Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy.

BACKGROUND: Modulating the DNA damage response and repair (DDR) pathways is a promising strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related protein, which is crucial for DDR. PATIENTS AND METHODS: This phase II trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma who had failed anti-programmed cell death protein 1 therapy. RESULTS: Among the 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Responses were evident across patients with acral, mucosal, and cutaneous melanoma. The median duration of response was 8.8 months (range, 3.8-11.7 months). The median progression-free survival was 7.1 months (95% confidence interval, 3.6-10.6 months), and the median overall survival was 14.2 months (95% confidence interval, 9.3-19.1 months). Common adverse events were largely hematologic and manageable with dose interruptions and reductions. Exploratory biomarker analysis suggested that tumors with an immune-enriched microenvironment or alterations in the DDR pathway were more likely to respond to the study treatment. CONCLUSION: We conclude that ceralasertib in combination with durvalumab has promising antitumor activity among patients with metastatic melanoma who have failed anti-programmed cell death protein 1 therapy, and constitute a population with unmet needs.

HLA-corrected tumor mutation burden and homologous recombination deficiency for the prediction of response to PD-(L)1 blockade in advanced non-small-cell lung cancer patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited response to ICIs remain unclear. PATIENTS AND METHODS: We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients. RESULTS: Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLC patients and 110 melanoma patients, TMB-based survival prediction was significantly improved. CONCLUSION: HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.

Is the Clinical Outcome Good or Bad in Patients Hospitalized Within 1 Year After Kidney Transplantation?

BACKGROUND: Although the hospitalization rate at early period of kidney transplantation (KT) is still high, the association between the hospitalization within 1 year after KT and graft survival is unclear. We investigated the incidence and causes of hospitalization and clinical outcome of the patients hospitalized within 1 year after KT. METHODS: We retrospectively analyzed 174 KT recipients (KTRs) hospitalized within 1 year after KT between 2013 and 2015. RESULTS: Among them, 84 (48%) KTRs were admitted within 1 year after KT, and the number of hospitalizations was 116. The mean time from KT to first hospitalization was 4.2 months. Seventy-eight percent of the patients were hospitalized for medical causes and 22% for surgical causes. The most common cause was cytomegalovirus infection (CMV) (23.3%), followed by acute rejection (11.2%) and urinary tract infection (10.3%). Recipients and donors in the hospitalized group were significantly older than the nonhospitalized group. The proportions of deceased donor KT, acute rejection, more than 50% panel-reactive antibody, and positive donor-specific antibody were significantly higher in the hospitalized group than in the nonhospitalized group. Graft and patient survivals were lower in the hospitalized group than in the nonhospitalized group. Deceased donor KT and acute rejection were independent risk factors for hospitalization. CONCLUSION: The incidence of KTRs hospitalized within 1 year after KT was high. Most causes of hospitalization were CMV infection, acute rejection, and urinary tract infection. Therefore, the immunosuppression status of these patients should be closely monitored to reduce the hospitalization rate.

Clinical Outcomes of Kidney Transplantation in Patients With Biopsy-Proven Glomerulonephritis.

BACKGROUND: The clinical outcomes after kidney transplantation (KT) according to the types of glomerulonephritis (GN) as the cause of end-stage renal disease (ESRD) are various, but there are not many studies on this. METHODS: Among 1,253 patients who had KT between November 1982 and January 2017, 183 recipients with biopsy-proven GN as the primary cause of ESRD were enrolled. We analyzed the incidence of recurrent GN and the factors associated with recurrence and graft and patient survivals. RESULTS: The types of GN were 95 IgA nephropathy, 47 focal segmental glomerulosclerosis, 14 membranous proliferative GN, 9 membranous GN, 8 lupus nephritis, 6 rapid progressive GN, and 4 Alport syndrome. The mean follow-up duration was 103 ± 81.7 months. Recurrence was reported in 36 patients, of which 20 grafts failed due to recurrence. The age of patients with GN recurrence was significantly younger than that of patients without GN recurrence (P = .030). The graft failure rate of KT recipients with recurrent GN was significantly higher than that of the recipients without recurrent GN (55.6% vs 18.4%, P < .001). In multivariate analysis, recurrence of primary GN, the number of HLA mismatches at AB, delayed graft function, and acute rejection were independent risk factors for graft failure. CONCLUSION: Recurrent GN remains a significant cause of graft loss in KT recipients. Surveillance of GN recurrence in the KT recipients with biopsy-proven GN can reduce allograft dysfunction.

Characteristics of Recipients With 10 or More Years of Allograft Survival in Deceased Donor Kidney Transplantation.

BACKGROUND: The development of immunosuppressants improved the short-term outcomes of deceased donor kidney transplantation (DDKT), but the long-term survival rate was not improved. METHODS: The study included 127 patients who received first-time kidneys from deceased donors at Keimyung University Dongsan hospital between October 1994 and June 2007. We analyzed the clinical features of recipients with long-term allograft survival. RESULTS: The mean follow-up period was 163 months. Among the 127 recipients, 53 (41.7%) maintained allograft survival for more than 10 years (AS group), 58 (45.7%) lost allograft function (AL group), and 16 (12.6%) were lost to follow-up. The 5- and 10-year allograft survival rates were 84.7% and 65.5%. The 5- and 10-year patient survival rates were 95.9% and 92.5%. The patient survival rate was significantly higher in the AS group than in the AL group. In the AS group, the use of basiliximab and mycophenolate mofetil (MMF) were significantly higher, and the number of HLA-DR mismatches and the incidence of rejection and infection were significantly lower. In multivariate Cox proportional hazards analysis, the use of MMF reduced the risk of allograft loss (hazard ratio [HR], 0.361; 95% confidence interval [CI], 0.172-0.757; P = .007). On the other hand, the incidence of rejection, hepatitis B virus-related liver cirrhosis (HBV-LC), and viral infection were independent risk factors for allograft loss (HR, 5.327; 95% CI, 2.813-10.090; P < .001; HR, 5.862; 95% CI, 1.891-18.168; P = .002; HR, 2.614; 95% CI, 1.355-5.043; P = .004, respectively). CONCLUSION: For long-term survival of allograft kidney in DDKT, it is important to use appropriate immunosuppressants including MMF and prevent complications such as rejection, HBV-LC, and viral infection.

Progression of Osteoporosis After Kidney Transplantation in Patients With End-Stage Renal Disease.

BACKGROUND: This study investigated the prevalence of osteoporosis and the risk factors for its progression in kidney transplant recipients (KTRs). METHODS: Dual energy X-ray absorptiometry was used to prospectively measure changes in bone mineral density (BMD) before kidney transplantation (KT) and 1 year after transplantation in 207 individuals. We also analyzed the risk factors of osteoporosis progression during this period. RESULTS: Prior to KT, the mean BMD score (T-score of the femur neck area) was -2.1 ± 1.2, and the prevalence of osteoporosis was 41.5% (86/207). At 1 year post-transplantation, the mean BMD score significantly decreased to -2.3 ± 1.1 (P < .001), and the prevalence of osteoporosis increased to 47.3% (98/207; P = .277). The BMD score worsened over the study period in 69.1% (143/207) of patients, improved in 24.1% (50/207), and showed no change in 6.8% (14/207). Minimal intact parathyroid hormone (iPTH) improvement after KT was found to be an independent risk factor of osteoporosis progression. CONCLUSIONS: This study demonstrates progressive loss of BMD after KT and sustained secondary hyperparathyroidism might influence the progression of osteoporosis.

Long-term Clinical Outcome of Aortic Arch Calcification in Kidney Transplant Recipients.

INTRODUCTION: Cardiovascular disease is the most common cause of death in kidney transplant recipients (KTRs). Aortic arch calcification (AoAC) is a major risk factor for cardiovascular disease in KTRs. This study aimed to evaluate the long-term outcomes of AoAC in KTRs. METHODS: We retrospectively evaluated AoAC in KTRs between 2000 and 2010 using chest radiography. AoAC was semiquantitatively estimated by calculating calcification score. Associations between clinical and biochemical parameters were evaluated. RESULTS: A total of 258 patients were enrolled; the mean age was 40.7 years, and 135 (52.3%) were males. Diabetes mellitus was present in 28 (10.9%), and deceased donor kidney transplantation (KT) had been performed in 95 (36.8%). Fifty-three (20.5%) patients had AoAC at the time of KT, with an AoAC score of 0.8 ± 2.0. The proportion of KTRs with AoAC gradually increased to 23.3%, 26.4%, and 28.7% at 1, 3, and 5 years, respectively, after KT. The AoAC score also gradually increased to 1.0 ± 2.3, 1.2 ± 2.8, and 1.6 ± 3.1, respectively, at 1, 3, and 5 years after KT. The 10-year graft survival rate was 83.2% in the AoAC group and 85.1% in the non-AoAC group. The 10-year patient survival rate was 90.6% in the AoAC group and 95.7% in the non-AoAC group. In multivariate analysis, age at KT, deceased-donor KT, and diabetes mellitus were independent predictors for all-cause mortality. CONCLUSIONS: AoAC is an independent predictor of poor cardiovascular outcome in KTRs. Age and dialysis duration were independent risk factors for AoAC. Age at KT, deceased-donor KT, and diabetes mellitus were independent predictors for all-cause mortality. Regular follow-up by chest radiography could be a simple and useful method to screen for AoAC and reduce cardiovascular mortality.

Kidney Transplantation in Korean Patients With End-Stage Renal Disease Aged 65 and Older: A Single-Center Experience.

BACKGROUND: The mean age of patients starting dialysis in Korea has increased to older than 60 years and the proportion of patients aged 65 and older exceeded 40% in 2014. Although the number of elderly dialysis patients is increasing rapidly, percentages of elderly patients undergoing kidney transplantation (KT) are very low. METHODS: We retrospectively reviewed the medical records of patients who underwent KT at Keimyung University Dongsan Medical Center between 1982 and 2016. Elderly patients (≥65 years old) were compared with the control group of patients in their early sixties (60-64 years old). RESULTS: Among a total of 1209 KT patients, those in their early sixties totaled 34 (2.8%) and the elderly totaled only 18 (1.5%). Patient and allograft survival rate showed no significant differences between the elderly and those in their early sixties. Death with a functioning graft accounted for 50% in both groups. However, occurrences of bacterial infection and tuberculosis were higher in the elderly (P = .011 and .047, respectively). In a multivariate analysis, longer duration of renal replacement therapy before KT and the occurrence of malignancy were independent risk factors for patient death (hazard ratio [HR], 1.027; P = .014; HR, 31.934; P = .016, respectively). Also, albuminuria at 6 months after KT was an independent risk factor for allograft loss (HR, 51.155; P = .016). CONCLUSION: The overall survival rate of the elderly was not significantly lower than those in their early sixties. Even in the elderly, KT should not be delayed. In addition, careful surveillance for malignancy and measures to decrease the risk of infection are necessary.

Long-term Clinical Outcomes of First and Second Kidney Transplantation in Patients With Biopsy-Proven IgA Nephropathy.

INTRODUCTION: The recurrence of IgA nephropathy (IgAN) after kidney transplantation (KT) has an effect on graft survival, but there are few reports about long-term clinical outcomes of KT with recurrent IgAN. This study shows the long-term clinical outcomes of KT in patients with IgAN. METHODS: All recipients who had biopsy-proven IgAN were followed from February 1990 to February 2016. We analyzed overall graft and patient survival rates, incidence of recurrent IgAN, factors affecting graft survival, and IgAN recurrence. RESULTS: There were 88 patients with first KT. The mean follow-up duration was 82.5 months. Twenty patients went through graft loss and 1 patient died due to sepsis. IgAN recurred in 15 patients, and 11 patients experienced graft failure. Among the patients who had failed graft after first KT, 7 patients underwent retransplantation. The graft survival period, presence of rejection, and proteinuria were the relevant risk factors for recurrence of IgAN. In the first KT patients, presence of rejection and 1-year serum creatinine were the significant risk factors for graft loss. But recurrence of IgAN was not a relevant risk factor. Overall graft survival rates at 5 and 10 years were 93.8% and 73.1% in the first transplantation group and 100% and 100% in the retransplantation group, respectively. CONCLUSION: Although IgAN recurrence was a significant risk factor for graft failure, the patient who underwent retransplantation showed favorable results. Retransplantation should be considered in patients who lost their first graft after recurrence of IgAN.

Long-term Clinical Outcomes of Kidney Re-transplantation.

BACKGROUND: Kidney re-transplantation is commonly considered to have a higher immunological risk than first kidney transplantation. Because of the organ shortage and increasing waiting lists, long-term outcomes of kidney re-transplantation are being studied. However, reports of re-transplantation outcomes are not common. We have reported our 30 years of experience with second kidney transplantations. METHODS: Of 1210 kidney transplantations between November 1982 and August 2016 performed in our hospital, 105 were second kidney transplantations (2nd KT). Living donor KT was 44; deceased donor KT was 61. RESULTS: Patient survival rates at 1, 5, and 10 years were 100%, 97.2%, and 90.7%, and graft survival rates were 97.0%, 94.6%, and 71.5%, respectively. The leading cause of graft failure in the 2nd KT was chronic rejection (60%). In addition, induction immunosuppressant, maintenance immunosuppressant, delayed graft function, and graft survival time at the 1st KT had a significant impact on graft survival time at the 2nd KT. CONCLUSIONS: Reasonable results in both patient survival and graft survival rates were found in the 2nd KT. Careful monitoring of immunologic risk is needed.

Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration.

Cerebellar degeneration-related protein 2 (cdr2) is expressed in the central nervous system, and its ectopic expression in tumor cells of patients with gynecological malignancies elicits immune responses by cdr2-specific autoantibodies and T lymphocytes, leading to neurological symptoms. However, little is known about the regulation and function of cdr2 in neurodegenerative diseases. Because we found that cdr2 is highly expressed in the midbrain, we investigated the role of cdr2 in experimental models of Parkinson's disease (PD). We found that cdr2 levels were significantly reduced after stereotaxic injection of 1-methyl-4-phenylpyridinium (MPP(+)) into the striatum. cdr2 levels were also decreased in the brains of post-mortem PD patients. Using primary cultures of mesencephalic neurons and MN9D cells, we confirmed that MPP(+) reduces cdr2 in tyrosine hydroxylase-positive dopaminergic neuronal cells. The MPP(+)-induced decrease of cdr2 was primarily caused by calpain- and ubiquitin proteasome system-mediated degradation, and cotreatment with pharmacological inhibitors of these enzymes or overexpression of calcium-binding protein rendered cells less vulnerable to MPP(+)-mediated cytotoxicity. Consequently, overexpression of cdr2 rescued cells from MPP(+)-induced cytotoxicity, whereas knockdown of cdr2 accelerated toxicity. Collectively, our findings provide insights into the novel regulatory mechanism and potentially protective role of onconeural protein during dopaminergic neurodegeneration.

Step-down vs. step-up noxious stimulation: differential effects on pain perception and patterns of brain activation.

BACKGROUND: We hypothesize that pain and brain responses are affected by changes in the presentation sequence of noxious stimuli that are, overall, identical in intensity and duration. METHODS: During functional magnetic resonance imaging (fMRI) scanning, 21 participants experienced three patterns of noxious stimulation: Up-type (step-up noxious stimulation, 15 s), Down-type (step-down noxious stimulation, 15 s), and Down-up-type (decreasing and increasing pattern of noxious stimulation, 15 s). The total intensity and duration of the three noxious stimulation patterns were identical, but the stimulation sequences were different. RESULTS: Pain and unpleasantness ratings in the Down- and Down-up-type noxious stimulations were lower than in the Up-type noxious stimulation. The left prefrontal cortex [(PFC, BA (Brodmann area) 10, (-45, 50, 1)] was more highly activated in the Down- and Down-up-type noxious stimulations than in the Up-type noxious stimulation. The S1, S2, insula, bilateral PFC (BA 46), and midcingulate cortex were more highly activated in the Up-type noxious stimulation than in the Down-type noxious stimulation. PFC BA 10 was located at an inferior level compared to the bilateral PFC BA 46 (Z axis = 1 for BA 10, compared to 22 and 25 for the right and left BA 46, respectively). When cortisol level was increased, the left hippocampal cortex, along with the left parahippocampal cortex, was greatly activated for the Up-type noxious stimulation. CONCLUSION: When pain cannot be avoided in clinical practice, noxious stimuli should be applied to patients in a step-down pattern that delivers the most intense pain first and the least intense pain last.

Effects of dietary garlic powder and {alpha}-tocopherol supplementation on performance, serum cholesterol levels, and meat quality of chicken.

This study was carried out to evaluate the effects of supplementing diets with garlic powder and alpha-tocopherol on performance, serum cholesterol levels, and meat quality of chickens. Three hundred 1-d-old male broiler chicks were assigned to 5 diet treatments (0, 1, 3, and 5% garlic powder and 3% garlic powder + 200 IU of alpha-tocopherol/kg) with 3 replications of 20 birds for 35 d. There were no significant differences in broiler performance among the treatments. Moisture and crude ash contents of chicken thigh muscle were not different among all treatments, but dietary garlic powder and alpha-tocopherol supplementation resulted in significantly higher CP and lower crude fat contents in comparison with control (P < 0.05). Increasing the levels of garlic powder and applying garlic powder plus alpha-tocopherol significantly decreased total and low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol in broiler blood (P < 0.05). The pH and TBA reactive substances values were significantly reduced (P < 0.05) by the inclusion of garlic powder and alpha-tocopherol. However, no significant differences in water-holding capacity or shear force values were observed among the treatments. For broiler thigh muscle color, L* (lightness) values were decreased (P < 0.05), and a* (redness) and b* (yellowness) values were increased (P < 0.05) with the increased garlic powder levels and the combination of garlic powder and alpha-tocopherol. In terms of fatty acid composition in thigh muscle, unlike saturated fatty acid and total saturated fatty acid, dietary garlic powder or garlic powder plus alpha-tocopherol supplementation increased unsaturated fatty acid, total unsaturated fatty acid, and total unsaturated fatty acid:total saturated fatty acid ratios. These results suggest that 5% garlic powder or 3% garlic powder plus 200 IU of alpha-tocopherol antioxidant properties were effective for enhancing lipid and color stability.

Global analysis of CpG methylation reveals epigenetic control of the radiosensitivity in lung cancer cell lines.

Epigenetic regulation by CpG methylation has an important role in tumorigenesis as well as in the response to cancer therapy. To analyze the mechanism of epigenetic control of radiosensitivity, the CpG methylation profiles of radiosensitive H460 and radioresistant H1299 human non-small cell lung cancer (NSCLC) cell lines were analyzed using microarray profiling. These analyses revealed 1091 differentially methylated genes (DMG) (absolute difference of mean beta-values, |Deltabeta |>0.5), including genes involved in cell adhesion, cell communication, signal transduction and transcriptional regulation. Among the 747 genes hypermethylated in radioresistant H1299 cells, CpG methylation of SERPINB5 and S100A6 in radioresistant H1299 cells was confirmed by methylation-specific PCR. Reverse transcriptase-PCR showed higher expression of these two genes in radiosensitive H460 cells compared with radioresistant H1299 cells. Downregulation of SERPINB5 or S100A6 by small interfering RNA in H460 cells increased the resistance of these cells to ionizing radiation. In contrast, promoter CpG sites of 344 genes, including CAT and BNC1, were hypomethylated in radioresistant H1299 cells. Suppression of CAT or BNC1 mRNA expression in H1299 cells also reduced the resistance of these cells to ionizing radiation. Thus, we identified DMGs by genome-wide CpG methylation profiling in two NSCLC cell lines with different responses to ionizing radiation, and our data indicated that these differences may be critical for epigenetic regulation of radiosensitivity in lung cancer cells.

Effects of dietary alpha-tocopherol, selenium, and their different combinations on growth performance and meat quality of broiler chickens.

This study investigated the effect of different levels of dietary supplementation with alpha-tocopherol or Se, or both, on growth performance and meat quality of broiler chickens. A total of 270 broiler chickens were assigned to 6 dietary treatments (0, 50, 100, or 200 IU of supplemental alpha-tocopherol; 0.3 ppm supplemental Se; or 100 IU of alpha-tocopherol plus 0.3 ppm Se) with 3 replicates of 15 chickens per pen. Growth performance was recorded at 1 and 35 d. At the end of this experiment, 10 broilers per pen were slaughtered, and thigh muscle was dissected from each carcass and stored at 4 degrees C for 1, 3, 7, and 10 d. During the experimental period, none of the experimental treatments significantly influenced the growth performance of broilers. Thigh muscle pH values of all treatments decreased over time. The pH values for 1, 3, and 10 d were not affected by all treatments, but a statistical difference among treatments was observed at 7 d. Thiobarbituric acid reactive substances and total plate counts in all treatments increased with increasing storage time. In TBA reactive substances values, there were significant differences (P < 0.05) among treatments during the storage period. Differences among treatments in total plate count were found at d 7 and 10. In all treatments, L* (lightness) and b* (yellowness) values decreased over time, and a* (redness) values increased with storage time. Significant differences in all treatments were found for L* values at 3 d and a* values at 7 and 10 d of storage. Overall, these data indicate that compared with other treatments, supplementation with 200 IU of alpha-tocopherol or 100 IU of alpha-tocopherol plus 0.3 ppm Se were most effective in increasing lipid oxidative stability and delaying microbial growth and these activities were not associated with pH.

The effect of gamma-irradiation on the viability of Cryptosporidium parvum.

Cryptosporidium parvum is 1 of the major causative organisms in waterborne diarrheal illness. Not only does C. parvum spread ubiquitously in our environment, it is also highly resistant to harsh environmental conditions and disinfectants. Therefore, a control measure for this protozoon is urgently required. This study investigated the effect of gamma-irradiation, in the range of 1,000-50,000 Gy, on the viability of C. parvum oocysts. Oocyst viability was determined by a combined indirect immunofluorescence and nucleic acid staining and animal infectivity study. The proportion of viable oocysts estimated by nucleic acid staining ranged from 94.2 to 89.4% in the 0- to 10,000-Gy groups, whereas it was reduced significantly to 58.6 or 45.7% in the 25,000- or 50,000-Gy group, respectively, at 24 hr postirradiation. In an animal infectivity study, oocysts irradiated with less than 10,000 Gy induced infections in mice wherein there were low numbers of oocysts per gram of feces amounting to 8-10.8% of the values in control mice, whereas with 50,000 Gy-irradiated oocysts, no oocysts were produced in the mice. This study suggests that at least 50,000 Gy of gamma-irradiation is necessary for the complete elimination of oocyst infectivity in mice.

Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women.

A case-control study was performed to assess the potential influence of CYP19 Arg(264)Cys and CYP1B1 Leu(432)Val polymorphisms on breast cancer risk in a series of Korean breast cancer patients and controls. The results suggest that the CYP19 Arg(264)Cys polymorphism modifies breast cancer risk (OR=1.5, 95% CI=1.1-2.2), especially in association with alcohol consumption (P for interaction=0.04), whereas the CYP1B1 Leu(432)Val polymorphism appears to play no role here.

Cytokine balance in the lungs of patients with acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) involves an intense inflammatory response in the lungs, with accumulation of both pro- and antiinflammatory cytokines in bronchoalveolar lavage fluid (BALF). Our goal was to determine how the balance between pro- and antiinflammatory mediators in the lungs changes before and after the onset of ARDS. We identified 23 patients at risk for ARDS and 46 with established ARDS and performed serial bronchoalveolar lavage (BAL). We used immunoassays to measure tumor necrosis factor alpha (TNF-alpha) and soluble TNF-alpha receptors I and II; interleukin 1 beta (IL-1 beta), IL-1 beta receptor antagonist, and soluble IL-1 receptor II; IL-6 and soluble IL-6 receptor; and IL-10. We used sensitive bioassays to measure net TNF-alpha, IL-1 beta, and IL-6 activity. Although individual cytokines increased before and after onset of ARDS, greater increases occurred in cognate receptors and/or antagonists, so that molar ratios of agonists/antagonists declined dramatically at the onset of ARDS. The molar ratios remained low for 7 d or longer, limiting the activity of soluble IL-1 beta and TNF-alpha in the lungs at the onset of ARDS. This significant antiinflammatory response early in ARDS may provide a key mechanism for limiting the net inflammatory response in the lungs.

[Application of DNA chip technology to biomedical research].

The completion of Human Genome Project enabled us to access to the information on nucleotide sequences of whole human genome. One of the most valuable information on human genome would be the list of approximately 35,000 genes. Although 35% of them are still needed to annotate their functions, we can genome-widely approach to various conditions including disease states. To analyze bunch of information at once, we need high-throughput technology containing most of genes. DNA chip successfully provide a stable platform technology for the massive screening of genomes. Microarrays can be used to obtain genome-wide fingerprint on transcriptional changes in various physiological and pathological conditions, leading to the mining novel genes related to those specific states. We can check the multiple molecular markers for diagnosis, prediction or prognosis of specific diseases. Data from microarray will provide huge amounts of experssion profile, which might induce the transformation of biomedical research.

Effect of epidural anesthesia and analgesia on perioperative outcome: a randomized, controlled Veterans Affairs cooperative study.

OBJECTIVE: To test the hypothesis that epidural anesthesia and postoperative epidural analgesia decrease the incidence of death and major complications during and after four types of intraabdominal surgical procedures. SUMMARY BACKGROUND DATA: Even though many beneficial aspects of epidural anesthesia have been reported, clinical trials of epidural anesthesia for outcome of surgical patients have shown conflicting results. METHODS: The authors studied 1,021 patients who required anesthesia for one of the intraabdominal aortic, gastric, biliary, or colon operations. They were assigned randomly to receive either general anesthesia and postoperative analgesia with parenteral opioids (group 1) or epidural plus light general anesthesia and postoperative epidural morphine (group 2). The patients were monitored for death and major complications during and for 30 days after surgery, as well as for postoperative pain, time of ambulation, and length of hospital stay. RESULTS: Overall, there was no significant difference in the incidence of death and major complications between the two groups. For abdominal aortic surgical patients, unlike the other three types of surgical patients, the overall incidence of death and major complications was significantly lower in group 2 patients (22%) than in group 1 patients (37%), stemming from differences in the incidence of new myocardial infarction, stroke, and respiratory failure between the two groups. Overall, group 2 patients received significantly less analgesic medication but had better pain relief than group 1 patients. In group 2 aortic patients, endotracheal intubation time was 13 hours shorter and surgical intensive care stay was 3.5 hours shorter. CONCLUSIONS: The effect of anesthetic and postoperative analgesic techniques on perioperative outcome varies with the type of operation performed. Overall, epidural analgesia provides better postoperative pain relief. Epidural anesthesia and epidural analgesia improve the overall outcome and shorten the intubation time and intensive care stay in patients undergoing abdominal aortic operations.