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Osimertinib induces a marked response in non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) gene mutations. However, acquired resistance to osimertinib remains an inevitable problem. In this study, we aimed to investigate osimertinib-resistant mechanisms and evaluate the combination therapy of afatinib and chemotherapy. We established osimertinib-resistant cell lines (PC-9-OR and H1975-OR) from EGFR-mutant lung adenocarcinoma cell lines PC-9 and H1975 by high exposure and stepwise method. Combination therapy of afatinib plus carboplatin (CBDCA) and pemetrexed (PEM) was effective in both parental and osimertinib-resistant cells. We found that expression of thrombospondin-1 (TSP-1) was upregulated in resistant cells using cDNA microarray analysis. We demonstrated that TSP-1 increases the expression of matrix metalloproteinases through integrin signaling and promotes tumor invasion in both PC-9-OR and H1975-OR, and that epithelial-to-mesenchymal transition (EMT) was involved in H1975-OR. Afatinib plus CBDCA and PEM reversed TSP-1-induced invasion ability and EMT changes in resistant cells. In PC-9-OR xenograft mouse models (five female Balb/c-Nude mice in each group), combination therapy strongly inhibited tumor growth compared with afatinib monotherapy (5 mg/kg, orally, five times per week) or CBDCA (75 mg/kg, intraperitoneally, one time per week) + PEM (100 mg/kg, intraperitoneally, one time per week) over a 28-day period. These results suggest that the combination of afatinib plus CBDCA and PEM, which effectively suppresses TSP-1 expression, may be a promising option in EGFR-mutated NSCLC patients after the acquisition of osimertinib resistance.
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Acrilamidas , Afatinib , Compuestos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Mutación , Trombospondina 1 , Humanos , Trombospondina 1/genética , Trombospondina 1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Resistencia a Antineoplásicos/genética , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Afatinib/farmacología , Afatinib/uso terapéutico , Receptores ErbB/genética , Ratones , Línea Celular Tumoral , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Carboplatino/farmacología , Carboplatino/uso terapéutico , Femenino , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Ratones Desnudos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones Endogámicos BALB C , Indoles , PirimidinasRESUMEN
The relationship between lung cancer surgery and venous thromboembolism (VTE) in Japan has not been elucidated. This was a post hoc analysis of the Cancer-VTE Registry. The 1057 patients who underwent surgery for lung cancer were divided into the surgery alone (SA) group (n = 598) and the surgery plus chemotherapy (SC) group (n = 459), and the 1-year incidences of VTE and cerebral ischemia were analyzed. In the SA and SC groups, composite VTE was observed in one (0.2%) and 15 (3.3%) patients, respectively, and cerebral ischemia was observed in eight (1.3%) and four (0.9%) patients, respectively. Lymph node metastasis was more common in patients with D-dimer >1.2 µg/ml (odds ratio: 1.781, P = .004). SA had a low risk of VTE but a high risk of cerebral ischemia. Chemotherapy increases the risk of VTE. The D-dimer level was related to VTE and advanced cancer.
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BACKGROUND: Amrubicin (AMR) is one of the most active agents for small-cell lung cancer (SCLC). However, hematologic toxicity and infection at a commonly used dose (40 mg/m2) is problematic; the optimal dose remains undetermined. PATIENTS AND METHODS: To evaluate the optimal dose of AMR in terms of efficacy and safety, we reviewed consecutive data on patients with relapsed SCLC who received AMR at doses of 40, 35, and 30 mg/m2 (on days 1-3) at Nippon Medical School Hospital between October 2010 and November 2021. RESULTS: We reviewed the data of 86 patients (20, 45, 27 who received AMR doses of 40, 35, 30 mg/m2, respectively) according to our study criteria. For patients ≥ 75 years, the proportion who received second-line treatment tended to be higher in the 30-35 mg/m2 group. Objective response rates were 37/46/35%, median progression-free survival (PFS) were 3.0/4.7/3.2 months, and median overall survival (OS) were 7.8/16.3/8.0 months, respectively. Grade 4 neutropenia occurred in 58/39/31% of patients, which was higher for the 40 mg/m2 group. The incidence of febrile neutropenia did not differ between groups. Multivariate analysis identified the AMR dose was not associated with longer PFS and OS. CONCLUSION: Treatment with AMR between 30 and 35 mg/m2 showed relatively mild hematologic toxicity compared with AMR at 40 mg/m2, without any significant difference in efficacy. Lower dose of AMR for relapsed SCLC could be a promising treatment option.
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Antineoplásicos , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVE: We implemented augmented reality (AR) in remote consultations for enhanced pressure injury (PI) care in homecare nursing and improved the efficiency of on-site technical education for homecare nurses. The study aimed to depict expert techniques using AR technology to improve PI healing time in a male patient. METHOD: We developed and implemented a new system that combines a transparent hand with an image and gives an output as a video image in the existing remote consultation software. The system was used to support remote care of PIs by nurses. RESULTS: We succeeded in superimposing the expert nurse's nonverbal hand gestures onto the patient's wound in real time. The visiting nurse's understanding of the system had improved and there was an improvement in the patient's PI healing. CONCLUSION: These results suggest that remote consultation using AR is effective to observe precise wound care demonstrations of the steps of the PI treatment and provide effective treatment.
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Realidad Aumentada , Servicios de Atención de Salud a Domicilio , Consulta Remota , Humanos , Masculino , Consulta Remota/métodos , Programas Informáticos , Resultado del TratamientoRESUMEN
OBJECTIVE: Osteomyelitis is a limb-threatening complication of diabetic foot ulcers. Early identification of the disease is key to ensuring successful prognosis. In this study, we describe ultrasonographic features for the identification of osteomyelitis. METHOD: Patients were screened through clinical, ultrasonographic and probe-to-bone tests. RESULTS: Ultrasonographic features in three patients that could be used to identify diabetic foot osteomyelitis included periosteal reaction, periosteal elevation, cortical erosions and presence of sequestrum, all of which were confirmed by a plain X-ray. CONCLUSION: An ultrasonographic examination could be used for the early detection of osteomyelitis, which could help clinicians devise prompt treatment strategies.
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Diabetes Mellitus , Pie Diabético , Osteomielitis , Pie Diabético/complicaciones , Pie Diabético/diagnóstico por imagen , Humanos , Osteomielitis/diagnóstico por imagen , Radiografía , InvestigaciónRESUMEN
The arsenic-contaminated groundwater has attracted attention in much south and southeast Asian deltas, however, mainly on the deep aquifers. Here, arsenic (As) concentration and its fractionation of the sediment cores in a shallow aquifer in Bangladesh were investigated using ICP-MS, FE-EPMA, XRD and 14C-AMS chronology techniques. The results of the present study indicated that the peak concentrations of As (54.7-79.1 µg/g) were in peat layers (at a depth of 7.5-8.0 m). Several types of iron (oxyhidr)oxides and framboidal pyrite, which contain As also, were found in the peat samples. The high concentrations of As were in an exchangeable form, As-bearing iron crystalline and As-bearing organic materials. We revealed that the As-rich peat layers were formed from 3170 to 3901 cal yrs before, due to the sea level decrease in this area. The 16S rRNA gene-based phylogenetic analysis revealed that the bacterial strains in the As-rich peats were mainly affiliated with genera Acinetobacter, Enterobacter, Escherichia, Bacillus, Clostridiaceae and Acinetobacter. The geo-accumulation index (Igeo) and ecological risk index assessment were calculated for the sediments, which shows that As-rich sediment layers were in range of moderately to heavily contaminated and considerable classes, respectively. Under the permanent saturated condition, the As-rich peat layers should be considered as an important potential driver of the groundwater As in this area.
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Arsénico , Agua Subterránea , Contaminantes Químicos del Agua , Arsénico/análisis , Bangladesh , Monitoreo del Ambiente/métodos , Sedimentos Geológicos/química , Agua Subterránea/química , Hierro/análisis , Óxidos/análisis , Filogenia , ARN Ribosómico 16S/genética , Suelo , Contaminantes Químicos del Agua/análisisRESUMEN
BACKGROUND: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. METHODS: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. RESULTS: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated ß-galactosidase (SA-ß-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice. CONCLUSIONS: Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.
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Carcinogénesis/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteínas de Fusión Oncogénica/metabolismo , Telomerasa/metabolismo , Animales , Carcinogénesis/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular , Proliferación Celular/genética , Senescencia Celular/genética , Daño del ADN , Modelos Animales de Enfermedad , Células Epiteliales , Femenino , Fibroblastos , Regulación Neoplásica de la Expresión Génica , Vectores Genéticos/genética , Humanos , Lentivirus/genética , Neoplasias Pulmonares/patología , Ratones , Proteínas de Fusión Oncogénica/genética , RNA-Seq , Telomerasa/genética , Homeostasis del Telómero/genética , TransfecciónRESUMEN
(1) Background: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable problem for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR-mutated lung cancer remains largely unknown. (2) Methods: Osimertinib- and afatinib-resistant EGFR-mutated lung cancer cells were established using a stepwise method. A microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells and evaluated by bioinformatics analysis through medical-industrial collaboration. (3) Results: Colorectal neoplasia differentially expressed (CRNDE) and DiGeorge syndrome critical region gene 5 (DGCR5) lncRNAs were highly expressed in EGFR-TKI-resistant cells by microarray analysis. RNA-protein binding analysis revealed eukaryotic translation initiation factor 4A3 (eIF4A3) bound in an overlapping manner to CRNDE and DGCR5. The CRNDE downregulates the expression of eIF4A3, mucin 1 (MUC1), and phospho-EGFR. Inhibition of CRNDE activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity, and restored sensitivity to EGFR-TKIs. (4) Conclusions: The results showed that CRNDE is associated with the development of resistance to EGFR-TKIs. CRNDE may be a novel therapeutic target to conquer EGFR-mutant NSCLC.
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ARN Helicasas DEAD-box/metabolismo , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Factor 4A Eucariótico de Iniciación/metabolismo , Neoplasias Pulmonares/genética , Mucina-1/metabolismo , Mutación/genética , Inhibidores de Proteínas Quinasas/farmacología , ARN Largo no Codificante/metabolismo , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Modelos Biológicos , Inhibidores de Proteínas Quinasas/uso terapéutico , ARN Largo no Codificante/genética , Transducción de Señal/efectos de los fármacosRESUMEN
AIMS: Given the utility of ultrasonography in assessing pressure injury, some ultrasonographic findings have already been used as indicators of deep tissue pressure injury. Despite reports showing that a cloud-like ultrasonographic pattern reflected the presence of deep tissue necrosis, identifying cloud-like patterns was difficult given the presence of similar findings, such as a cobblestone-like pattern. This case series reports patients with pressure injuries who presented with a cloud-like (five cases) and cobblestone-like (four cases) pattern during ultrasonography. METHODS: This study was conducted at a Japanese university hospital. Participants included patients who underwent routine examination by an interdisciplinary pressure injury team. Pressure injury severity was assessed using the DESIGN-R® scoring system and the wound size were measured using ImageJ software based on the wound photograph. RESULTS: Among the five cases showing a cloud-like pattern upon ultrasonography, all exhibited an increase in the total DESIGN-R® score, while three exhibited an increase in wound size. On the other hand, all four cases showing a cobblestone-like pattern displayed no increase in the total DESIGN-R® score and a decrease in wound size. CONCLUSION: This study suggested that distinguishing between cloud-like and cobblestone-like ultrasonography patterns is necessary for determining the presence or absence of deep tissue pressure injury. In order to comprehensively assess pressure injuries with ultrasonography, future studies should be conducted in a large number of participants.
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Úlcera por Presión/diagnóstico por imagen , Ultrasonografía/métodos , Pesos y Medidas/instrumentación , Heridas y Lesiones/clasificación , Anciano , Anciano de 80 o más Años , Femenino , Hospitales Universitarios/organización & administración , Hospitales Universitarios/estadística & datos numéricos , Humanos , Japón , Masculino , Persona de Mediana Edad , Úlcera por Presión/clasificación , Ultrasonografía/estadística & datos numéricos , Cicatrización de Heridas/fisiologíaRESUMEN
INTRODUCTION: Insufficient educational resources on sports dentistry result in varying lecture implementations across dental schools, which cause knowledge gaps amongst students. Thus, a new interactive sports dentistry-related computer-assisted learning (CAL) module was created to facilitate dental school undergraduate students' education. This study compared the CAL module's learning effectiveness with conventional video lectures (VL) and assessed its effectiveness when used over several years at a university, and examined its validation in different university contexts, and students' perceptions. MATERIALS AND METHODS: Participants were 305 fifth-year students. Students from a university in Tokyo participated for 3 years and those from a university in Saitama for 1 year. In each year, the students were divided into two groups-CAL and VL. They studied their assigned modules in 20-min lessons. A written test was administered to determine their knowledge acquisition levels, along with a questionnaire. RESULTS: Two hundred sixty-two consenting participants were included in the statistical analysis. The CAL groups' test scores at both schools were significantly higher than the VL groups' every year (p < .001). Furthermore, test results from all years revealed no gender differences or repetition of the school years at either school. Most students at both universities evaluated the CAL module as excellent. CONCLUSION: The interactive CAL module generated consistently strong results over multiple years, during which it was used by a diverse group of students at two universities. The students highly rated the module's learning process as well as its contents.
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Instrucción por Computador , Universidades , Computadores , Odontología , Educación en Odontología , Evaluación Educacional , Humanos , AprendizajeRESUMEN
Phomopsis asparagi is one of the most serious fungal pathogens, which causes stem blight disease in Asparagus officinalis (AO), adversely affecting its production worldwide. Recently, the development of novel asparagus varieties using wild Asparagus genetic resources with natural P. asparagi resistance has become a priority in Japan due to the lack of resistant commercial AO cultivars. In this study, comparative metabolome and transcriptome analyses of susceptible AO and resistant wild Asparagus kiusianus (AK) 24 and 48 h postinoculated (AOI_24 hpi, AOI_48 hpi, AKI_24 hpi and AKI_48 hpi, respectively) with P. asparagi were conducted to gain insights into metabolic and expression changes associated with AK species. Following infection, the resistant wild AK showed rapid metabolic changes with increased levels of flavonoids and steroidal saponins and decreased asparagusic acid glucose ester content, compared with the susceptible AO plants. Transcriptome data revealed a total of 21 differentially expressed genes (DEGs) as the core gene set that displayed upregulation in the resistant AK versus susceptible AO after infection with P. asparagi. Kyoto Encyclopedia of Genes and Genomes pathway analysis of these DEGs identified 11 significantly enriched pathways, including flavonoid biosynthesis and primary metabolite metabolism, in addition to plant signaling and defense-related pathways. In addition, comparative single-nucleotide polymorphism and Indel distributions in susceptible AO and resistant AK plants were evaluated using the latest AO reference genome Aspof.V1. The data generated in this study are important resources for advancing Asparagus breeding programs and for investigations of genetic linkage mapping, phylogenetic diversity and plant defense-related genes.
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Asparagus/inmunología , Resistencia a la Enfermedad , Phomopsis , Enfermedades de las Plantas/inmunología , Asparagus/genética , Asparagus/metabolismo , Asparagus/microbiología , Resistencia a la Enfermedad/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Metabolómica , Enfermedades de las Plantas/microbiología , Polimorfismo de Nucleótido Simple/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: Although previous studies have demonstrated the ability of ultrasound to detect stool in the colon and rectum, the clinical utility of evaluating constipation via ultrasonic imaging by nurses has not been determined. In this case report, we observed fecal retention, assessed the presence of constipation, and performed defecation care in an older adult patient in a home care setting in a city near the metropolitan area in Japan. CASE: An 85-year-old male with advanced stage prostate cancer and multiple metastases was diagnosed with fecal impaction via digital rectal examination and evaluation of stool consistency. He was managed by regular digital evacuation of stool, but ultrasonic imaging indicated constipation with fecal retention in both the rectum and the colon despite this bowel evacuation program. When faced with this situation, we advocate a bowel management program that considers both intestinal elimination dysfunction and fecal transport dysfunction. Based on ultrasonic imaging, stool consistency was altered by promoting water intake, and we promoted self-defecation by asking the patient to attempt to move his bowels (regardless of cues to defecation) by sitting on the toilet every morning. As a result, the number of weekly enemas and digital dis-impaction episodes decreased while the number of spontaneous defecations increased. CONCLUSION: This case report demonstrated that ultrasonography improved bowel management in this patient with clinically severe chronic constipation.
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Estreñimiento/diagnóstico por imagen , Servicios de Atención de Salud a Domicilio/tendencias , Ultrasonografía/instrumentación , Anciano de 80 o más Años , Estreñimiento/diagnóstico , Humanos , Japón , Masculino , Sistemas de Atención de Punto/tendencias , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/terapia , Ultrasonografía/métodos , Ultrasonografía/tendenciasRESUMEN
PURPOSE: This study aimed to clarify the influence of different wiping methods on cleaning agent residue in hair follicles when using skin cleaning agents that are "removable-by-wiping." METHODS: A total of 18 male volunteers were recruited and a cleaning agent containing 10% fluorescein sodium salt (cleaning agent) was used in this study. After gentle washing, the cleaning agent was removed via the washing method (control) or three distinct wiping methods (experiment). Hairs were obtained from the measurement area. The fluorescence intensities of the residual cleaning agent on the hair root and hair bulb were then evaluated after normalizing for autofluorescence from the hair. Fluorescence intensity was used to estimate the amount of cleaning agent residue. RESULTS: No significant differences were found among cleaning agent removal methods (hair root: P = 0.67, hair bulb: P = 0.62) with respect to the amount of residual cleaning agent on hair. CONCLUSION: Cleaning agent residual index did not differ according to removal method. Cleaning agent remained in the hair follicle (hair roots, hair bulbs) despite removal from the skin by washing or wiping. Further studies are required to apply "removable-by-wiping" cleaning agents for people with vulnerable skin.
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Fármacos Dermatológicos , Detergentes , Folículo Piloso , Cuidados de la Piel/métodos , Humanos , Masculino , Adulto JovenRESUMEN
Providing defecation care can be challenging because bowel movements cannot be directly observed in home-care settings, and the objective evaluation of constipation symptoms is difficult, particularly for elderly patients with cognitive impairment. We evaluated the use of rectal ultrasonography (US) to assess the properties and volume of feces in three cases with different fecal properties. Case 1: In a 94-year-old man with normal feces (Bristol stool score: BS type 4), rectal US revealed a crescent-shaped high-echo area without acoustic shadow that was present until the next defecation. Case 2: In a 92-year-old woman with hard stool (BS type 1), rectal US showed a crescent-shaped strong-echo area with acoustic shadow that was present until the next defecation. The length of the high-echo area gradually increased during the observation period and decreased after defecation in Cases 1 and 2. Case 3: In a 67-year-old man with watery stool (BS type 7), rectal US revealed a low-peripheral-frequency-echo area without acoustic shadow. Rectal ultrasonography was able to demonstrate the presence or absence of hard stool, which was observed as a crescent-shaped a strong, high-echo area with acoustic shadow; the presence or absence of hard stool may be evaluated based on these findings. Furthermore, the fecal volume may be able to be evaluated based on the long diameter of the crescent-shaped high-echo area. Determining the best course of defecation care based on the fecal properties/volume evaluated using rectal US will likely be possible in the future.
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Heces , Recto/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Estreñimiento , Defecación , Diarrea , Femenino , Humanos , Masculino , UltrasonografíaRESUMEN
Cisplatin is a highly effective anticancer drug for treatment of various tumors including non-small-cell lung cancer (NSCLC), and is especially useful in cases nonresponsive to molecular-targeted drugs. Accumulating evidence has shown that cisplatin activates the p53-dependent apoptotic pathway, but it also induces apoptosis in p53-mutated cancer cells. Here we demonstrated that DNA-damage inducible proapoptotic BH3 (Bcl-2 homology region 3)-only Bcl-2 family members, Noxa, Puma, Bim and Bid, are not involved in cisplatin-induced apoptosis in human NSCLC cell lines. In contrast, the expression of proapoptotic multidomain Bcl-2-family members, Bak and Bax, was induced by cisplatin in p53-dependent and -independent manners, respectively. Moreover, in wild-type p53-expressing cells, cisplatin mainly used the Bak-dependent apoptotic pathway, but this apoptotic pathway shifted to the Bax-dependent pathway by loss-of-function of p53. Furthermore, both Bak- and Bax-induced apoptosis was enhanced by the antiapoptotic Bcl-2 family member, Bcl-XL knockdown, but not by Mcl-1 knockdown. From this result, we tested the effect of ABT-263 (Navitoclax), the specific inhibitor of Bcl-2 and Bcl-XL, but not Mcl-1, and found that ABT-263 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells in the presence or absence of p53. These results indicate a novel regulatory system in cisplatin-induced NSCLC cell apoptosis, and a candidate efficient combination chemotherapy method against lung cancers.
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Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Sulfonamidas/farmacología , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mutación , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/genéticaRESUMEN
We developed a new assessment tool for diabetic foot ulcers because no such tool specifically for diabetic foot ulcer exists. The diabetic foot ulcer assessment scale (DFUAS) has 11 domain items. The minimum and maximum scores on this scale are 0 and 98, respectively; higher scores indicate more severe wounds. The aim of this study was to evaluate the concurrent validity, construct validity and predictive validity of DFUAS in Indonesia. A prospective cohort study was conducted on patients with diabetic foot ulcer at Kitamura wound clinic in Indonesia. A total of 62 patients with 70 diabetic foot ulcers were assessed with DFUAS tool, Bates-Jensen wound assessment tool (BWAT), and pressure ulcer scale for healing (PUSH). Concurrent validity was determined by correlation of the DFUAS total score with the external criterion (BWAT, PUSH, and wound surface area). A comparison between the total DFUAS score and chronic wound status was made to determine construct validity. We also analyzed 41 wounds that were followed for 4 weeks to evaluate predictive validity. The correlation coefficient total scores of the DFUAS against the BWAT, PUSH, and wound surface area were 0.92, 0.87, and 0.82, respectively. The comparison of the total DFUAS score with chronic wound status was p < 0.001. The predictive validity test indicated that a DFUAS cutoff score of 12 produced the best balance of sensitivity, specificity, positive predictive value, and negative predictive value (89%, 71%, 86%, and 77%, respectively). In conclusion, the newly developed DFUAS is a valid tool for assessing diabetic foot ulcers.
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BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors have anti-tumor effects against renal cell carcinoma, pancreatic neuroendocrine cancer and breast cancer. In this study, we analyzed the antitumor effects of mTOR inhibitors in small cell lung cancer (SCLC) cells and sought to clarify the mechanism of resistance to mTOR inhibitors. METHODS: We analyzed the antitumor effects of three mTOR inhibitors including everolimus in 7 SCLC cell lines by MTS assay. Gene-chip analysis, receptor tyrosine kinases (RTK) array and Western blotting analysis were performed to identify molecules associated with resistance to everolimus. RESULTS: Only SBC5 cells showed sensitivity to everolimus by MTS assay. We established two everolimus resistant-SBC5 cell lines (SBC5 R1 and SBC5 R10) by continuous exposure to increasing concentrations of everolimus stepwise. SPP1 and MYC were overexpressed in both SBC5 R1 and SBC5 R10 by gene-chip analysis. High expression levels of eukaryotic translation initiation factor 4E (eIF4E) were observed in 5 everolimus-resistant SCLC cells and SBC5 R10 cells by Western blotting. MYC siRNA reduced eIF4E phosphorylation in SBC5 cells, suggesting that MYC directly activates eIF4E by an mTOR-independent bypass pathway. Importantly, after reduction of MYC or eIF4E by siRNAs, the SBC5 parent and two SBC5-resistant cells displayed increased sensitivity to everolimus relative to the siRNA controls. CONCLUSION: These findings suggest that eIF4E has been shown to be an important factor in the resistance to everolimus in SCLC cells. Furthermore, a link between MYC and mTOR-independent eIF4E contribute to the resistance to everolimus in SCLC cells. Control of the MYC-eIF4E axis may be a novel therapeutic strategy for everolimus action in SCLC.
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Factor 4E Eucariótico de Iniciación/biosíntesis , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Factor 4E Eucariótico de Iniciación/genética , Everolimus/administración & dosificación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal/efectos de los fármacos , Sirolimus/administración & dosificación , Carcinoma Pulmonar de Células Pequeñas/patología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genéticaRESUMEN
BACKGROUND: Lung adenocarcinoma patients with EGFR gene mutations have shown a dramatic response to gefitinib. However, drug resistance eventually emerges which limits the mean duration of response. With that in view, we examined the correlations between MET gene status as assessed by fluorescence in situ hybridization (FISH) with overall survival (OS) and progression-free survival (PFS) in adenocarcinoma patients with EGFR gene mutations who had received gefitinib therapy. METHODS: We evaluated 35 lung cancer samples with EGFR mutation from adenocarcinoma patients who had received gefitinib. Gene copy numbers (GCNs) and amplification of MET gene before gefitinib therapy was examined by FISH. MET protein expression was also evaluated by immunohistochemistry (IHC). RESULTS: FISH assessment showed that of the 35 adenocarcinoma samples, 10 patients (29%) exhibited high polysomy (5 copiesâ¦mean MET per cell) and 1 patient (3%) exhibited amplification (2â¦MET gene (red)/CEP7q (green) per cell). IHC evaluation of MET protein expression could not confirm MET high polysomy status. The Eleven patients with MET FISH positivity had significantly shorter progression-free survival (PFS) and overall survival (OS) than the 24 patients who were MET FISH-negative (PFS: p = 0.001 and OS: p = 0.03). Median PFS and OS with MET FISH-positivity were 7.6 months and 16.8 months, respectively, whereas PFS and OS with MET FISH-negativity were 15.9 months and 33.0 months, respectively. Univariate analysis revealed that MET FISH-positivity was the most significant independent factor associated with a high risk of progression and death (hazard ratio, 3.83 (p = 0.0008) and 2.25 (p = 0.03), respectively). CONCLUSIONS: Using FISH analysis to detect high polysomy and amplification of MET gene may be useful in predicting shortened PFS and OS after Gefitinib treatment in lung adenocarcinoma. The correlation between MET gene status and clinical outcomes for EGFR-TKI should be further evaluated using large scale samples.
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Adenocarcinoma/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Pronóstico , Proteínas Proto-Oncogénicas c-met/biosíntesis , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Gefitinib , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas c-met/genética , Quinazolinas/administración & dosificaciónRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Propolis is a resinous substance collected by honeybees from various plant sources and has been used in traditional folk medicine for centuries. Propolis has various biological properties, including antibacterial, antiviral, anti-inflammatory, and anti-tumor properties. The use of propolis in oral health care is attributable to its antimicrobial and anti-inflammatory effects. However, limited evidence exists on the in vivo efficacy of propolis against periodontal pathogens. AIM OF THE STUDY: We aimed to evaluate the efficacy of Brazilian green propolis (BGP)-containing toothpaste for improving the oral environment and define its antibacterial compounds. MATERIALS AND METHODS: Overall, 48 student volunteers aged 18-40 years (24 females and 24 males) were randomly categorized into the BGP and placebo groups. The BGP and placebo groups received toothpaste with and without BGP, respectively. After a baseline assessment, the plaque index (PI) score, gingival index (GI) score, and proportion of periodontal pathogens on the tongue surface were analyzed at 0, 1, and 2 weeks. Antibacterial compounds were identified using liquid-liquid partitioning, high-performance liquid chromatography purification, and nuclear magnetic resonance methods. RESULTS: The concentration of BGP in the toothpaste was set at 0.0347 w/v%. Compared with the placebo group, the BGP group demonstrated a reduction in the PI score (p<0.05) but not in the GI score, as well as a reduction in Porphyromonas gingivalis (Pg)/Total bacteria (Tb), Fusobacterium nucleatum (Fn)/Tb, and Aggregatibacter actinomycetemcomitans (Aa)/Tb (p<0.05) but not in Streptococcus salivalius/Tb. Effect sizes for Pg, Fn and Aa were 0.360, 0.556, and 0.164, respectively. The antibacterial compounds of the BGP-containing toothpaste included a mixture of kaempferide/betuletol. CONCLUSIONS: We confirmed the efficacy of propolis toothpaste with an optimal kaempferide/betuletol ratio for improving oral microbiota, thereby suggesting that BGP toothpaste is clinically useful in maintaining oral health and preventing periodontal disease.
RESUMEN
BACKGROUND: Transabdominal ultrasound is used to detect fecal impaction, but the rectum is difficult to visualize without bladder urine or with gastrointestinal gas. OBJECTIVE: We developed a transgluteal cleft approach that is unaffected by these factors and sought to determine if our ultrasound method could detect and classify fecal matter in the lower rectum using this approach. METHODS: We classified ultrasound images from hospitalized patients into four groups: Group 1 (bowed and rock-like echogenic areas), Group 2 (irregular and cotton candy-like hyperechoic areas), Group 3 (flat and mousse-like hyperechoic areas), and Group 4 (linear echogenic areas in the lumen). Stool characteristics were classified as hard, normal, and muddy/watery. Sensitivity and specificity were determined based on fecal impaction and stool classification accuracy. RESULTS: We obtained 129 ultrasound images of 23 patients. The sensitivity and specificity for fecal retention in the rectum were both 100.0%. The recall rates were 71.8% for Group 1, 93.1% for Group 2, 100.0% for Group 3, and 100.0% for Group 4. The precision rates were 96.6% for Group 1, 71.1% for Group 2, 88.9% for Group 3, and 100.0% for Group 4. Our method was 89.9% accurate overall. CONCLUSION: Transgluteal cleft approach ultrasound scanning can detect and classify fecal properties with high accuracy.