RESUMEN

Non-small cell lung cancer (NSCLC) patients without targetable driver mutation have limited treatment options. In this study, we aimed to explore a new therapeutic strategy by using established nine patient-derived xenograft (PDX) and two-dimensional (2D) /3D culture models with specific genetic alternations. The gene mutations and copy number aberrations were detected by next-generation sequencing and confirmed using polymerase chain reaction (PCR) followed by DNA sequencing, and genomic DNA quantitative PCR. Protein expression was evaluated by immunohistochemistry. Drug sensitivities of PDX/2D/3D models were evaluated by in vivo and in vitro antitumor assays. RNA interference was performed to silence gene expression. Our study found that 44.4 % (4/9) of cases had CDKN2A homozygous deletion (homdel), while 33.3 % (3/9) had CDKN2B homdel. Additionally, 22.2 % (2/9) had amplification (amp) in wildtype CDK4, 44.4 % (4/9) in CDK6, and 44.4 % (4/9) in EGFR. Among the cases, 77.8 % (7/9) lacked CDKN2A, and 33.3 % (3/9) had high CDK4, CDK6, and EGFR had high protein expression. Moreover, 33.3 % (3/9) had KRAS mutations, and 66.7 % (6/9) had TP53 mutations. Antitumor activity of osimertinib plus palbociclib was assessed in four PDX/2D/3D models, two of which had simultaneous EGFR amp and CDKN2A/2B homdel. The data showed that NSCLC with EGFR amp and CDKN2A/2B homdel were sensitive to combined drugs. Additional oncogenic KRAS mutation reduced the drug's antitumor effect. EGFR amp is responsible for osimertinib sensitivity. Osimertinib plus palbociclib effectively treat NSCLC with wildtype EGFR and CDK6 amp and CDKN2A/2B homdel in the absence of oncogenic KRAS mutation.

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INTRODUCTION: Data on the incidence rates of hungry bone syndrome after parathyroidectomy in patients on dialysis are inconsistent, as the published rates vary from 15.8% to 92.9%. METHODS: Between 2009 and 2019, 120 hemodialysis patients underwent parathyroidectomy for secondary hyperparathyroidism at the Chang Gung Memorial Hospital. The patients were stratified into two groups based on the presence (n = 100) or absence (n = 20) of hungry bone syndrome after parathyroidectomy. FINDINGS: Subtotal parathyroidectomy was the most common surgery performed (76.7%), followed by total parathyroidectomy with autoimplantation (23.3%). Pathological examination revealed parathyroid hyperplasia. Hungry bone syndrome developed within 0.3 ± 0.3 months and lasted for 11.1 ± 14.7 months. After surgery, compared with patients without hungry bone syndrome, patients with hungry bone syndrome had lower levels of nadir corrected calcium (P < 0.001), as well as lower nadir (P < 0.001) and peak (P < 0.001) intact parathyroid hormone levels. During 59.3 ± 44.0 months of follow-up, persistence and recurrence of hyperparathyroidism occurred in 25 (20.8%) and 30 (25.0%) patients, respectively. Furthermore, patients with hungry bone syndrome had a lower rate of persistent hyperparathyroidism than those without hungry bone syndrome (P < 0.001). Four patients (3.3%) underwent a second parathyroidectomy. Patients with hungry bone syndrome received fewer second parathyroidectomies than those without hungry bone syndrome (P < 0.001). Finally, a multivariate logistic regression model revealed that the preoperative blood ferritin level was a negative predictor of the development of hungry bone syndrome (P = 0.038). DISCUSSION: Hungry bone syndrome is common (83.3%) after parathyroidectomy for secondary hyperparathyroidism in patients undergoing hemodialysis, and this complication should be monitored and managed appropriately.

Asunto(s)

Hiperparatiroidismo Secundario , Hipocalcemia , Humanos , Diálisis Renal/efectos adversos , Hipocalcemia/diagnóstico , Hipocalcemia/etiología , Hipocalcemia/cirugía , Hiperparatiroidismo Secundario/etiología , Hiperparatiroidismo Secundario/cirugía , Calcio , Paratiroidectomía/efectos adversos , Hormona Paratiroidea , Estudios Retrospectivos

RESUMEN

Literature data regarding the response rate to COVID-19 vaccination in chronic kidney disease (CKD) patients remain inconclusive. Furthermore, studies have reported a relationship between lead exposure and susceptibility to viral infections. This study examined immune responses to COVID-19 vaccines in patients with CKD and lead exposure. Between October and December 2021, 50 lead-exposed CKD patients received two doses of vaccination against COVID-19 at Chang Gung Memorial Hospital. Patients were stratified into two groups based on the median blood lead level (BLL): upper (≥1.30 µg/dL, n = 24) and lower (<1.30 µg/dL, n = 26) 50th percentile. The patients were aged 65.9 ± 11.8 years. CKD stages 1, 2, 3, 4 and 5 accounted for 26.0%, 20.0%, 22.0%, 8.0% and 24.0% of the patients, respectively. Patients in the lower 50th percentile of BLL had a lower proportion of CKD stage 5 than patients in the upper 50th percentile BLL group (p = 0.047). The patients in the lower 50th percentile BLL group also received a higher proportion of messenger RNA vaccines and a lower proportion of adenovirus-vectored vaccines than the patients in the upper 50th percentile BLL group (p = 0.031). Notably, the neutralizing antibody titers were higher in the lower 50th percentile than in the upper 50th percentile BLL group. Furthermore, the circulating levels of granulocyte-colony stimulating factor, interleukin-8, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α were higher in the upper 50th percentile than in the lower 50th percentile BLL group. Therefore, it was concluded that lead-exposed CKD patients are characterized by an impaired immune response to COVID-19 vaccination with diminished neutralizing antibodies and augmented inflammatory reactions.

Asunto(s)

COVID-19 , Insuficiencia Renal Crónica , Humanos , Plomo , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , Inmunidad

RESUMEN

Although paraquat (PQ) induces oxidative damage and inflammatory responses in the lungs, the mechanism underlying PQ-induced acute kidney injury in patients is unclear. Immunosuppressive therapy with glucocorticoids and the immunosuppressant cyclophosphamide (CP) has been employed to treat patients with PQ poisoning. This study examined whether PQ could concurrently cause renal injury, inflammatory responses, and oxidative damage in the kidneys, and whether CP and dexamethasone (DEX) could suppress PQ-induced alterations. Mice were assigned to eight groups: Control, PQ, DEX, PQ plus DEX, CP, PQ plus CP, DEX plus CP, and PQ plus DEX with CP. DEX, CP, and DEX plus CP reversed PQ-induced renal injury, as indicated by urinary albumin-to-creatinine ratios and urea nitrogen levels in serum. The treatments also attenuated PQ-induced renal infiltration of leukocytes and macrophages and induction of the Il6, Tnf, Icam, Cxcl2, Tlr4, and Tlr9 genes encoding the inflammatory mediators in the kidneys. However, DEX only partially suppressed the macrophage infiltration, whereas DEX plus CP provided stronger protection than DEX or CP alone for the induction of Il6 and Cxcl2. Moreover, through the detection of F2-isoprostanes (F2-IsoPs) and isofurans in the kidneys and lungs and F2-IsoPs in the plasma and urine, the therapies were found to suppress PQ-induced lipid peroxidation, although DEX was less effective. Finally, PQ decreased ubiquinol-9:ubiquinone-9 ratios in the kidneys. This effect of PQ was not found under CP treatment, but the ratio was lower than that of the control group. Our findings suggest that the suppression of PQ-induced inflammatory responses by DEX and CP in the kidneys can mitigate oxidative damage and acute kidney injury.

Asunto(s)

Lesión Renal Aguda , Paraquat , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Albúminas , Animales , Creatinina , Ciclofosfamida/farmacología , Dexametasona/farmacología , F2-Isoprostanos , Terapia de Inmunosupresión , Inmunosupresores , Mediadores de Inflamación , Interleucina-6/genética , Interleucina-6/metabolismo , Peroxidación de Lípido , Ratones , Nitrógeno , Paraquat/toxicidad , Receptor Toll-Like 4 , Receptor Toll-Like 9 , Urea

RESUMEN

BACKGROUND: Hemodialysis is often recommended to treat severe lithium poisoning. Nevertheless, the application rate of hemodialysis in patients with lithium poisoning is varied across different groups and the effect of hemodialysis is still undetermined. Therefore, this study aimed to analyze the hemodialysis rate of patients with lithium poisoning and to explore the clinical features of lithium-poisoned-patients treated or untreated with hemodialysis. METHODS: Between 2001 and 2019, 36 patients treated at the Chang Gung Memorial Hospital for the management of lithium poisoning were stratified according to whether they were treated with hemodialysis (n = 7) or not (n = 29). RESULTS: The patients were aged 50.7 ± 18.1 years. The poisoning patterns were acute on chronic (61.1%), chronic (25.0%) and acute (13.9%). The precipitating factors of dehydration and infection were noted in 36.1% and 25.0% of patients, respectively. Bipolar disorder (72.2%), depressive disorder (27.8%) and psychotic disorder (11.1%) were the top three psychiatric comorbidities. The hemodialysis group not only had a lower Glasgow Coma Scale (GCS) score (p = 0.001) but also had a higher respiratory failure rate (p = 0.033), aspiration pneumonia rate (p = 0.033) and acute kidney injury network (AKIN) score (p = 0.002) than the non-hemodialysis group. Although none of the patients died of lithium poisoning, the hemodialysis group required more endotracheal intubation (p = 0.033), more intensive care unit admission (p = 0.033) and longer hospitalization (p = 0.007) than the non-hemodialysis group. CONCLUSION: The analytical results revealed zero mortality rate and low hemodialysis rate (1.9%). Compared with patients without hemodialysis, patients receiving hemodialysis suffered severer lithium-associated complications and needed a more intensive care unit admission and longer hospital stay.

Asunto(s)

Trastorno Bipolar , Intoxicación , Antidepresivos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Humanos , Unidades de Cuidados Intensivos , Litio/uso terapéutico , Intoxicación/epidemiología , Intoxicación/terapia , Diálisis Renal , Estudios Retrospectivos

RESUMEN

The molecular mechanism of myeloid sarcoma (MS) formation remains nuclear. Our clinical and mouse model findings from a previous study revealed that cooperation of KMT2A (MLL) translocation (MLL-t) with activating N-/K-RAS mutations promoted MS formation in a shorter latency. To improve the understanding of MS formation, in this study, we performed imaging cell trafficking analysis and demonstrated that cells harboring cooperating mutations migrated more slowly to omental adipose tissues and more cells were retained in adipose tissues in vivo. Comparison of transcriptome profiling among three pairs of mouse MLL/AF10(OM-LZ) leukemia cell lines harboring activating and wild-type KRAS identified 77 differentially expressed genes (DEGs) with >1.5-fold change. Functional annotation of these 77 DEGs using Gene Ontology (GO) enrichment analysis followed by cluster analysis revealed that GO terms related to development/differentiation have the highest enrichment score. The roles of Hoxa10 and Hoxa11, two genes which mapped to this cluster, were further characterized. Silencing Hoxa10 and Hoxa11 in cells harboring cooperating mutations prolonged the survival and reduced MS formation, respectively, in the recipient mice. Data of imaging cell trafficking as well as competitive engraftment and clonal expansion analyses indicated that silencing or overexpressing Hoxa11 in mouse leukemia cells affected cell migration and retention in omental adipose tissue. Although silencing Hoxa11 in leukemia cells did not affect Cxcr4 expression, it resulted in increased transwell migration, motility in confined spaces 3 µm in size, and cell protrusion. Our results revealed that Hoxa10 plays an important role in survival and Hoxa11 contributes to MS formation in MLL-t acute myeloid leukemia with activating KRAS mutation.

Asunto(s)

Proteínas de Homeodominio/metabolismo , Leucemia Mieloide Aguda , Sarcoma Mieloide , Animales , Movimiento Celular/genética , Proteínas de Homeodominio/genética , Humanos , Ratones , Mutación , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Factores de Transcripción/genética

RESUMEN

BACKGROUND: Anemia and pancytopenia are not uncommon in patients with chronic kidney disease (CKD). Nevertheless, there is insufficient literature analyzing bone marrow pathology in patients with CKD or end-stage kidney disease (ESKD) receiving dialysis. METHODS: This observational cohort study included 22 patients with ESKD and 23 patients with CKD that received bone marrow biopsy and aspiration at Chang Gung Memorial Hospital. Demographic, hematological, and biochemical data were collected at the time of bone marrow study for analysis. RESULTS: Bone marrow aspiration demonstrated that patients with ESKD had a lower percentage of blasts than patients with CKD (0.52 ± 0.84 versus 1.06 ± 0.78 %, p = 0.033). Bone marrow biopsy revealed that the overall incidence of hypocellular bone marrow was 55.6%. Furthermore, patients with ESKD had higher proportion of hypocellular bone marrow than patients with CKD (72.7% versus 39.1%, p = 0.023). In a multivariate logistic regression model, it was revealed that ESKD status (odds ratio 9.43, 95% confidence interval 1.66-53.63, p = 0.011) and megakaryocyte count within bone marrow (odds ratio 0.48, 95% confidence interval 0.29-0.79, p = 0.004) were significant predictors for bone marrow hypocellularity. CONCLUSION: Bone marrow hypocellularity is common in patients with kidney dysfunction. Hypocellular marrow occurs more frequently in patients with ESKD than patients with CKD.

RESUMEN

Cytokine-mediated inflammation is involved in the pathophysiology of paraquat toxicity. Nevertheless, few human studies have examined fluctuations in circulating cytokine levels. Blood samples were obtained from 21 patients with paraquat poisoning and compared to those of 18 healthy controls. All paraquat patients received a standard detoxification protocol composed of hemoperfusion, pulse therapies of methylprednisolone and cyclophosphamide, followed by dexamethasone therapy. Nonsurvivors not only had higher scores for the severity index of paraquat poisoning (P=0.004) but also presented with higher white blood cell counts (P=0.046) than survivors. Multiplex immunoassays revealed higher circulating levels of interleukin 2 (IL-2), interleukin 9 (IL-9), interleukin 10 (IL-10) and macrophage inflammatory protein-1 beta (MIP-1ß) in survivors than in healthy controls. Furthermore, the circulating levels of interleukin 1 beta (IL-1ß), IL-2, interleukin 5 (IL-5), interleukin 8 (IL-8), IL-9, IL-10, interleukin 12 (IL-12 p70), interleukin 17A (IL-17A), eotaxin, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein 10 (IP-10) and MIP-1ß were higher in nonsurvivors than in healthy controls. Finally, the circulating levels of IL-1ß and MCP-1 were higher in nonsurvivors than in survivors. Therefore, the observation of cytokine-mediated inflammation is in line with the detoxification protocol because glucocorticoids and cyclophosphamide are potent anti-inflammatory agents. Additionally, circulating levels of IL-1ß and MCP-1 could serve as promising prognostic markers for patients with paraquat poisoning.

Asunto(s)

Leucemia , Proteína de la Leucemia Mieloide-Linfoide , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Proteína de la Leucemia Mieloide-Linfoide/genética

RESUMEN

Reports on the prevalence of torus mandibularis among dialysis patients have been limited and inconclusive. A wide variety of oral manifestations has been found in patients with hyperparathyroidism. Furthermore, uremia-related changes in facial bone structures have been described in the literature. This prospective observational study examined 322 hemodialysis patients treated at the Chang Gung Memorial Hospital from 1 August to 31 December 2016. Two subgroups were identified: patients with torus mandibularis (n = 25) and those without (n = 297). Clinical oral examinations including inspection and palpation were employed. Our study found that most mandibular tori were symmetric (84.0%), nodular (96.0%), less than 2 cm in size (96.0%), and located in the premolar area (92.0%). Poor oral hygiene was observed among these patients, with 49.7% and 24.5% scoring 3 and 4, respectively, on the Quigley-Hein plaque index. More than half (55.0%) of patients lost their first molars. Multivariate logistic regression analysis revealed that blood phosphate level (odds ratio = 1.494, p = 0.029) and younger age (odds ratio = 0.954, p = 0.009) correlated significantly with torus mandibularis. The prevalence of torus mandibularis in patients receiving hemodialysis in this study was 7.8%. Younger age and a higher blood phosphate level were predictors for torus mandibularis in these patients.

Asunto(s)

Exostosis , Tracto Gastrointestinal , Humanos , Prevalencia , Estudios Prospectivos , Diálisis Renal/efectos adversos

RESUMEN

This study analysed the clinical patterns and outcomes of elderly patients with organophosphate intoxication. A total of 71 elderly patients with organophosphate poisoning were seen between 2008 and 2017. Patients were stratified into two subgroups: survivors (n = 57) or nonsurvivors (n = 14). Chlorpyrifos accounted for 33.8% of the cases, followed by methamidophos (12.7%) and mevinphos (11.3%). Mood, adjustment and psychotic disorder were noted in 39.4%, 33.8% and 2.8% of patients, respectively. All patients were treated with atropine and pralidoxime therapies. Acute cholinergic crisis developed in all cases (100.0%). The complications included respiratory failure (52.1%), aspiration pneumonia (50.7%), acute kidney injury (43.7%), severe consciousness disturbance (25.4%), shock (14.1%) and seizures (4.2%). Some patients also developed intermediate syndrome (15.5%) and delayed neuropathy (4.2%). The nonsurvivors suffered higher rates of hypotension (P < 0.001), shock (P < 0.001) and kidney injury (P = 0.001) than survivors did. Kaplan-Meier analysis indicated that patients with shock suffered lower cumulative survival than did patients without shock (log-rank test, P < 0.001). In a multivariate-Cox-regression model, shock was a significant predictor of mortality after intoxication (odds ratio 18.182, 95% confidence interval 2.045-166.667, P = 0.009). The mortality rate was 19.7%. Acute cholinergic crisis, intermediate syndrome, and delayed neuropathy developed in 100.0%, 15.5%, and 4.2% of patients, respectively.

Asunto(s)

Lesión Renal Aguda/tratamiento farmacológico , Antídotos/uso terapéutico , Insecticidas/toxicidad , Intoxicación por Organofosfatos/tratamiento farmacológico , Neumonía por Aspiración/tratamiento farmacológico , Insuficiencia Respiratoria/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/mortalidad , Lesión Renal Aguda/fisiopatología , Afecto/efectos de los fármacos , Anciano , Atropina/uso terapéutico , Cloropirifos/antagonistas & inhibidores , Cloropirifos/toxicidad , Femenino , Humanos , Insecticidas/antagonistas & inhibidores , Masculino , Mevinfos/antagonistas & inhibidores , Mevinfos/toxicidad , Persona de Mediana Edad , Intoxicación por Organofosfatos/etiología , Intoxicación por Organofosfatos/mortalidad , Intoxicación por Organofosfatos/fisiopatología , Compuestos Organotiofosforados/antagonistas & inhibidores , Compuestos Organotiofosforados/toxicidad , Neumonía por Aspiración/inducido químicamente , Neumonía por Aspiración/mortalidad , Neumonía por Aspiración/fisiopatología , Compuestos de Pralidoxima/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/etiología , Trastornos Psicóticos/mortalidad , Trastornos Psicóticos/fisiopatología , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/mortalidad , Insuficiencia Respiratoria/fisiopatología , Estudios Retrospectivos , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/mortalidad , Convulsiones/fisiopatología , Choque/inducido químicamente , Choque/tratamiento farmacológico , Choque/mortalidad , Choque/fisiopatología , Análisis de Supervivencia , Resultado del Tratamiento

RESUMEN

Lysine methyltransferase 2A (KMT2A, also known as MLL) translocations (MLL­t) are frequently associated with mutations in RAS pathway genes in acute myeloid leukemia (AML). Previous findings with a mouse model showed that cooperation of MLL/AF10 with tyrosine­protein phosphatase non­receptor type 11 (PTPN11)G503A accelerated leukemia development, but increased cytarabine (Ara­C) sensitivity of leukemia cells. To identify the genes responsible for reduced survival and Ara­C resistance, transcriptomic profiling between six pairs of mouse MLL/AF10(OM­LZ) leukemia cells harboring activating and wild­type KRAS or PTPN11 was compared. A total of 23 differentially expressed genes (DEGs) with >1.5­fold­change between the paired cell lines were identified. The Gene Ontology (GO) terms overrepresented in these 23 DEGs included 'immune system process', 'actin filament binding', 'cellular response to interferon­alpha' and 'sequence­specific DNA'. Among the four genes (Hoxa11, PR domain zinc finger protein 5, Iroquois­class homeodomain protein IRX­5 and homeobox protein PKNOX2) mapped to the GO term 'sequence­specific DNA', HOXA11 upregulation was associated with AML harboring MLL­t and RAS signaling mutations based on a meta­analysis using data deposited in Oncomine™ and analysis of the clinical samples in the present study. Microarray data revealed that only Hoxa11 was upregulated in those cells harboring activating PTPN11. Functional studies of Hoxa11 knockdown or overexpression in MLL/AF10(OM­LZ) cells revealed that Hoxa11 expression levels were associated with survival in vivo and Ara­C sensitivity/apoptosis in vitro. In addition, Hoxa11 regulated the expression of the apoptosis­related genes, NF­κB inhibitor α, transcription factor p65 and transformation­related protein p53. Furthermore, the results of a meta­analysis using Heuser's AML dataset supported the finding that chemotherapy responders have higher expression levels of HOXA11. These results indicated that the expression of HOXA11 increased cell apoptosis and predicted an improved response to Ara­C in AML.

Asunto(s)

Citarabina/farmacología , N-Metiltransferasa de Histona-Lisina/genética , Proteínas de Homeodominio/genética , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Regulación hacia Arriba , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos , Perfilación de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Ratones , Mutación , Trasplante de Neoplasias , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Transducción de Señal/efectos de los fármacos , Proteínas ras/metabolismo

RESUMEN

Although patients with diabetes mellitus mostly present with enlarged or normal-sized kidneys throughout their life, a small proportion of patients have small kidneys. This longitudinal study enrolled 83 diabetic patients treated with peritoneal dialysis (PD) between 2015 and 2019. Patients were stratified into two groups, those with enlarged or normal (n = 67) or small (n = 16) kidneys, based on their kidney sizes before dialysis. Patients with small kidney size were not only older (76.63 ± 10.63 vs. 68.03 ± 11.26 years, P = 0.007), suffered longer duration of diabetes mellitus (272.09 ± 305.09 vs. 151.44 ± 85.31 month, P = 0.006) and predominantly female (75.0 vs. 41.8%, P = 0.017), but also had lower serum levels of creatinine (9.63 ± 2.82 vs. 11.74 ± 3.32 mg/dL, P = 0.022) and albumin (3.23 ± 0.67 vs. 3.60 ± 0.47 g/dL, P = 0.010) than patients with enlarged or normal kidney size. At the end of analysis, 14 (16.9%) patients died. Patients with small kidney size demonstrated higher all-cause (50.0 vs. 9.0%, P < 0.001) and infection-related (43.8 vs. 7.5%, P < 0.001) mortality than patients with enlarged or normal kidney size. In a multivariate-logistic-regression model, small kidney size was a powerful predictor of mortality (odds ratio 6.452, 95% confidence interval 1.220-34.482, P = 0.028). Diabetic patients with small kidney size at the beginning of PD carry a substantial risk for mortality.

Asunto(s)

Nefropatías Diabéticas/mortalidad , Fallo Renal Crónico/mortalidad , Riñón/patología , Diálisis Peritoneal , Anciano , Anciano de 80 o más Años , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/terapia , Femenino , Humanos , Fallo Renal Crónico/patología , Fallo Renal Crónico/terapia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Diálisis Peritoneal/estadística & datos numéricos , Análisis de Supervivencia , Taiwán/epidemiología

RESUMEN

BACKGROUND: Previous studies have shown that environmental cadmium exposure could disrupt salivary gland function and is associated with dental caries and reduced bone density. Therefore, this cross-sectional study attempted to determine whether tooth decay with tooth loss following cadmium exposure is associated with some dental or skeletal traits such as malocclusions, sagittal skeletal pattern, and tooth decay. METHODS: Between August 2019 and June 2020, 60 orthodontic patients with no history of previous orthodontics, functional appliances, or surgical treatment were examined. The patients were stratified into two groups according to their urine cadmium concentrations: high (>1.06 µg/g creatinine, n = 28) or low (<1.06 µg/g creatinine, n = 32). RESULTS: The patients were 25.07 ± 4.33 years old, and most were female (female/male: 51/9 or 85%). The skeletal relationship was mainly Class I (48.3%), followed by Class II (35.0%) and Class III (16.7%). Class I molar relationships were found in 46.7% of these patients, Class II molar relationships were found in 15%, and Class III molar relationships were found in 38.3%. The mean decayed, missing, and filled surface (DMFS) score was 8.05 ± 5.54, including 2.03 ± 3.11 for the decayed index, 0.58 ± 1.17 for the missing index, and 5.52 ± 3.92 for the filled index. The mean index of complexity outcome and need (ICON) score was 53.35 ± 9.01. The facial patterns of these patients were within the average low margin (26.65 ± 5.53 for Frankfort-mandibular plane angle (FMA)). There were no significant differences in the above-mentioned dental indices between patients with high urine cadmium concentrations and those with low urine cadmium concentrations. Patients were further stratified into low (<27, n = 34), average (27-34, n = 23), and high (>34, n = 3) FMA groups. There were no statistically significant differences in the urine cadmium concentration among the three groups. Nevertheless, a marginally significant p-value of 0.05 for urine cadmium concentration was noted between patients with low FMA and patients with high FMA. CONCLUSION: This analysis found no association between environmental cadmium exposure and dental indices in our orthodontic patients.

RESUMEN

BACKGROUND: Skeletal muscle injuries are very common in sports medicine. Conventional therapies have limited clinical efficacy. New treatment methods should be developed to allow athletes to return to play with better function. PURPOSE: To evaluate the in vitro differentiation potential of bone marrow-derived mesenchymal stem cells and the in vivo histologic and physiologic effects of mesenchymal stem cell therapy on muscle healing after contusion injury. STUDY DESIGN: Controlled laboratory study. METHODS: Bone marrow cells were flushed from both femurs of 5-week-old C57BL/6 mice to establish immortalized mesenchymal stem cell lines. A total of 36 mice aged 8 to 10 weeks were used to develop a muscle contusion model and were divided into 6 groups (6 mice/group) on the basis of the different dosages of IM2 cells to be injected (0, 1.25 × 105, and 2.5 × 105 cells with/without F-127 in 100 µL of phosphate-buffered saline). Histological analysis of muscle regeneration was performed, and the fast-twitch and tetanus strength of the muscle contractions was measured 28 days after muscle contusion injury, after injections of different doses of mesenchymal stem cells with or without the F-127 scaffold beginning 14 days after contusion injury. RESULTS: The mesenchymal stem cell-treated muscles exhibited numerous regenerating myofibers. All the groups treated with mesenchymal stem cells (1.25 × 105 cells, 2.5 × 105 cells, 1.25 × 105 cells plus F-127, and 2.5 × 105 cells plus F-127) exhibited a significantly higher number of regenerating myofibers (mean ± SD: 111.6 ± 14.77, 133.4 ± 21.44, 221.89 ± 32.65, and 241.5 ± 25.95, respectively) as compared with the control group and the control with F-127 (69 ± 18.79 and 63.2 ± 18.98). The physiologic evaluation of fast-twitch and tetanus strength did not reveal differences between the age-matched uninjured group and the groups treated with various doses of mesenchymal stem cells 28 days after contusion. Significant differences were found between the control group and the groups treated with various doses of mesenchymal stem cells after muscle contusion. CONCLUSION: Mesenchymal stem cell therapy increased the number of regenerating myofibers and improved fast-twitch and tetanus muscle strength in a mouse model of muscle contusion. However, the rapid decay of transplanted mesenchymal stem cells suggests a paracrine effect of this action. Treatment with mesenchymal stem cells at various doses combined with the F-127 scaffold is a potential therapy for a muscle contusion. CLINICAL RELEVANCE: Mesenchymal stem cell therapy has an effect on sports medicine because of its effects on myofiber regeneration and muscle strength after contusion injury.

Asunto(s)

Contusiones , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Músculo Esquelético/lesiones , Animales , Médula Ósea , Contusiones/terapia , Ratones , Ratones Endogámicos C57BL , Regeneración

RESUMEN

Leukemogenic potential of MLL fusion with the coiled-coil domain-containing partner genes and the downstream target genes of this type of MLL fusion have not been clearly investigated. In this study, we demonstrated that the coiled-coil-four-helix bundle structure of EB1 that participated in the MLL/EB1 was required for immortalizing mouse bone marrow (BM) cells and producing myeloid, but not lymphoid, cell lines. Compared to MLL/AF10, MLL/EB1 had low leukemogenic ability. The MLL/EB1 cells grew more slowly owing to increased apoptosis in vitro and induced acute monocytic leukemia with an incomplete penetrance and longer survival in vivo. A comparative analysis of transcriptome profiling between MLL/EB1 and MLL/AF10 cell lines revealed that there was an at least two-fold difference in the induction of 318 genes; overall, 51.3% (163/318) of the genes were known to be bound by MLL, while 15.4% (49/318) were bound by both MLL and MLL/AF9. Analysis of the 318 genes using Gene Ontology-PANTHER overrepresentation test revealed significant differences in several biological processes, including cell differentiation, proliferation/programmed cell death, and cell homing/recruitment. The Ets1 gene, bound by MLL and MLL/AF9, was involved in several biological processes. We demonstrated that Ets1 was selectively upregulated by MLL/EB1. Short hairpin RNA knockdown of Ets1 in MLL/EB1 cells reduced the expression of CD115, apoptosis rate, competitive engraftment to BM and spleen, and incidence of leukemia and prolonged the survival of the diseased mice. Our results demonstrated that MLL/EB1 upregulated Ets1, which controlled the balance of leukemia cells between apoptosis and BM engraftment/clonal expansion. Novelty and impact of this study The leukemogenic potential of MLL fusion with cytoplasmic proteins containing coiled-coil dimerization domains and the downstream target genes of this type of MLL fusion remain largely unknown. Using a retroviral transduction/transplantation mouse model, we demonstrated that MLL fusion with the coiled-coil-four-helix bundle structure of EB1 has low leukemogenic ability; Ets1, which is upregulated by MLL/EB1, plays a critical role in leukemic transformation by balance between apoptosis and BM engraftment/clonal expansion.

Asunto(s)

Trasplante de Médula Ósea , Transformación Celular Neoplásica/patología , N-Metiltransferasa de Histona-Lisina/metabolismo , Leucemia Experimental/patología , Leucemia Monocítica Aguda/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteína Proto-Oncogénica c-ets-1/metabolismo , Animales , Apoptosis , Diferenciación Celular , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Leucemia Experimental/genética , Leucemia Experimental/metabolismo , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Células 3T3 NIH , Proteínas de Fusión Oncogénica , Proteína Proto-Oncogénica c-ets-1/genética

RESUMEN

Paraquat intoxication is characterized by multi-organ failure, causing substantial mortality and morbidity. Many paraquat patients experience acute kidney injury (AKI), sometimes requiring hemodialysis. We observed 222 paraquat-intoxicated patients between 2000 and 2012, and divided them into AKI (n = 103) and non-AKI (n = 119) groups. The mortality rate was higher for AKI than non-AKI patients (70.1% vs. 40.0%, P < 0.001). Patients with AKI had a longer time to hospital arrival (P = 0.003), lower PaO2 (P = 0.006) and higher alveolar-arterial O2 difference (P < 0.001) 48 h after admission, higher sequential organ failure assessment 48-h score (P < 0.001), higher severity index of paraquat poisoning (SIPP) score (P = 0.016), lower PaCO2 at admission (P = 0.031), higher PaO2 at admission (P = 0.015), lower nadir PaCO2 (P = 0.001) and lower nadir HCO3 (P = 0.004) than non-AKI patients. Multivariate logistic regression indicated that acute hepatitis (P < 0.001), a longer time to hospital arrival (P < 0.001), higher SIPP score (P = 0.026) and higher PaO2 at admission (P = 0.014) were predictors of AKI. The area under the receiver operating characteristic curve confirmed that an Acute Kidney Injury Network 48-hour score ≥ 2 predicted AKI necessitating hemodialysis with a sensitivity of 0.6 and specificity of 0.832. AKI is common (46.4%) following paraquat ingestion, and acute hepatitis, the time to hospital arrival, SIPP score and PaO2 at admission were powerful predictors of AKI. Larger studies with longer follow-up durations are warranted.

RESUMEN

This study aimed to identify predictors of success rate of mesenchymal stem cell (MSC) isolation from human deciduous teeth pulp. A total of 161 deciduous teeth were extracted at the dental clinic of Chang Gung Memorial Hospital. The MSCs were isolated from dental pulps using a standard protocol. In total, 128 colonies of MSCs were obtained and the success rate was 79.5%. Compared to teeth not yielding MSCs successfully, those successfully yielding MSCs were found to have less severe dental caries (no/mild-to-moderate/severe: 63.3/24.2/12.5% versus 12.5/42.4/42.4%, P < 0.001) and less frequent pulpitis (no/yes: 95.3/4.7% versus 51.5/48.5%, P < 0.001). In a multivariate regression model, it was confirmed that the absence of dental caries (OR = 4.741, 95% CI = 1.564-14.371, P = 0.006) and pulpitis (OR = 9.111, 95% CI = 2.921-28.420, P < 0.001) was significant determinants of the successful procurement of MSCs. MSCs derived from pulps with pulpitis expressed longer colony doubling time than pulps without pulpitis. Furthermore, there were higher expressions of proinflammatory cytokines, interleukin- (IL-) 6 and monocyte chemoattractant protein- (MCP-) 1, P < 0.01, and innate immune response [toll-like receptor 1 (TLR1) and TLR8, P < 0.05; TLR2, TLR3, and TLR6, P < 0.01] in the inflamed than noninflamed pulps. Therefore, a carious deciduous tooth or tooth with pulpitis was relatively unsuitable for MSC processing and isolation.

Asunto(s)

Separación Celular/métodos , Pulpa Dental/citología , Células Madre Mesenquimatosas/citología , Diente Primario/citología , Diferenciación Celular , Humanos

RESUMEN

PTPN11 mutation, a RAS signaling pathway mutation, is associated with MLL translocations in acute leukemia. A girl with MLL/AF10 AML was found to carry PTPN11G503A . To study the impact of PTPN11G503A cooperating with MLL/AF10 on leukemogenesis, we established a retroviral transduction/transplantation mouse model. Compared to the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11wt , the cells harboring PTPN11G503A were hypersensitive to GM-CSF and IL3, and more resistant to death upon treatment with daunorubicin but sensitive to cytarabine. The cells harboring PTPN11G503A autonomously differentiated into macrophages (1.8%) in the medium containing IL3. Further studies showed that the cells had an elevated (∼2.9-fold) Csf1 transcription level and secreted more (∼4.5-fold) M-CSF to the medium which can stimulate monocyte/macrophage differentiation of BM cells. Mice transplanted with the cells harboring PTPN11G503A had a higher concentration of M-CSF in plasma. When mixed with the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11wt , the cells harboring PTPN11G503A had an increased competitive engraftment and clonal expansion in the BM and spleen of recipient mice, although no competitive growth advantage was observed in the in vitro co-culturing assays. The mice transplanted with the MLL/AF10(OM-LZ) cells harboring PTPN11wt developed myelomonocytic leukemia, while those transplanted with the cells harboring PTPN11G503A -induced monocytic leukemia in a shorter latency. Our results demonstrated that addition of PTPN11G503A to MLL/AF10 affected cell proliferation, chemo-resistance, differentiation, in vivo BM recruitment/clonal expansion and accelerated disease progression.

Asunto(s)

Transformación Celular Neoplásica/genética , Leucemia Monocítica Aguda/etiología , Leucemia Mielomonocítica Aguda/etiología , Mutación Missense , Proteína de la Leucemia Mieloide-Linfoide/fisiología , Proteínas de Fusión Oncogénica/fisiología , Mutación Puntual , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Animales , Médula Ósea/patología , Diferenciación Celular/efectos de los fármacos , Técnicas de Cocultivo , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Activación Enzimática/genética , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Lactante , Interleucina-3/farmacología , Leucemia Monocítica Aguda/genética , Leucemia Mielomonocítica Aguda/genética , Factor Estimulante de Colonias de Macrófagos/sangre , Macrófagos/citología , Ratones , Ratones Endogámicos C57BL , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/fisiología , Quimera por Radiación , Transducción Genética , Células Tumorales Cultivadas/trasplante

RESUMEN

A paucity of literature exists on risk factors for mortality in charcoal burning suicide. In this observational study, we analyzed the data of 126 patients with charcoal burning suicide that seen between 2002 and 2013. Patients were grouped according to status of renal damage as acute kidney injury (N = 49) or non-acute kidney injury (N = 77). It was found that patients with acute kidney injury suffered severer complications such as respiratory failure (P = 0.002), myocardial injury (P = 0.049), hepatic injury (P < 0.001), rhabdomyolysis (P = 0.045) and out-of-hospital cardiac arrest (P = 0.028) than patients without acute kidney injury. Moreover, patients with acute kidney injury suffered longer hospitalization duration (16.9 ± 18.3 versus 10.7 ± 10.9, P = 0.002) and had higher mortality rate (8.2% versus 0%, P = 0.011) than patients without injury. In a multivariate Cox regression model, it was demonstrated that serum creatinine level (P = 0.019) and heart rate (P = 0.022) were significant risk factors for mortality. Finally, Kaplan-Meier analysis revealed that patients with acute kidney injury suffered lower cumulative survival than without injury (P = 0.016). In summary, the overall mortality rate of charcoal burning suicide population was 3.2%, and acute kidney injury was a powerful predictor of mortality. Further studies are warranted.

Asunto(s)

Lesión Renal Aguda/complicaciones , Quemaduras/mortalidad , Intento de Suicidio , Lesión Renal Aguda/mortalidad , Adulto , Carbón Orgánico , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Paro Cardíaco Extrahospitalario/epidemiología , Paro Cardíaco Extrahospitalario/genética , Insuficiencia Respiratoria/epidemiología , Insuficiencia Respiratoria/etiología , Estudios Retrospectivos , Rabdomiólisis/epidemiología , Rabdomiólisis/etiología , Medición de Riesgo , Adulto Joven