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.

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.

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.

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.

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.

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.

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.

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 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.

Incidence and cardiac effects of systemic venous air embolism. Echocardiographic evidence of arterial embolization via noncardiac shunt.

Central nervous system dysfunction in venous air embolism may result from air entering the arterial circulation. Using two-dimensional and pulsed-wave Doppler echocardiography, this study not only documented the frequent presence of air in the right heart chambers of patients undergoing upright neurosurgery or pacemaker insertion, but also documented the presence of air in the left atrium and left ventricle of one patient via noncardiac shunt. Studies in dogs confirmed paradoxical air embolism in the absence of anatomic communications between right and left heart chambers. Systemic venous air also produced a dose-dependent increase in pulmonary artery pressure and diastolic flattening of the ventricular septum with increase in left ventricular filling pressure despite preserved systolic function.

Uteroglobin gene polymorphisms affect the progression of immunoglobulin A nephropathy by modulating the level of uteroglobin expression.

Uteroglobin (UG) is an anti-inflammatory/immunomodulatory protein. Targeted disruption of UG rendered mouse glomerulonephritis resembling immunoglobulin (Ig)A nephropathy (IgAN). Sequence analysis on exon 1 of UG showed several putative binding sites for transcription factors, and polymorphisms in this site might influence the expression level of UG as a competitive protein. We speculated that the single nucleotide polymorphism at the 38th nucleotide (A to G) from the transcription initiation site of UG exon 1 would impact the progression of IgA nephropathy (IgAN). Polymerase chain reaction-restriction fragment length polymorphism and single-strand conformation polymorphism were instituted to determine the genetic polymorphism. Luciferase assay was performed using the gene constructs containing a region 404-bp long located upstream of UG exon 1 initiation site to analyse whether this polymorphism would affect the expression level. UG polymorphism was distributed no differently in patients with IgAN (n = 111) compared to 60 healthy control subjects. An excess of A genotype was found in one patient having progressive disease (P = 0.03) and the risk for the disease progression increased as the number of A alleles increased (P for trend = 0.03) after follow-up for 116 months. The odds ratio for progression with the AA genotype was 4.9 (95% Cl = 1.0-23.9) compared to patients having the GG genotype. Significant interactive effects of hypertension and genetic polymorphisms of UG on the disease progression were observed (P for interaction = 0.001). In the luciferase assay, the gene construct with A at the 38th site showed a decreased activity of 74 +/- 8.4% compared to that showed by G gene construct. Our results suggest that polymorphism at the 5' UTR region of UG exon 1 is an important marker for the progression of IgAN and may modulate the level of protein expression.

c-Fes tyrosine kinase binds to and activates STAT3 after granulocyte-macrophage colony-stimulating factor stimulation.

Granulocyte-macrophage colony stimulating factor (GM-CSF) induces proliferation and maturation of myeloid progenitor cells and also activates neutrophils. In order to investigate the pleiotropic effects of GM-CSF stimulation, we examined the signaling pathways of protein tyrosine kinases (PTKs) and signal transducers and activators of transcription (STATs) in GM-CSF-dependent proliferation of leukemia cells. Using TF-1, a GM-CSF-dependent human erythroleukemia cell line, we found that GM-CSF enhanced DNA-binding and tyrosine phosphorylation of STAT3. GM-CSF receptor (GM-CSFR) and c-Fes tyrosine kinase were also activated upon GM-CSF stimulation. Furthermore, c-Fes formed a complex with STAT3. Experiments using a c-Fes mutant that lacked tyrosine kinase activity revealed that the activation of STAT3 is kinase-dependent, but that the c-Fes-STAT3 interaction is not affected by c-Fes tyrosine kinase activity. The results suggest that STAT3 is activated by c-Fes tyrosine kinase through direct interaction during hematopoietic cell proliferation induced by GM-CSF.

Development of thymic carcinoma in transgenic mice expressing SV40 T antigen.

We produced transgenic mice using SV40 Tag gene under the control of its own enhancer and promoter. Three transgenic lines (SNU-SVT125, 127, 248) consistently developed thymic carcinoma as well as choroid plexus carcinoma and dysplastic renal tubule. In SNU-SVT248 line, SV40 Tag transgene was expressed at thymus, spleen and kidney. Thymic epithelium showed high level expression of SV40 Tag in immunohistochemistry. Histopathological and electron microscopic analysis revealed that poorly differentiated carcinoma was derived from type 2 to 4 thymic epithelial cell. Our transgenic mice would provide a model for studies on the pathogenesis of thymic carcinoma and on the regulation of thymopoiesis by epithelial cells.

Effect of pentoxifylline on radiation response of non-small cell lung cancer: a phase III randomized multicenter trial.

PURPOSES: The objectives of this prospective clinical trial were to determine whether pentoxifylline improves the radiation response and survival in patients with non-small cell lung cancer. MATERIALS AND METHODS: From July 1993 through October 1994, 64 patients with histologically confirmed Stage I, II and III non-small cell lung cancer were randomly divided into pentoxifylline (Pento)+Radiotherapy (RT) group and RT alone group. Out of the 64 patients, only 47 patients who had measurable tumors on chest X-ray views were analyzed and divided into Pento+RT group (n=27) and RT alone group (n=20). Total tumor dose of 65-70 Gy was delivered as conventional fractionated radiation schedules. Pento was given to the patients 3 x 400 mg/day with a daily dose of 1200 mg during RT. RESULTS: Complete response (CR), partial response (PR), and stable in Pento+RT group were three (11%), 13 (48%), and 11 (41%), respectively, as compared with corresponding values of three (15%), 13 (65%), and four (20%) in the RT alone group. The median time to relapse in the Pento+RT group was 11 months which was 2 months longer than for the RT alone group (P>0.05). All the patients in both groups showed lower than or equal to grade 2 dysphagia, odynophagia, pulmonary fibrosis, and pneumonitis. The median survival was 18 months in the Pento+RT group and 7 months in the RT alone group. The 1-year survival rate was 60% in the Pento+RT group and 35% in the RT alone group, the 2-year survival rate was 18% in the Pento+RT group and 12% in the RT alone group. But these differences were not statistically significant (P>0.05). CONCLUSION: We concluded that Pento is a modestly effective radiation response modifier and provide benefit in the treatment of non-small cell lung cancer.

Senescence-like changes induced by hydroxyurea in human diploid fibroblasts.

Hydroxyurea was found to inhibit the growth of human diploid fibroblasts, which resulted in senescence-like changes both in morphology and replicative potential similar to the replicative senescence. SA-beta-gal activity, a typical characteristic of the replicative senescence was also induced through a long-term treatment of the presenescent cells with 400-800 microgM of hydroxyurea for about 3 weeks. In addition, we determined the levels of cyclin-dependent kinase inhibitors, p21(Waf1) and p16(INK4a), and the p53 tumor suppressor in order to monitor its effect on cell cycle and stress responses. We observed a great induction of both p53 and p21(Waf1), but not of p16(INK4a) in the premature senescent cells. UV-irradiation of the premature senescent cells showed a decreased level of DNA fragmentation presumably ascribed to the reduced activation of stress-activated protein kinases. These results suggest that a chronic hydroxyurea treatment induces the cellular senescence in association with the induction of p53 and p21(Waf1).