proteins. Notably, olomoucine effectively prevented amifostine and/or Adp53-induced Cdc2 kinase activation and subsequent apoptosis. Our data shows that amifostine alone can induce apoptosis of human lung cancer cells, and that the combination of Adp53 with amifostine resulted in significantly higher levels of apoptosis. In addition, it appears that Cdc2 kinase plays an important role in the induction of apoptosis by amifostine and Adp53.


Subject(s)
Amifostine/therapeutic use , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Genes, p53/genetics , Genetic Therapy/methods , Lung Neoplasms/therapy , Adenoviridae , Apoptosis/genetics , CDC2 Protein Kinase/physiology , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Combined Modality Therapy , Cyclin-Dependent Kinase Inhibitor p21/genetics , Gene Expression , Genes, bcl-2/genetics , Genetic Vectors , Humans , Lung Neoplasms/genetics , bcl-2 Homologous Antagonist-Killer Protein/genetics , bcl-2-Associated X Protein/genetics
18.
Cancer Gene Ther ; 13(1): 82-90, 2006 Jan 01.
Article in English | MEDLINE | ID: mdl-16037823

ABSTRACT

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy and oncolytic adenovirotherapy have been investigated extensively in xenografic human tumor models established in immunocompromised nude mice. However, the effects of these therapies on syngeneic murine tumors in immunocompetent settings were not well documented. We hypothesized that TRAIL gene therapy used with an oncolytic adenovirus would overcome the weaknesses of the two therapies used individually. In this study, we evaluated the antitumor effects of an oncolytic adenovirus, Delta24, in both human and murine breast cancer cell lines. We also analyzed the effects of TRAIL gene therapy combined with oncolytic virotherapy in these cancer cells. Our results showed that Delta24 can replicate and help the E1-deleted adenovector replicate in murine cancer cells. We also found that these two therapies combined had greater antitumor activity than either one alone in both human and murine breast cancer cells lines and in the syngeneic breast cancer models established in immunocompetent mice. Moreover, Delta24 virotherapy alone and combined with TRAIL gene therapy dramatically reduced the spontaneous liver metastasis that originated in the subcutaneous 4T1 tumor established in Balb/c mice. These findings provide important considerations in the development and preclinical assessments of oncolytic virotherapy.


Subject(s)
Adenoviridae/metabolism , Apoptosis Regulatory Proteins/therapeutic use , Membrane Glycoproteins/therapeutic use , Oncolytic Virotherapy/methods , Tumor Necrosis Factor-alpha/therapeutic use , Adenoviridae/genetics , Adenovirus E1A Proteins/metabolism , Animals , Apoptosis Regulatory Proteins/genetics , Evaluation Studies as Topic , Female , Genetic Vectors/therapeutic use , Humans , Immunocompetence , Membrane Glycoproteins/genetics , Mice , Mice, Inbred BALB C , TNF-Related Apoptosis-Inducing Ligand , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/genetics
19.
Environ Pollut ; 142(2): 354-66, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16343714

ABSTRACT

Higher ozone concentrations east of southern Lake Michigan compared to west of the lake were used to test hypotheses about injury and growth effects on two plant species. We measured approximately 1000 black cherry trees and over 3000 milkweed stems from 1999 to 2001 for this purpose. Black cherry branch elongation and milkweed growth and pod formation were significantly higher west of Lake Michigan while ozone injury was greater east of Lake Michigan. Using classification and regression tree (CART) analyses we determined that departures from normal precipitation, soil nitrogen and ozone exposure/peak hourly concentrations were the most important variables affecting cherry branch elongation, and milkweed stem height and pod formation. The effects of ozone were not consistently comparable with the effects of soil nutrients, weather, insect or disease injury, and depended on species. Ozone SUM06 exposures greater than 13 ppm-h decreased cherry branch elongation 18%; peak 1-h exposures greater than 93 ppb reduced milkweed stem height 13%; and peak 1-h concentrations greater than 98 ppb reduced pod formation 11% in milkweed.


Subject(s)
Air Pollution/adverse effects , Asclepias/growth & development , Oxidants, Photochemical/toxicity , Ozone/toxicity , Prunus/growth & development , Air Pollution/analysis , Climate , Environmental Monitoring/methods , Fertilizers/analysis , Fresh Water , Michigan , Nitrogen/analysis , Oxidants, Photochemical/analysis , Ozone/analysis , Plant Leaves/growth & development , Soil/analysis
20.
Dis Esophagus ; 17(1): 38-43, 2004.
Article in English | MEDLINE | ID: mdl-15209739

ABSTRACT

Pathologic complete response in the resected esophagus can be achieved in approximately 30% of patients with locally advanced esophageal or gastroesophageal junction carcinoma after preoperative chemoradiation therapy. These patients tend to have a longer survival than those who have less than pathologic complete response. Post-chemoradiation esophageal biopsy (PCEB) is used to check for the presence of residual tumor before a definitive resection is performed, but the clinical significance of PCEB findings is not clear due to the possibility of sampling bias and the superficial nature of the specimen obtained. We evaluated the use of PCEB (defined as biopsy taken within 30 days before esophagectomy) in predicting residual cancer in post-treatment esophagectomy specimens. PCEB was performed in 65 of 183 (36%) patients with locally advanced esophageal or gastroesophageal junction carcinoma, who received preoperative chemoradiation therapy. The cancer status in PCEB was correlated with the residual cancer in the esophagectomy specimens. PCEB had no cancer in 80% (52 of 65) of patients (Bx-negative) and cancer in 20% (13 of 65) of patients (Bx-positive). There was no difference in the presence of residual cancer (either in esophagus or lymph node) in esophagectomy specimens between Bx-negative patients (77%, 40 of 52) or Bx-positive patients (92%, 12 of 13), P = 0.44. The positive predictive value of biopsy was 92% (12 of 13), negative predictive value 23% (12 of 52), sensitivity 23% (12 of 52) and specificity 92% (12 of 13). There was no difference in the residual cancer staging in the esophagectomy specimen between Bx-positive and Bx-negative patients. In contrast, residual metastatic carcinoma in lymph nodes was more frequent in Bx-positive patients (69.2%, 9 of 13) than in Bx-negative patients (28.8%, 15 of 52), P = 0.01. Our data suggest that PCEB is a specific but not a sensitive predictor of residual cancer following esophagectomy. Bx-positive patients tend to have more frequent residual tumor in lymph nodes. The utility of PCEB in predicting residual cancer in the lymph nodes needs to be explored further along with molecular predictors of response to preoperative therapy.


Subject(s)
Biopsy, Needle , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Esophagogastric Junction/pathology , Neoplasm, Residual/pathology , Chemotherapy, Adjuvant , Combined Modality Therapy , Esophageal Neoplasms/mortality , Esophagectomy/methods , Esophagectomy/mortality , Esophagogastric Junction/surgery , Female , Humans , Immunohistochemistry , Male , Neoplasm Staging , Postoperative Care , Predictive Value of Tests , Preoperative Care/methods , Probability , Prognosis , Radiotherapy, Adjuvant , Retrospective Studies , Sensitivity and Specificity , Survival Analysis
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