Hepatic and metabolic outcomes induced by sub-chronic exposure to polystyrene microplastics in mice.

Microplastics (MPs) have attracted significant attention due to their global distribution in living environments. Although some studies have reported MP-induced hepatotoxicity in mouse models, a systematic approach to MP-mediated liver toxicity was still lacking. Therefore, we used a mouse model to study the sub-chronic effects of MP exposure on the liver. Female C57BL/6 mice, aged 6 weeks, received an oral administration of 0.3 mg of Nile Red-labeled polystyrene (PS) microplastics, with particle sizes of 0.5 µm (submicron) and 5 µm (micron), via gavage, while control mice received vehicle only. Each mouse was exposed to MPs twice a week for 12 weeks. After sacrifice, the levels of MP accumulation, oxidative stress, inflammation, and pathological changes were measured in the mouse liver, and blood samples were collected for serum biochemistry analysis. Our results demonstrated that 0.5 µm PS-MPs were accumulated in mouse livers post-MP exposure, but not in the 5 µm MP exposure group. Simultaneously, increased levels of glucose, triglyceride, alanine transaminase (ALT), aspartate transaminase (AST), superoxide dismutase, 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), interleukin-6, and lipid droplets were found in the 0.5 µm MP exposure group, while the fewer responses, including elevated liver weight index, glucose, high-density lipoprotein, AST, and decreased HNE-MA were observed in 5 µm MP exposure group. These results indicate that sub-chronic exposure to submicron MPs causes MP deposition in mouse livers, which further induces oxidative stress, increases inflammatory cytokines and perturbs glucose and lipid homeostasis, which might trigger more severe metabolic dysfunction or non-alcoholic steatohepatitis-like hepatotoxicity.

TGFB1I1 promotes cell proliferation and migration in urothelial carcinoma.

Urothelial carcinoma (UC) is common cancer worldwide with a high prevalence in Taiwan, especially in the upper urinary tract, including the renal pelvis and ureter, also classifying as upper urinary tract urothelial carcinoma. Here, we aim to find a representative prognostic marker that strongly correlates to this type of carcinoma. Transforming growth factor beta-1-induced transcript 1 (TGFB1I1) is a cofactor of cellular TGF-ß1 and interacts with various nuclear receptors. The previous study showed that TGFB1I1 promotes focal adhesion formation, contributing to the epithelial-mesenchymal transition (EMT) with actin cytoskeleton and vimentin through TGFB1I1 regulation. We aim to reveal the role of TGFB1I1 in the tumorigenesis of UC. In silico and clinicopathological data of upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC) were accessed and analyzed for IHC staining regarding tumor characteristics, including survival outcome. Finally, an in vitro study was performed to demonstrate the biological changes of UC cells. In UTUC, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage, papillary configuration, and frequent mitosis. Meanwhile, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage and histological grade in UBUC. Moreover, the in vitro study shows that TGFB1I1 affects cell proliferation, viability, migration and wound healing. The EMT markers also decreased upon TGFB1I1 knockdown. In this study, we identified that TGFB1I1 regulates UC cell proliferation and viability and induces the EMT to facilitate cell migration in vitro, leading to its essential role in promoting tumor aggressiveness in both UTUC and UBUC.

Distribution and toxicity of submicron plastic particles in mice.

Although microplastics (MPs) have become a global issue, the biodistribution and toxicities of MPs were still unclear. In this study, c57BL/6 mice were treated with submicron-sized MPs labeled with Nile red fluorescence by oral gavage three times a week for four consecutive weeks. Flow cytometry and microscopy technique were used to examine the concentration and distribution of MPs in various tissues and biofluids. The oxidative stress and inflammation were assessed via liquid chromatography-mass spectrometry and enzyme-linked immunosorbent assay, respectively. Submicron-sized MP signals were found in the intestines, liver, spleen, kidney, lungs, blood, and urine of mice after MP exposure. Increased oxidative stress in mouse urine and elevated inflammatory cytokines in mouse kidney were also recorded. In conclusion, flow cytometry is a useful tool for examining the number concentrations of MPs. Increased oxidative stress and inflammation after MP treatment indicates that the toxicity of MP warrants further investigation.

Association of exposure to air pollutants with gestational diabetes mellitus in Chiayi City, Taiwan.

Introduction: We investigated the associations of exposure to particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5) and several gaseous pollutants with risk of gestational diabetes mellitus (GDM) in Taiwan. Methods: We retrospectively identified pregnant women who underwent a two-step approach to screen for GDM between 2006 and 2014. Information on concentrations of air pollutants (including PM2.5, sulfur dioxide [SO2], nitrogen oxides [NOx], and ozone [O3]) were collected from a single fixed-site monitoring station. We conducted logistic regression analyses to determine the associations between exposure to air pollutants and risk of GDM. Results: A total of 11210 women were analyzed, and 705 were diagnosed with GDM. Exposure to PM2.5 during the second trimester was associated with a nearly 50% higher risk of GDM (odds ratio [OR] 1.47, 95% CI 0.96 to 2.24, p=0.077). The associations were consistent in the two-pollutant model (PM2.5 + SO2 [OR 1.73, p=0.038], PM2.5 + NOx [OR 1.52, p=0.064], PM2.5 + O3 [OR 1.96, p=0.015]), and were more prominent in women with age <30 years and body mass index <25 kg/m2 (interaction p values <0.01). Discussion: Exposure to PM2.5 was associated with risk of GDM, especially in women who were younger or had a normal body mass index.

Three month inhalation exposure to low-level PM2.5 induced brain toxicity in an Alzheimer's disease mouse model.

Although numerous epidemiological studies revealed an association between ambient fine particulate matter (PM2.5) exposure and Alzheimer's disease (AD), the PM2.5-induced neuron toxicity and associated mechanisms were not fully elucidated. The present study assessed brain toxicity in 6-month-old female triple-transgenic AD (3xTg-AD) mice following subchronic exposure to PM2.5 via an inhalation system. The treated mice were whole-bodily and continuously exposed to real-world PM2.5 for 3 months, while the control mice inhaled filtered air. Changes in cognitive and motor functions were evaluated using the Morris Water Maze and rotarod tests. Magnetic resonance imaging analysis was used to record gross brain volume alterations, and tissue staining with hematoxylin and eosin, Nissl, and immunohistochemistry methods were used to monitor pathological changes in microstructures after PM2.5 exposure. The levels of AD-related hallmarks and the oxidative stress biomarker malondialdehyde (MDA) were assessed using Western blot analysis and liquid chromatography-mass spectrometry, respectively. Our results showed that subchronic exposure to environmental levels of PM2.5 induced obvious neuronal loss in the cortex of exposed mice, but without significant impairment of cognitive and motor function. Increased levels of phosphorylated-tau and MDA were also observed in olfactory bulb or hippocampus after PM2.5 exposure, but no amyloid pathology was detected, as reported in previous studies. These results revealed that a relatively lower level of PM2.5 subchronic exposure from the environmental atmosphere still induced certain neurodegenerative changes in the brains of AD mice, especially in the olfactory bulb, entorhinal cortex and hippocampus, which is consistent with the nasal entry and spreading route for PM exposure. Systemic factors may also contribute to the neuronal toxicity. The effects of PM2.5 after a more prolonged exposure period are needed to establish a more comprehensive picture of the PM2.5-mediated development of AD.

Utility of RGNEF in the Prediction of Clinical Prognosis in Patients with Rectal Cancer Receiving Preoperative Concurrent Chemoradiotherapy.

Rectal cancer is a heterogeneous malignancy with different clinical responses to preoperative concurrent chemoradiotherapy (CCRT). To discover the significant genes associated with CCRT response, we performed data mining of a transcriptomic dataset (GSE35452), including 46 rectal cancer patients who received preoperative CCRT and underwent standardized curative resection. We identified ARHGEF28 as the most significantly upregulated gene correlated with resistance to CCRT among the genes related to Rho guanyl-nucleotide exchange factor activity (GO:0005085). We enrolled 172 patients with rectal cancer receiving CCRT with radical surgery. The expression of ARHGEF28 encoded protein, Rho guanine nucleotide exchange factor (RGNEF), was assessed using immunohistochemistry. The results showed that upregulated RGNEF immunoexpression was considerably correlated with poor response to CCRT (p = 0.018), pre-CCRT positive nodal status (p = 0.004), and vascular invasion (p < 0.001). Furthermore, high RGNEF expression was significantly associated with worse local recurrence-free survival (p < 0.0001), metastasis-free survival (MeFS) (p = 0.0029), and disease-specific survival (DSS) (p < 0.0001). The multivariate analysis demonstrated that RGNEF immunoexpression status was an independent predictor of DSS (p < 0.001) and MeFS (p < 0.001). Using Gene Ontology enrichment analysis, we discovered that ARHGEF28 overexpression might be linked to Wnt/ß-catenin signaling in rectal cancer progression. In conclusion, high RGNEF expression was related to unfavorable pathological characteristics and independently predicted worse clinical prognosis in patients with rectal cancer undergoing CCRT, suggesting its role in risk stratification and clinical decision making.

Primary renal angiosarcoma mimicking urothelial carcinoma - A case report and literature reviews.

Angiosarcoma (AS) is a rare aggressive tumor originating from endothelial cells. We reported a 66-year-old female with primary renal angiosarcoma (PRA) who presented as urothelial carcinoma with hematuria and dysuria. Based on ureterorenoscopic tumor biopsy, the initial diagnosis suggested low-grade non-invasive urothelial carcinoma. However, the specimen retrieved from nephroureterectomy confirmed the diagnosis of primary renal angiosarcoma. Primary renal angiosarcoma could uncommonly present as urothelial carcinoma in renal pelvis. Surgical resection remains to be the most effective therapy but there is no consensus about adjuvant therapies. The overall prognosis of primary renal angiosarcoma is dismal.

Expression and prognostic utility of SSX2IP in patients with nasopharyngeal carcinoma.

Cell adhesion affects carcinogenesis, tumor progression, and metastasis. We datamined a published transcriptome (GSE12452) of nasopharyngeal carcinoma (NPC) and identified SSX2IP as a significantly upregulated gene in NPC carcinogenesis among genes associated with cell adhesion (GO:0007155). Consequently, we assessed SSX2IP protein expression and its prognostic significance in 124 patients with NPC using immunohistochemistry and the H-score method. The status of SSX2IP immunoexpression correlated with clinical and pathological characteristics, as well as oncological outcomes. High levels of SSX2IP expression were significantly associated with more advanced primary tumor and TNM stages. Kaplan-Meier and log-rank analyses revealed that high levels of SSX2IP expression, and advanced tumor stage and lymph node metastasis were significantly associated with lower rates of local recurrence-free survival (LRFS), distant metastasis-free survival (DMeFS), and disease-specific (DSS) survival. Multivariate analysis showed that high levels of SSX2IP expression significantly predicted DSS (hazard ratio [HR], 4.290; 95% confidence interval [CI], 2.271-8.102; p < 0.001), DMeFS (HR, 4.159' 95% CI, 2.072-8.345; p < 0.001), and LRFS (HR, 3.007' 95% CI,: 1.418-6.378; p = 0.004). We associated high levels of SSX2IP immunoexpression with aggressive pathological features and worse oncological outcomes, suggesting its potential therapeutic value for patients with NPC.

Risk factors for restless legs syndrome in hemodialysis patients in Taiwan: A case-control study.

Restless legs syndrome (RLS) increases the risks of cardiovascular disease and death in hemodialysis (HD) patients. Previous studies of risk factors for RLS in HD patients have yielded varying results. We attempted to identify risk factors for RLS in HD patients in Taiwan.This case-control study recruited 59 HD patients with RLS and 353 HD patients without RLS from the largest HD center in Taiwan during the period from April 1, 2015 through August 31, 2015. Demographic and disease characteristics, information from the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic questionnaire, and IRLSSG Severity Scale scores were collected by interview. Clinical laboratory data were abstracted from medical records and then analyzed with logistic regression and Pearson correlation analysis. A P value of less than .05 was considered to indicate statistical significance.A dialysis duration of longer than 5 years (odds ratio [OR] = 2.32; 95% CI = 1.23-4.39; P = .002) and a low high-density lipoprotein cholesterol level (<40 mg/dL in men; <50 mg/dL in women) (OR = 2.73; 95% CI = 1.44-5.15; P = .009) were associated with increased risk of RLS. Among the 59 patients with RLS, 48 (81.3%) had moderate or severe symptoms (IRLSSG Severity Scale >10), and RLS severity was significantly correlated with dialysis duration (r = .26; P = .043).Among HD patients, RLS was more common among those receiving dialysis for longer than 5 years and those with a low serum high-density lipoprotein cholesterol (HDL-C) level.

Qualitative CT Criterion for Subsolid Nodule Subclassification: Improving Interobserver Agreement and Pathologic Correlation in the Adenocarcinoma Spectrum.

RATIONALE AND OBJECTIVES: The main aim of this study was to evaluate the clinical validity and correlation with pathologic invasiveness in the pulmonary adenocarcinoma spectrum based on the novel qualitative computed tomography criterion for subsolid nodule (SSN) classification, which classified SSN into pure ground-glass nodule, heterogeneous ground-glass nodule, and part-solid nodule. In addition, we compared the performance of the conventional and novel classifications. MATERIALS AND METHODS: The computed tomography images of 41 SSN nodules were interpreted by six observers independently, and the SSN characteristics were classified according to both the conventional and the novel classification systems. Each observer assessed 41 nodules in two different classifications separated by a minimum of 8 weeks. The kappa (κ) coefficient test was used to determine the reliability. The correlation between pulmonary adenocarcinoma spectrum and the SSN classification was analyzed with Spearman correlation coefficients. RESULTS: Interobserver agreement (κ) was 0.702 (range 0.42-0.89) and 0.707 (range 0.58-0.88) for the conventional and the novel classifications for SSN, respectively, and intraobserver agreement (κ) was 0.92 and 0.88 for the conventional and the novel classifications for SSN, respectively. The novel SSN classification (correlation coefficient range 0.622-0.732) is more strongly correlated with the pathologic invasiveness degree of lesions in adenocarcinoma spectrum than the conventional SSN classification (correlation coefficient range 0.458-0.644). CONCLUSIONS: The agreement between observers on the novel SSN classification system was good and had better correlation with pathologic invasiveness than the conventional SSN classification. Further studies are needed to confirm these results on interobserver agreement.

Sustained renal inflammation following 2 weeks of inhalation of occupationally relevant levels of zinc oxide nanoparticles in Sprague Dawley rats.

Exposure to zinc oxide (ZnO) has been linked to adverse health effects, but the renal effects of ZnO nanoparticles (ZnONPs) remain unclear. The objective of this study was to determine the renal toxicity of inhaled ZnONPs. Sprague Dawley (SD) rats were exposed to occupationally relevant levels of 1.1 (low dose) and 4.9 mg/m3 (high dose) ZnONPs or high-efficiency particulate arresting-filtered air (HEPA-FA) via inhalation for 2 weeks. Histopathological examinations of rat kidneys were performed at 24 hours, 7 days, and 1 month after exposure. A significant increase in microscopic inflammatory foci with pronounced periglomerular inflammation and interstitial lymphocytic infiltration was found in rats exposed to low and high doses of ZnONPs compared with rats exposed to HEPA-FA at the three time points following 2 weeks of exposure. Tubulitis featuring lymphocytic infiltrate within the tubular epithelium was found after 24 hours but had disappeared at 7 and 30 days in both the low- and high-dose exposure groups. Our findings demonstrate that inhaled ZnONPs cause sustained renal periglomerular and interstitial inflammation through lymphocytic infiltration. These findings provide histopathological evidence regarding sustained renal inflammation of nanoparticle exposure in rats and may provide some insight into the occupational health effects of ZnONPs on exposed workers.

Semiquantative Visual Assessment of Sub-solid Pulmonary Nodules ≦3 cm in Differentiation of Lung Adenocarcinoma Spectrum.

We aimed to analyze CT features of persistent subsolid nodules (SSN) ≦3 cm diagnosed pathologically as adenocarcinoma spectrum to investigate whether parameters enable distinction between invasive pulmonary adenocarcinomas (IPAs) and pre-invasive lesions. A total of 129 patients with 141 SSNs confirmed with surgically pathologic proof were retrospectively reviewed. Of 141 SSNs, there were 57 pure ground-glass nodules (GGNs), 22 heterogeneous GGNs, and 62 part-solid nodules. SSN subclassification showed a significant linear trend with invasive degree of the adenocarcinoma spectrum (pure GGNs 7%; heterogeneous GGNs 36.4%; part-solid nodules 85.5%, P for trend <0.0001). For IPA detection in 141 SSNs, a solid part of ≧3 mm was the most specificity (sensitivity, 76.9%; specificity, 94.7%), followed by air-bronchogram sign (sensitivity, 53.8%; specificity, 89.5%), SSN subclassification (sensitivity, 81.5%; specificity, 88.2%), and a lesion size ≧12 mm (sensitivity, 84.6%; specificity, 76.3%). For IPA detection in 79 pure or heterogeneous GGNs, the heterogeneous GGN sign was the most useful finding, with most specificity (sensitivity, 66.7%; specificity, 79.1%), followed by CT attenuation (HU) of ≧-493 (sensitivity, 75%; specificity, 74.6%) and a lesion size ≧10 mm (sensitivity, 83.3%; specificity, 70.1%). In conclusion, this simple combined visual and semiquantitative analysis of CT features helps distinguish IPAs from pre-invasive lesions.

Primary extranodal natural killer/T-cell lymphoma of bronchus and lung: A case report and review of literature.

Primary pulmonary non-Hodgkin's lymphoma (NHL) is very rare. It represents less than 1% of all NHL, and 0.5-1% of all primary pulmonary malignancies. Almost all cases of primary pulmonary NHL originate from B-cell lineage. We present a case of a 53-year-old man with primary extranodal NK/T-cell lymphoma of the bronchus and lung, presented progressive dyspnea caused by right lower lung consolidation, and pleural effusion. Initial chest computed tomography suggested advanced lung cancer. Bronchofiberscopy showed a polypoid tumor on which a biopsy was performed. Histologically, the diffusely infiltrative atypical cells were positive for cytoplasmic CD3, CD56, granzyme B, and negative for cytokeratin, CD20 immunostains, suggesting NK/T cell lineages. In situ hybridization for Epstein-Barr virus encoded ribonucleic acid (EBER) was positive. Herein, we discuss the clinicopathological features of this case and review the literature on primary extranodal NK/T-cell lymphoma of the lung. Compared with other patients, who died after the first cycle of chemotherapy and/or within three months, our patient had longer survival under aggressive chemotherapy and auto-peripheral blood stem cell transplantation.

Assessing medical students' performance in core competencies using multiple admission programs for colleges and universities: from the perspective of multi-source feedback.

BACKGROUND: Since 1994, Taiwanese medical universities have employed the multiple application method comprising "recommendations and screening" and "admission application." The purpose of this study is to examine whether medical students admitted using different admission programs gave different performances. METHODS: To evaluate the six core competencies for medical students proposed by Accreditation Council for Graduate Medical Education (ACGME), this study employed various assessment tools, including student opinion feedback, multi-source feedback (MSF), course grades, and examination results.MSF contains self-assessment scale, peer assessment scale, nursing staff assessment scale, visiting staff assessment scale, and chief resident assessment scale. In the subscales, the CronbachÊs alpha were higher than 0.90, indicating good reliability. Research participants consisted of 182 students from the School of Medicine at Chang Gung University. RESULTS: Regarding studentsÊ average grade for the medical ethics course, the performance of students who were enrolled through school recommendations exceeded that of students who were enrolled through the National College University Entrance Examination (NCUEE) p = 0.011), and all considered "teamwork" as the most important. Different entry pipelines of students in the "communication," "work attitude," "medical knowledge," and "teamwork" assessment scales showed no significant difference. The improvement rate of the students who were enrolled through the school recommendations was better than that of the students who were enrolled through the N CUEE in the "professional skills," "medical core competencies," "communication," and "teamwork" projects of self-assessment and peer assessment scales. However, the students who were enrolled through the NCUEE were better in the "professional skills," "medical core competencies," "communication," and "teamwork" projects of the visiting staff assessment scale and the chief resident assessment scale. CONCLUSION: Collectively, the performance of the students enrolled through recommendations was slightly better than that of the students enrolled through the NCUEE, although statistical significance was found in certain parts of the grades only.

Subglottic stenosis induced by extranodal mucosa-associated lymphoid tissue lymphoma.

Mucosa-associated lymphoid tissue (MALT) lymphoma is usually associated with a chronic inflammatory disease or autoimmune disorders from which lymphoid tissue of MALT type arises as a prerequisite for lymphoma proliferation. Primary hematopoietic neoplasms of the larynx are rare. MALT lymphomas of the larynx are believed to arise from preexisting or acquired lymphoid tissue of the upper airway which is documented in the supraglottic region. Therefore, these are mainly located in the supraglottic and glottic areas, with only a few reported in the subglottic region. We report on a 50-year-old woman with a hoarseness, stridor, and developing exertional dyspnea. On indirect laryngoscope, multiple nodular lesions with smooth surface over the subglottis with subglottic steonsis was found. The biopsy confirmed the diagnosis of a MALT lymphoma. We hope to promote awareness and consideration of MALT lymphoma in the differential diagnosis in subglottic steonsis.

The impact of type of assistance on characteristics of peritonitis in elderly peritoneal dialysis patients.

BACKGROUND: The elderly patients are the fastest-growing end-stage renal disease (ESRD) population in Taiwan. Assisted peritoneal dialysis (PD) has been employed to overcome the barriers to PD. The aim of this retrospective, single-center study was to describe the status of assisted PD and the impact of type of assistance on peritonitis in elderly patients in Taiwan. METHODS: One hundred and two patients initiated PD at the age of 65 or older between 2000 and 2008; 79 episodes of peritonitis occurred during the follow-ups. The patients and episodes of peritonitis were divided into three groups based on the type of assistance: (1) self-care: patients performing dialysis independently, (2) family: patients whose dialysis was performed by family, (3) caregiver: patients whose dialysis was performed by a private caregiver. Patient characteristics and incidence, etiology and outcomes of peritonitis were compared. RESULTS: There were 26 (25.5%), 44 (43.1%), and 32 (31.4%) patients in the self-care, family, and caregiver groups, respectively. The overall peritonitis rate was 1/33 patient-months. Patients in the caregiver group were older and had more comorbidities than the self-care group. They had a trend of higher overall peritonitis rate (1/24 patient-months, P = 0.077) and fungal peritonitis rate (P = 0.060) compared to the self-care and family groups, but this was statistically non-significant. CONCLUSIONS: Three-fourths of elderly PD patients in the present study required assistance from family members or private caregivers. Caregiver-assisted patients were significantly older and had more comorbidities. Also, a non-significant trend of higher peritonitis incidence was observed in these patients.

Effect of T cells on vascular permeability in early ischemic acute kidney injury in mice.

Although previous studies have demonstrated that microvascular dysfunction and inflammation occur in ischemia-reperfusion injury (IRI), the underlying mechanisms are poorly understood. We hypothesized that T cells could mediate renal vascular permeability (RVP) during IRI. We evaluated renal vascular permeability by extravasation of Evans blue dye from the kidney in CD3, CD4 or CD8 T cell deficient mice as well as in TNF receptor knock out mice in our mouse model of kidney ischemia-reperfusion injury. In wild type mice, RVP was significantly increased at 3 h, peaked at 6 h and declined by 24 h after ischemia. Immunohistochemistry revealed that CD3(+) T cells trafficked into ischemic kidney at 1 h and peaked at 6 h. Gene microarray analysis demonstrated that endothelial-related genes including TNF-alpha were up-regulated in ischemic kidney. The production of TNF-alpha and IFN-gamma protein was increased in CD3 and CD4 T cells from the blood and kidney after ischemia. The rise in RVP after ischemia in wild type mice was attenuated in CD3, CD4 or CD8 T cell deficient mice as well as in TNF receptor knock out mice. The attenuation of RVP in CD3 T-cell deficient mice after ischemia was restored by adoptive transfer of T cells from WT mice. Our data demonstrate that T cells directly contribute to the increased RVP after kidney ischemia-reperfusion, potentially through T cell cytokine production.

A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity.

Recent evidence supports a role for an inflammatory pathogenesis of cisplatin nephrotoxicity, but immune cell-mediated mechanisms in this disease are still largely unknown. The role for T lymphocytes on cisplatin-induced acute kidney injury was examined with C57BL/6 T cell-deficient (nu/nu) mice and CD4- or CD8-deficient mice and their wild-type (WT) littermates. All mice received a single dose of cisplatin at 40 mg/kg (intraperitoneally) and were followed up for 72 h. At 72 h after cisplatin administration, T cell-deficient mice had a marked attenuation in renal dysfunction (serum creatinine 3.2+/-0.5 versus 0.8+/-0.1 mg/dl; P=0.007), kidney tubular injury (scores 1.44+/-0.15 versus 0.22+/-0.08; P<0.0001), and survival. Adoptive transfer of T cells into nu/nu mice followed by cisplatin enhanced renal dysfunction and tubular injury. The increase in renal myeloperoxidase activity after cisplatin administration was blunted in nu/nu mice. Renal TNF-alpha, IL-1beta, and keratinocyte-derived chemokine protein expression was increased in WT mice but not in nu/nu mice after cisplatin administration. T cell levels significantly increased in kidneys of WT mice after cisplatin administration as early as at 1 h, peaked at 12 h, and declined by 24 h. CD4- and, to a lesser degree, CD8-deficient mice were relatively protected from cisplatin-induced mortality and renal dysfunction compared with WT mice. These data demonstrate that T lymphocytes are direct mediators of experimental cisplatin nephrotoxicity. Targeting T lymphocytes could lead to improved ways to administer cisplatin safely to cancer patients.