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1.
ChemSusChem ; 17(15): e202301145, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-38578225

RESUMO

Graphitic nanoplatelets (GnPs), edge-selectively carboxylated graphitic nanoplatelets (ECGnPs), are functionalized with a carboxylic acid at the edge increasing their surface area, and are highly dispersible in various solvents. However, there is a limit in that the basal plane remains intact because it is functionalized only in the part where the radical is generated at the edge. Here, we activate ECGnPs to have porous structures by flowing CO2 at 900 °C. Etching of the ECGnPs structure was performed through the Boudouard reaction, and the surface area increased from 579 m2 g-1 to a maximum of 2462 m2 g-1. In addition, the pore structure was investigated with various adsorption gases (CH4, Ar, CO2, H2, and N2) according to the reaction time. This study provides the overall green chemistry in that it utilizes CO2 from manufacturing to activation compared to the process of activating with conventional chemical treatment.

2.
Nanoscale ; 16(14): 7110-7122, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38501279

RESUMO

This study was initiated due to the physically unexplainable tumor controls resulting from metal nanoparticle (MNP) experiments even under MV X-ray irradiation. A more accurate explanation of the mechanism of radiosensitization induced by MNP is warranted, considering both its physical dose enhancement and biological sensitization, as related research is lacking. Thus, we aimed to examine the intricate dynamics involved in MNP-induced radiosensitization. We conducted specifically designed clonogenic assays for the A549 lung cancer cell line with MNP irradiated by 6 MV and 300 kVp X-rays. Two types of MNP were employed: one based on iron oxide, promoting ferroptosis, and the other on gold nanoparticles known for inducing a significant dose enhancement, particularly at low-energy X-rays. We introduced the lethality enhancement factor (LEF) as the fraction in the cell killing attributed to biological sensitization. Subsequently, Monte Carlo simulations were conducted to evaluate the radial dose profiles for each MNP, corresponding to the physical enhancement. Finally, the local effect model was applied to the clonogenic assay results on real cell images. The LEF and the dose enhancement in the cytoplasm were incorporated to increase the accuracy in the average lethal events and, consequently, in the survival fraction. The results reveal an increased cell killing for both of the MNP under MV and kV X-ray irradiation. In both types of MNP, the LEF reveals a biological sensitization evident. The sensitizer enhancement ratio, derived from the calculations, exhibited only 3% and 1% relative differences compared to the conventional linear-quadratic model for gold and ferroptosis inducer nanoparticles, respectively. These findings indicate that MNPs sensitize cells via radiation through mechanisms akin to ferroptosis inducers, not exclusively relying on a physical dose enhancement. Their own contributions to survival fractions were successfully integrated into computational modeling.


Assuntos
Neoplasias Pulmonares , Nanopartículas Metálicas , Humanos , Raios X , Ouro/farmacologia , Simulação por Computador , Método de Monte Carlo
3.
Front Oncol ; 13: 1186311, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37384292

RESUMO

Purpose: Accurate risk stratification can improve lymphoma management, but current volumetric 18F-fluorodeoxyglucose (FDG) indicators require time-consuming segmentation of all lesions in the body. Herein, we investigated the prognostic values of readily obtainable metabolic bulk volume (MBV) and bulky lesion glycolysis (BLG) that measure the single largest lesion. Methods: The study subjects were a homogeneous cohort of 242 newly diagnosed stage II or III diffuse large B-cell lymphoma (DLBCL) patients who underwent first-line R-CHOP treatment. Baseline PET/CT was retrospectively analyzed for maximum transverse diameter (MTD), total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), MBV, and BLG. Volumes were drawn using 30% SUVmax as threshold. Kaplan-Meier survival analysis and the Cox proportional hazards model assessed the ability to predict overall survival (OS) and progression-free survival (PFS). Results: During a median follow-up period of 5.4 years (maximum of 12.7 years), events occurred in 85 patients, including progression, relapse, and death (65 deaths occurred at a median of 17.6 months). Receiver operating characteristic (ROC) analysis identified an optimal TMTV of 112 cm3, MBV of 88 cm3, TLG of 950, and BLG of 750 for discerning events. Patients with high MBV were more likely to have stage III disease; worse ECOG performance; higher IPI risk score; increased LDH; and high SUVmax, MTD, TMTV, TLG, and BLG. Kaplan-Meier survival analysis showed that high TMTV (p = 0.005 and < 0.001), MBV (both p < 0.001), TLG (p < 0.001 and 0.008), and BLG (p = 0.018 and 0.049) were associated with significantly worse OS and PFS. On Cox multivariate analysis, older age (> 60 years; HR, 2.74; 95% CI, 1.58-4.75; p < 0.001) and high MBV (HR, 2.74; 95% CI, 1.05-6.54; p = 0.023) were independent predictors of worse OS. Older age (hazard ratio [HR], 2.90; 95% CI, 1.74-4.82; p < 0.001) and high MBV (HR, 2.36; 95% CI, 1.15-6.54; p = 0.032) were also independent predictors of worse PFS. Furthermore, among subjects ≤60 years, high MBV remained the only significant independent predictor of worse OS (HR, 4.269; 95% CI, 1.03-17.76; p = 0.046) and PFS (HR, 6.047; 95% CI, 1.73-21.11; p = 0.005). Among subjects with stage III disease, only greater age (HR, 2.540; 95% CI, 1.22-5.30; p = 0.013) and high MBV (HR, 6.476; 95% CI, 1.20-31.9; p = 0.030) were significantly associated with worse OS, while greater age was the only independent predictor of worse PFS (HR, 6.145; 95% CI, 1.10-4.17; p = 0.024). Conclusions: MBV easily obtained from the single largest lesion may provide a clinically useful FDG volumetric prognostic indicator in stage II/III DLBCL patients treated with R-CHOP.

4.
Allergy ; 78(5): 1292-1306, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36609802

RESUMO

BACKGROUND: Staphylococcus (S) aureus colonization is known to cause skin barrier disruption in atopic dermatitis (AD) patients. However, it has not been studied how S. aureus induces aberrant epidermal lipid composition and skin barrier dysfunction. METHODS: Skin tape strips (STS) and swabs were obtained from 24 children with AD (6.0 ± 4.4 years) and 16 healthy children (7.0 ± 4.5 years). Lipidomic analysis of STS samples was performed by mass spectrometry. Skin levels of methicillin-sensitive and methicillin-resistant S. aureus (MSSA and MRSA) were evaluated. The effects of MSSA and MRSA were evaluated in primary human keratinocytes (HEKs) and organotypic skin cultures. RESULTS: AD and organotypic skin colonized with MRSA significantly increased the proportion of lipid species with nonhydroxy fatty acid sphingosine ceramide with palmitic acid ([N-16:0 NS-CER], sphingomyelins [16:0-18:0 SM]), and lysophosphatidylcholines [16:0-18:0 LPC], but significantly reduced the proportion of corresponding very long-chain fatty acids (VLCFAs) species (C22-28) compared to the skin without S. aureus colonization. Significantly increased transepidermal water loss (TEWL) was found in MRSA-colonized AD skin. S. aureus indirectly through interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, and IL-33 inhibited expression of fatty acid elongase enzymes (ELOVL3 and ELOVL4) in HEKs. ELOVL inhibition was more pronounced by MRSA and resulted in TEWL increase in organotypic skin. CONCLUSION: Aberrant skin lipid profiles and barrier dysfunction are associated with S. aureus colonization in AD patients. These effects are attributed to the inhibition of ELOVLs by S. aureus-induced IL-1ß, TNF-α, IL-6, and IL-33 seen in keratinocyte models and are more prominent in MRSA than MSSA.


Assuntos
Dermatite Atópica , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Criança , Humanos , Staphylococcus aureus , Interleucina-33/farmacologia , Interleucina-6 , Dermatite Atópica/patologia , Lipídeos
5.
Hum Pathol ; 113: 9-19, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33771538

RESUMO

MYC-rearranged large B-cell lymphoma with BCL2 and/or BCL6 rearrangement, double-hit (DH) or triple-hit (TH) lymphoma, is associated with poor survival after standard treatment. To investigate the clinical impact of single-hit (SH) MYC rearrangement, we analyzed 241 cases of diffuse large B-cell lymphoma (DLBCL) for MYC, BCL2, and BCL6 rearrangement by fluorescence in situ hybridization. Fifty-five of 241 (22.8%) cases showed MYC rearrangements. Twenty-three cases were diagnosed as DLBCL; 18 as high-grade B-cell lymphoma (HGBCL)-DH; 3 as HGBCL-TH; and 11 as HGBCL, not otherwise specified. Both DH and TH lymphomas showed high-grade morphology (P = 0.002), higher stage (P = 0.022), and more frequent germinal center B-cell-like phenotype (P = 0.008). SH lymphomas displayed high-grade morphology (P = 0.002) but were not different from MYC-negative lymphomas in cell of origin, clinical stage, international prognostic index (IPI), or extranodal involvement. Patients with DH/TH lymphomas had worse overall survival (OS) (P = 0.016) and progression-free survival (PFS) (P < 0.001), while OS and PFS of SH lymphomas were not different from those of MYC-negative lymphomas. There was no survival difference between cases of BCL2 and BCL6 rearrangements. Poorer prognostic factors included higher ECOG class, higher IPI, and DH or TH translocation for OS, and higher IPI and DH or TH translocation for PFS. Higher IPI was an independent prognostic factor for OS and PFS. In conclusion, large B-cell lymphomas with single MYC rearrangement showed high-grade morphology but were otherwise not different from MYC-negative lymphomas.


Assuntos
Biomarcadores Tumorais/genética , Rearranjo Gênico , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Progressão da Doença , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fenótipo , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Fatores de Tempo
6.
PLoS One ; 14(10): e0223913, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31671118

RESUMO

Probiotics are dietary supplements containing viable, non-pathogenic microorganisms that interact with the gastrointestinal microflora and directly with the immune system. The possible health effects of probiotics include modulating the immune system and exerting antibacterial, anticancer, and anti-mutagenic effects. The purpose of this study was to isolate, identify, and characterize novel strains of probiotics from the faeces of Korean infants. Various assays were conducted to determine the physiological features of candidate probiotic isolates, including Gram staining, 16S rRNA gene sequencing, tolerance assays to stimulated gastric juice and bile salts, adherence ability assays, antibiotic susceptibility testing, and assays of immunomodulatory effects. Based on these morphological and biochemical characteristics, five potential probiotic isolates (Enterococcus faecalis BioE EF71, Lactobacillus fermentum BioE LF11, Lactobacillus plantarum BioE LPL59, Lactobacillus paracasei BioE LP08, and Streptococcus thermophilus BioE ST107) were selected. E. faecalis BioE EF71 and L. plantarum BioE LPL59 showed high tolerance to stimulated gastric juice and bile salts, and S. thermophilus BioE ST107 as well as these two strains exhibited stronger adherence ability than reference strain Lactobacillus rhamnosus GG. All five strains inhibited secretion of lipopolysaccharide-induced pro-inflammatory cytokines IL-6 and TNF-α in RAW264.7 macrophages in vitro. L. fermentum BioE LF11, L. plantarum BioE LPL59, and S. thermophilus BioE ST107 enhanced the production of anti-inflammatory cytokine IL-10. Overall, our findings demonstrate that the five novel strains have potential as safe probiotics and encouraged varying degrees of immunomodulatory effects.


Assuntos
Fezes/microbiologia , Probióticos/isolamento & purificação , Animais , Aderência Bacteriana , Ácidos e Sais Biliares/metabolismo , Criança , Pré-Escolar , Citocinas/metabolismo , Farmacorresistência Bacteriana , Feminino , Humanos , Concentração de Íons de Hidrogênio , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/metabolismo , Fatores Imunológicos/farmacologia , Lactente , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Probióticos/metabolismo , Probióticos/farmacologia , Células RAW 264.7
7.
Biochem Biophys Res Commun ; 512(3): 604-610, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30910357

RESUMO

Accumulation of senescent cells leads to aging related phenotypes in various organs. Sarcopenia is a frequently observed aging-related disease, which is associated with the loss of muscle mass and functional disability. Physical activity represents the most critical treatment method for preventing decreased muscle size, mass and strength. However, the underlying mechanism as to how physical activity provides this beneficial effect on muscle function has not yet been fully understood. In particular, one unresolved question about aging is how the boost in catabolism induced by aerobic exercise affects skeletal muscle atrophy and other senescence phenotypes. Here we show that pre-activation of AMPK with the AMPK activator, AICAR can mitigate the diminished cellular viability of skeletal muscle cells induced by doxorubicin, which accelerates senescence through free radical production. Pre-incubation for 3 h with AICAR decreased doxorubicin-induced phosphorylation of AMPK in a differentiated skeletal muscle cell line. Accordingly, cellular viability of skeletal muscle cells was recovered in the cells pre-treated with AICAR then administered doxorubicin as compared to that of doxorubicin-only treatment. In accordance with the results of cellular experiments, we verified that 4 weeks of treadmill exercise decreased the senescence marker, p16 and p21 in 19-month-old mice compared to sedentary mice. In this study, we provide new evidence that prior activation of AMPK can reduce doxorubicin induced cell senescence phenotypes. The evidence in this paper suggest that aerobic exercise-activated catabolism in the skeletal muscle may prevent cellular senescence, partially through the cell cycle regulation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Músculo Esquelético/citologia , Condicionamento Físico Animal , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Antibióticos Antineoplásicos/efeitos adversos , Linhagem Celular , Senescência Celular/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Ativação Enzimática/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Ribonucleotídeos/farmacologia
8.
Biol Blood Marrow Transplant ; 25(7): 1312-1319, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30910603

RESUMO

A phase I/II trial was conducted to explore the safety and activity of the addition of bortezomib on days -6, -3, and +1 relative to the day of autologous stem cell transplantation (ASCT) to a conditioning regimen with busulfan and melphalan (BuMel; 3.2 mg/kg/day busulfan on days -5 to -3 and 140 mg/m2/day melphalan on day -2) in patients with multiple myeloma (MM) following bortezomib-based induction chemotherapy. In phase I, doses of bortezomib (.7, 1.0, and 1.3 mg/m2) with BuMel were administered to groups of 3 patients each. No dose-limiting toxicities were observed. The maximum tolerated dose of bortezomib was 1.3 mg/m2/day. A subsequent cohort with 41 patients was analyzed in a phase II trial to identify safety and efficacy. The phase II trial showed a 75% response rate, including very good partial response (VGPR) or better, and a 55% rate of complete response (CR) at 3 months; For post-transplantation best response, an 83% rate of VGPR or better (68% CR) was observed. With a median follow-up of 31.4 months, the median progression-free survival (PFS) was 26.8 months. The probability of 2 year-PFS was 56.5%, and median overall survival (OS) could not calculated. Specifically, high-risk cytogenetics were associated with adverse survival outcomes compared with standard-risk cytogenetics (median PFS, 12.2 months versus 35.7 months, P = .039; median OS, 26.7 months versus 73.3 months; P = .086). With a median of 11 days to neutrophil engraftment and 10 days for platelet engraftment, no graft failure or delayed engrafting were observed. The most common grade 3 or severe nonhematologic adverse events included neutropenic fever (73.2%) and stomatitis (14.6%). Except for 3 patients with transplantation-related mortality due to sepsis, other adverse events were manageable. These findings demonstrate that bortezomib is safe and has a potential role in conditioning regimens in combination with BuMel for patients with transplantation-eligible MM.


Assuntos
Bortezomib/administração & dosagem , Bussulfano/administração & dosagem , Melfalan/administração & dosagem , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Adulto , Idoso , Autoenxertos , Bortezomib/efeitos adversos , Bussulfano/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida
9.
Cancer Res Treat ; 51(2): 611-622, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30025443

RESUMO

PURPOSE: Pembrolizumab, a programmed cell death protein 1 (PD1) inhibitor inhibits the interplay between PD1 of T-cell and programmed cell death ligand 1 (PDL1) on tumor cells. Although pembrolizumab has been tried to various subtypes of non-Hodgkin lymphoma (NHL), realworld data about the efficacy of pembrolizumab in NHL patients are limited. MATERIALS AND METHODS: We analyzed the outcome of 30 relapsed or refractory NHL patients treated with pembrolizumab, and compared the outcome between Epstein-Barr virus (EBV)‒positive and negative subtypes because EBV infection of tumor cells can upregulate PDL1 expression. RESULTS: Seven patients with EBV-positive NHL showed a response including NK/T-cell lymphoma (6/14, 44%) and primary mediastinal B-cell lymphoma (1/4, 25%) whereas EBV-negative subtypes did not respond such as diffuse large B-cell lymphoma and T-lymphoblastic lymphoma. We also evaluated PDL1 expression using tumor tissue of 76 patients. High PDL1 expression (positive staining of > 50% of tumor cells) was more frequent in NK/T-cell lymphoma and primary mediastinal B-cell lymphoma than other subtypes. Thus, PDL1 expression was significantly higher in EBV-positive (18/32, 56%) than EBV-negative NHL (4/38, 11%, p < 0.001). Furthermore, NK/T-cell lymphoma patients with high PDL1 expression showed a higher response (4/6, 67%) than those with low PDL1 expression (1/5, 20%). CONCLUSION: Pembrolizumab could be useful as a salvage treatment for relapsed or refractory EBV-positive NHL, especially NK/T-cell lymphoma. However, its efficacy in EBV-negative NHL with low or absent PDL1 expression is still not clear although pembrolizumab could be a potential treatment option for relapsed or refractory NHL.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4 , Humanos , Imuno-Histoquímica , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/etiologia , Linfoma não Hodgkin/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Resultado do Tratamento
10.
Angew Chem Int Ed Engl ; 57(13): 3415-3420, 2018 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-29392856

RESUMO

A three-dimensional (3D) cage-like organic network (3D-CON) structure synthesized by the straightforward condensation of building blocks designed with gas adsorption properties is presented. The 3D-CON can be prepared using an easy but powerful route, which is essential for commercial scale-up. The resulting fused aromatic 3D-CON exhibited a high Brunauer-Emmett-Teller (BET) specific surface area of up to 2247 m2 g-1 . More importantly, the 3D-CON displayed outstanding low pressure hydrogen (H2 , 2.64 wt %, 1.0 bar and 77 K), methane (CH4 , 2.4 wt %, 1.0 bar and 273 K), and carbon dioxide (CO2 , 26.7 wt %, 1.0 bar and 273 K) uptake with a high isosteric heat of adsorption (H2 , 8.10 kJ mol-1 ; CH4 , 18.72 kJ mol-1 ; CO2 , 31.87 kJ mol-1 ). These values are among the best reported for organic networks with high thermal stability (ca. 600 °C).

11.
Mod Pathol ; 30(1): 4-14, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27687005

RESUMO

The prognostic role of MYC has been well documented in non-central nervous system diffuse large B-cell lymphoma; however, it remains controversial in central nervous system diffuse large B-cell lymphoma. To investigate the prognostic value of MYC, we analyzed the MYC protein expression by immunohistochemistry, mRNA expression by RNA in situ hybridization, and gene status by fluorescence in situ hybridization in 74 cases of central nervous system diffuse large B-cell lymphoma. Moreover, we examined the correlation between MYC translocation, mRNA expression, and protein expression. The mean percentage of MYC immunopositive cells was 49%. Using a 44% cutoff value, 49 (66%) cases showed MYC protein overexpression. The result of mRNA in situ hybridization using the RNA scope technology was obtained using the H-scoring system; the median value was 34.2. Using the cutoff value of 63.5, 16 (22%) cases showed MYC mRNA overexpression. MYC gene rearrangement was detected in five out of 68 (7%) cases. MYC translocation showed no statistically significant correlation with mRNA expression; however, all MYC translocation-positive cases showed MYC protein overexpression, with a higher mean percentage of MYC protein expression than that of translocation-negative cases (78 vs 48%, P=0.001). The level of MYC mRNA expression was moderately correlated with the level of MYC protein expression (P<0.001). The mean percentage of MYC protein expression in the high MYC mRNA group was higher than that in the low MYC mRNA group (70 vs 47%, P<0.001). A univariate analysis showed that age over 60 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and MYC protein overexpression were significantly associated with an increased risk of death. MYC translocation and MYC mRNA expression had no prognostic significance. On multivariate analysis, MYC protein overexpression and ECOG score retained prognostic significance.


Assuntos
Neoplasias do Sistema Nervoso Central/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Adulto Jovem
12.
Oncotarget ; 7(52): 86433-86445, 2016 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-27835906

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although rituximab therapy improves clinical outcome, some patients develop resistant DLBCL; however, the genetic alterations in these patients are not well documented. To identify the genetic background of refractory DLBCL, we conducted whole-exome sequencing and transcriptome sequencing for six patients with refractory and seven with responsive DLBCL. The average numbers of pathogenic somatic single nucleotide variants and indels in coding regions were 71 in refractory patients (range 28-120) and 38 (range 19-66) in responsive patients. Missense mutations of TP53 were exclusive in 50% (3/6) of refractory patients and involved the DNA-binding domain of TP53. All missense mutations of TP53 were accompanied by copy number deletions. RAB11FIP5, PRKCB, PRDM15, FNBP4, AHR, CEP128, BRE, DHX16, MYO6, and NMT1 mutations were recurrent in refractory patients. MYD88, B2M, SORCS3, and WDFY3 mutations were more frequent in refractory patients than in responsive patients. REL-BCL11A fusion was found in two refractory patients; one had both fusion and copy number gain. Recurrent copy gains of POU2AF1, SLC1A4, REL11, FANCL, CACNA1D, TRRAP, and CUX1 with significantly increased average expression were found in refractory patients. The expression profile revealed enriched gene sets associated with treatment resistance, including oxidative phosphorylation and ATP-binding cassette transporters. In conclusion, this study integrated both genomic and transcriptomic alterations associated with refractory DLBCL and found several treatment-resistance alterations that may contribute to refractoriness.


Assuntos
Exoma , Linfoma Difuso de Grandes Células B/genética , Transcriptoma , Variações do Número de Cópias de DNA , Fusão Gênica , Genes p53 , Humanos , Mutação
13.
J Med Eng Technol ; 39(3): 185-90, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25716188

RESUMO

To conduct mass screening and thereby reduce the spread of infection, a compact (13.5 cm × 8.5 cm × 2.5 cm), highly-mobile and hand-held infection-screening system was developed for rapid medical inspection in mass gathering places such as airports. The system is capable of non-contact vital-sign monitoring using two integrated sensors: a 24-GHz microwave radar for measuring heart and respiration rates and a thermopile array for capturing facial temperature. Subsequently, the system detects infected individuals using a linear discriminant function (LDA) from the derived vital-signs data. The system was tested on 10 subjects under two conditions (resting as normal and exercising as pseudo-infected, i.e. a 10-min bicycle ergometer at 100 W exercise); the normal and pseudo-infected conditions were classified successfully via LDA for all subjects (p < 0.01; classification error rate < 5%). The proposed non-contact system can be applied for preventing secondary exposure of medical doctors at the outbreak of highly pathogenic infectious diseases such as the Ebola virus.


Assuntos
Controle de Infecções/métodos , Programas de Rastreamento/instrumentação , Adulto , Aeroportos , Desenho de Equipamento , Frequência Cardíaca , Humanos , Programas de Rastreamento/métodos , Micro-Ondas , Radar , Reprodutibilidade dos Testes , Taxa Respiratória , Temperatura Cutânea , Adulto Jovem
14.
Ann Hum Genet ; 79(2): 99-107, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25644864

RESUMO

Hereditary transthyretin (TTR)-related amyloidosis (ATTR) seems to be a rare autosomal-dominant inherited form of systemic amyloidosis. Studies indicate considerable heterogeneity in the disease's presentation and genotype; however, there is little data from Korea, where the prevalence of hereditary ATTR is very low. In this study, we investigated the phenotypic and genotypic spectra of hereditary ATTR in Korea. Direct sequencing analysis was performed to detect TTR gene mutations in amyloidosis patients whose results of TTR immunohistochemical staining were positive or equivocal. Clinical presentation was categorized as exclusively cardiac, exclusively neurologic, or mixed phenotype. Of 12 genetic tests performed, seven were positive for TTR mutations. D58A (c.173A>C) was the most common mutation in this study (57%, 4/7). The majority of those patients with hereditary ATTR had the mixed phenotype (86%, 6/7). The patients with D58A mutation had older ages of disease onset (median, 61 years vs. 42 years; P = 0.08), and a higher incidence of gastrointestinal involvement (75% vs. 0%; P = 0.03) than those with other identified TTR mutations. A significant male predominance was also noted in this study (P = 0.01).


Assuntos
Neuropatias Amiloides Familiares/genética , Análise Mutacional de DNA , Mutação de Sentido Incorreto , Adulto , Substituição de Aminoácidos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia
16.
J Am Med Inform Assoc ; 21(e1): e129-35, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24043318

RESUMO

OBJECTIVE: To optimize a new visit-independent, population-based cancer screening system (TopCare) by using operations research techniques to simulate changes in patient outreach staffing levels (delegates, navigators), modifications to user workflow within the information technology (IT) system, and changes in cancer screening recommendations. MATERIALS AND METHODS: TopCare was modeled as a multiserver, multiphase queueing system. Simulation experiments implemented the queueing network model following a next-event time-advance mechanism, in which systematic adjustments were made to staffing levels, IT workflow settings, and cancer screening frequency in order to assess their impact on overdue screenings per patient. RESULTS: TopCare reduced the average number of overdue screenings per patient from 1.17 at inception to 0.86 during simulation to 0.23 at steady state. Increases in the workforce improved the effectiveness of TopCare. In particular, increasing the delegate or navigator staff level by one person improved screening completion rates by 1.3% or 12.2%, respectively. In contrast, changes in the amount of time a patient entry stays on delegate and navigator lists had little impact on overdue screenings. Finally, lengthening the screening interval increased efficiency within TopCare by decreasing overdue screenings at the patient level, resulting in a smaller number of overdue patients needing delegates for screening and a higher fraction of screenings completed by delegates. CONCLUSIONS: Simulating the impact of changes in staffing, system parameters, and clinical inputs on the effectiveness and efficiency of care can inform the allocation of limited resources in population management.


Assuntos
Detecção Precoce de Câncer , Administração dos Cuidados ao Paciente/organização & administração , Fluxo de Trabalho , Simulação por Computador , Promoção da Saúde , Humanos , Modelos Teóricos , Pesquisa Operacional
17.
Artigo em Inglês | MEDLINE | ID: mdl-25571068

RESUMO

The outbreak of infectious diseases such as influenza, dengue fever, and severe acute respiratory syndrome (SARS) are threatening the global health. Especially, developing countries in the South-East Asia region have been at serious risk. Rapid and highly reliable screening of infection is urgently needed during the epidemic season at mass gathering places, such as airport quarantine facilities, public health centers, and hospital outpatients units, etc. To meet this need, our research group is currently developing a multiple vital-signs based infection screening system that can perform human medical inspections within 15 seconds. This system remotely monitors facial temperature, heart and respiration rates using a thermopile array and a 24-GHz microwave radar, respectively. In this work, we redesigned our previous system to make a higher performance with a user-friendly interface. Moreover, the system newly included a multivariable logistic regression model (MLRM) to determine the possibility of infection. We tested the system on 34 seasonal influenza patients and 35 normal control subjects at the Japan Self-Defense Forces Central Hospital. The sensitivity and specificity of the screening system using the MLRM were 85.3% and 88.6%, respectively.


Assuntos
Monitoramento Epidemiológico , Influenza Humana/diagnóstico , Influenza Humana/epidemiologia , Programas de Rastreamento/métodos , Pandemias/prevenção & controle , Sinais Vitais , Adulto , Feminino , Humanos , Influenza Humana/transmissão , Japão , Masculino , Pessoa de Meia-Idade , Saúde Pública , Adulto Jovem
19.
J Craniofac Surg ; 19(2): 446-52, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18362725

RESUMO

Conventional histologic or histomorphometric evaluation provides clear evidence of the bone healing process. However, the sample preparation process is tedious and destructive, and the three-dimensional (3D) anisotropic information of the bone trabeculae is compromised. Micro-computed tomography (microCT) has been introduced as an alternative to these traditional evaluation methods. microCT is noninvasive and provides a faster approach to evaluate and quantify cancellous bone. Most previous studies that used microCT have focused on studying trabecular structures of cancellous bone. In this study, we used microCT to analyze the micro-architecture of the regenerated membranous bone using a rabbit cranial defect model. Two 1 cm diameter circular bony defects were created in 12 New Zealand white rabbits. Specimens were harvested at 6 weeks and 12 weeks after surgery and were scanned using a MicroCT machine (Skyscan 1072, Aartselaar, Belgium). The specimens were then sectioned and stained with Goldner's trichrome. Bone volume density (BV/TV), bone surface density (BS/BV), and trabecular thickness (TbTh) were determined from histomorphometric and two-dimensional (2D) and 3D microCT analysis. Pearson's correlation coefficient (gamma), paired t-tests, and intraclass correlation coefficients from measurements between the 2D and 3D microCT and histomorphometry were calculated. There were very strong positive correlations of BV/TV between histomorphometric and 2D or 3D microCT measurements. Correlation between histomorphometric and 2D microCT measurements for BS/BV was moderate, whereas correlation between histomorphometric and 3D microCT measurements was weak. Weak correlations in TbTh among the three methods were found. In conclusion, the present study suggests that, in evaluating micro-architectures in regenerated bones, the correlation between measuring methods vary according to the features measured.


Assuntos
Doenças Ósseas/fisiopatologia , Regeneração Óssea/fisiologia , Osso Parietal/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Animais , Compostos Azo , Densidade Óssea/fisiologia , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/patologia , Corantes , Modelos Animais de Doenças , Amarelo de Eosina-(YS) , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Verde de Metila , Microrradiografia , Osso Parietal/diagnóstico por imagem , Osso Parietal/patologia , Coelhos
20.
Clin Rheumatol ; 25(2): 258-61, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16453079

RESUMO

A 39-year-old woman presented with acute onset of arthralgia in both wrists. Although her primary gastric cancer was in remission after previous treatment, carcinomatous arthritis was suggested by the osteolytic radiographic findings and refractoriness to nonsteroidal anti-inflammatory drugs, which was then confirmed by synovial fluid cytopathology. In view of the high incidence of gastric cancer in Korea, gastric cancer involving the carpal bones should be considered when we encounter a patient presenting with inflammatory peripheral joint arthritis, which might be the first sign of recurrence.


Assuntos
Artrite/etiologia , Articulações do Carpo , Neoplasias Gástricas/complicações , Adulto , Neoplasias Ósseas/secundário , Ossos do Carpo , Feminino , Humanos , Síndromes Paraneoplásicas
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