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Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements.
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Elementos Alu , RNA Helicases DEAD-box/metabolismo , Atrofia Geográfica/imunologia , Atrofia Geográfica/patologia , Inflamassomos/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Ribonuclease III/metabolismo , Animais , Proteínas de Transporte/metabolismo , Atrofia Geográfica/metabolismo , Humanos , Inflamassomos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Epitélio Pigmentado da Retina/patologia , Receptores Toll-Like/metabolismoRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor survival rate, largely due to the lack of early diagnosis. Although myeloid cells are crucial in the tumour microenvironment, whether their specific subset can be a biomarker of PDAC progression is unclear. METHODS: We analysed IL-22 receptor expression in PDAC and peripheral blood. Additionally, we analysed gene expression profiles of IL-10R2+/IL-22R1+ myeloid cells and the presence of these cells using single-cell RNA sequencing and murine orthotropic PDAC models, respectively, followed by examining the immunosuppressive function of IL-10R2+/IL-22R1+ myeloid cells. Finally, the correlation between IL-10R2 expression and PDAC progression was evaluated. RESULTS: IL-10R2+/IL-22R1+ myeloid cells were present in PDAC and peripheral blood. Blood IL-10R2+ myeloid cells displayed a gene expression signature associated with tumour-educated circulating monocytes. IL-10R2+/IL-22R1+ myeloid cells from human myeloid cell culture inhibited T cell proliferation. By mouse models for PDAC, we found a positive correlation between pancreatic tumour growth and increased blood IL-10R2+/IL-22R1+ myeloid cells. IL-10R2+/IL-22R1+ myeloid cells from an early phase of the PDAC model suppressed T cell proliferation and cytotoxicity. IL-10R2+ myeloid cells indicated tumour recurrence 130 days sooner than CA19-9 in post-pancreatectomy patients. CONCLUSIONS: IL-10R2+/IL-22R1+ myeloid cells in the peripheral blood might be an early marker of PDAC prognosis.
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Biomarcadores Tumorais , Carcinoma Ductal Pancreático , Subunidade beta de Receptor de Interleucina-10 , Células Mieloides , Recidiva Local de Neoplasia , Neoplasias Pancreáticas , Receptores de Interleucina , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/sangue , Humanos , Animais , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/sangue , Camundongos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Receptores de Interleucina/genética , Células Mieloides/metabolismo , Células Mieloides/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Subunidade beta de Receptor de Interleucina-10/genética , Feminino , Masculino , Microambiente Tumoral/genética , Linhagem Celular TumoralRESUMO
In this study, the nonclinical pharmacokinetics of OLX702A-075-16, an RNA interference (RNAi) therapeutic currently in development, were investigated. OLX702A-075-16 is a novel N-acetylgalactosamine conjugated asymmetric small-interfering RNA (GalNAc-asiRNA) used for the treatment of an undisclosed liver disease. Its unique 16/21-mer asymmetric structure reduces nonspecific off-target effects without compromising efficacy. We investigated the plasma concentration, tissue distribution, metabolism, and renal excretion of OLX702A-075-16 following a subcutaneous administration in mice and rats. For bioanalysis, high-performance liquid chromatography with fluorescence detection (HPLC-FD) was used. The results showed rapid clearance from plasma (0.5 to 1.5 h of half-life) and predominant distribution to the liver, and/or kidney. Less than 1% of the liver concentration of OLX702A-075-16 was detected in the other tissues. Metabolite profiling using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) revealed that the intact duplex OLX702A-075-16 was the major compound in plasma. The GalNAc moiety was predominantly metabolized from the sense strand in the liver, with the unconjugated sense strand of OLX702A-075-16 accounting for more than 95% of the total exposure in the rat liver. Meanwhile, the antisense strand was metabolized by the sequential loss of nucleotides from the 3'-terminus by exonuclease, with the rat liver samples yielding the most diverse truncated forms of metabolites. Urinary excretion over 96 h was less than 1% of the administered dose in rats. High plasma protein binding of OLX702A-075-16 likely inhibited its clearance through renal filtration. Significance Statement This study presents the first comprehensive characterization of the in vivo pharmacokinetics of GalNAc-asiRNA. The pharmacokinetic insights gained from this research will aid in understanding toxicology and efficacy, optimizing delivery platforms, and improving the predictive power of preclinical species data for human applications.
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BACKGROUND AND AIMS: Post-cholecystectomy biliary strictures can be treated surgically or nonsurgically. Although endoscopic or percutaneous treatments are the preferred approaches, these methods are not feasible in cases in which complete stricture occlusion prevents the successful passage of a guidewire. The utility of magnetic compression anastomosis (MCA) in patients with post-cholecystectomy complete biliary obstruction that cannot be treated conventionally was evaluated. METHODS: MCA was performed in 10 patients with post-cholecystectomy biliary strictures that did not resolve with conventional endoscopic or percutaneous treatment. One magnet was delivered through the percutaneous transhepatic biliary drainage tract, and another was advanced via ERCP of the common bile duct. After magnet approximation and recanalization, a fully covered self-expandable metal stent (FCSEMS) was placed for 3 months and then replaced for an additional 3 months. Stricture resolution was evaluated after FCSEMS removal. RESULTS: Among the 10 patients who underwent MCA for post-cholecystectomy biliary stricture, the biliary injury was Strasberg type B in 2, type C in 3, and type E in 5. Recanalization was successful in all patients (technical success rate, 100%). The mean follow-up period after recanalization was 50.2 months (range, 13.2-116.8 months). Partial restenosis after MCA occurred in 2 patients at 24.1 and 1.6 months after stent removal. ERCP with FCSEMS placement resolved the recurrent stenosis in both patients. CONCLUSIONS: MCA is a useful nonsurgical alternative treatment for complete biliary obstruction after cholecystectomy that cannot be resolved by use of conventional methods.
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The process of cancer metastasis is dependent on the cancer cells' capacity to detach from the primary tumor, endure in a suspended state, and establish colonies in other locations. Anchorage dependence, which refers to the cells' reliance on attachment to the extracellular matrix (ECM), is a critical determinant of cellular shape, dynamics, behavior, and, ultimately, cell fate in nonmalignant and cancer cells. Anchorage-independent growth is a characteristic feature of cells resistant to anoikis, a programmed cell death process triggered by detachment from the ECM. This ability to grow and survive without attachment to a substrate is a crucial stage in the progression of metastasis. The recently discovered phenomenon named "adherent-to-suspension transition (AST)" alters the requirement for anchoring and enhances survival in a suspended state. AST is controlled by four transcription factors (IKAROS family zinc finger 1, nuclear factor erythroid 2, BTG anti-proliferation factor 2, and interferon regulatory factor 8) and can detach cells without undergoing the typical epithelial-mesenchymal transition. Notably, AST factors are highly expressed in circulating tumor cells compared to their attached counterparts, indicating their crucial role in the spread of cancer. Crucially, the suppression of AST substantially reduces metastasis while sparing primary tumors. These findings open up possibilities for developing targeted therapies that inhibit metastasis and emphasize the importance of AST, leading to a fundamental change in our comprehension of how cancer spreads.
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Metástase Neoplásica , Neoplasias , Humanos , Neoplasias/patologia , Adesão Celular , Matriz Extracelular/metabolismo , Transição Epitelial-Mesenquimal , Anoikis , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating cancer due to its poor survival rate, early detection, and resectability. This study aimed to determine the peripheral blood mononuclear cell (PBMC) immune biomarkers in patients with PDAC and investigate the PDAC-specific peripheral blood biomarker panel and validate its clinical performance. METHODS: In this prospective, blinded, case-control study, a biomarker panel formula was generated using a development cohort-including healthy controls, patients at high risk of PDAC, and patients with benign pancreatic disease, PDAC, or other gastrointestinal malignancies-and its diagnostic performance was verified using a validation cohort, including patients with ≥ 1 lesion suspected as PDAC on computed tomography (CT). RESULTS: RNA-sequencing of PBMCs from patients with PDAC identified three novel immune cell markers, IL-7R, PLD4, and ID3, as specific markers for PDAC. Regarding the diagnostic performance of the regression formula for the three biomarker panels, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 84.0%, 78.8%, 47.2%, 95.6%, and 79.8%, respectively. Based on the formula scores for the biomarker panel, the false-negative rate (FNR) of the biomarkers was 8% (95% confidence interval [CI] 3.0-13.0), which was significantly lower than that based on CT in the validation cohort (29.2%, 95% CI 20.8-37.6). CONCLUSIONS: The regression formula constructed using three PBMC biomarkers is an inexpensive, rapid, and convenient method that shows clinically useful performance for the diagnosis of PDAC. It aids diagnoses and differential diagnoses of PDAC from pancreatic disease by lowering the FNR compared to CT. Clinical trial registration Clinical Research Information Service, KCT0004614 (08 January 2020).
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Leucócitos Mononucleares , Estudos de Casos e Controles , Estudos Prospectivos , Biomarcadores Tumorais/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , RNA Mensageiro , RNA , Neoplasias PancreáticasRESUMO
Asymmetric small interfering RNAs (asiRNAs) that mediate RNA interference have been investigated for therapeutic use in various tissues, including skin tissue. Androgenetic alopecia (AGA) is caused by a combination of genetic factors, resulting in sensitivity to dihydrotestosterone (DHT), which binds to the androgen receptor (AR) to mediate a series of biomolecular changes leading to hair loss. This study aimed to evaluate the therapeutic potential of a cell-penetrating, AR-targeting asiRNA (cp-asiAR) for AGA treatment, which was designed to silence the AR gene. AGA mouse models were developed by stimulation with DHT, and ex vivo human scalp tissues were also used for analysis. Cp-asiAR-mediated changes in mRNA expression and protein levels of AR were assessed along with the examination of phenotypic improvements in mouse model of AGA. We also assessed downstream signaling associated with AR in primary human dermal papilla (DP) cells. Several cp-asiARs were screened for selecting the optimal sequence of AR using cell lines in vitro. A cholesterol-conjugated, chemically modified cp-asiAR candidate was optimized under passive uptake conditions in vitro. Intradermal cp-asiAR injection efficiently reduced mRNA and protein levels corresponding to AR in mouse models. Moreover, cp-asiAR injection promoted hair growth in mouse models with DHT-induced AGA. In ex vivo human hair follicle culture, the proportion of telogen hair decreased, and the mean hair bulb diameter increased in the cp-asiAR-treated group. In isolated primary human DP cells, AR expression was effectively downregulated by cp-asiAR. Furthermore, cp-asiAR attenuated DHT-mediated increases in interleukin-6, transforming growth factor-ß1, and dickkopf-1 levels. No significant toxicity was observed in DP cells after cp-asiAR treatment. Cp-asiAR treatment showed effective downregulation of AR expression and prevention of DHT-mediated alterations in the hair cycle and hair diameter, indicating its potential as a novel therapeutic option for AGA.
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Alopecia , Receptores Androgênicos , Camundongos , Animais , Humanos , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , RNA Interferente Pequeno/metabolismo , Alopecia/tratamento farmacológico , Alopecia/genética , Cabelo/metabolismo , Folículo Piloso , Modelos Animais de Doenças , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND AND AIM: Endoscopic post-papillectomy bleeding is a serious adverse event with a prevalence ranging from 2% to 45.3%. Conventional hemostatic methods, including diluted epinephrine injection before papillectomy or argon plasma coagulation after papillectomy, did not show a preventive role in reducing immediate or delayed post-papillectomy bleeding. Therefore, we aimed to assess the efficacy and safety of a hemostatic powder spray for post-papillectomy bleeding and compare with those of conventional modalities. METHODS: Patients who underwent endoscopic papillectomy were enrolled in five tertiary hospitals. The group was divided into hemostatic spray and conventional control groups according to the bleeding control methods. The main outcome measurements were delayed bleeding rate and any adverse events related to the procedures. RESULTS: A total of 40 patients who received a hemostatic spray (n = 18) or conventional hemostatic methods (n = 22) after endoscopic papillectomy were included. The prevalence of delayed bleeding was not different in the two groups: 27.8% and 36.4% in hemostatic spray and conventional control groups (P = 0.564), respectively. The adverse events such as post-papillectomy pancreatitis and cholangitis were not different in the two groups. There were no procedure-related mortalities. CONCLUSION: Hemostatic spray is technically feasible and safe for the prevention or management of post-papillectomy bleeding. Hemostatic spray can be one of the options for post-papillectomy bleeding control methods owing to its convenient use.
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Hemostáticos , Pancreatite , Humanos , Endoscopia , Epinefrina , Coagulação com Plasma de Argônio , Pancreatite/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Endobiliary brushings are routinely used in the diagnosis, treatment, and prognostication of biliary strictures. However, standard Papanicolaou (Pap) staining has a low sensitivity in this setting, and the accuracy of brush cytology has not been established for indeterminate strictures. We therefore evaluated the diagnostic merit of methionyl-transfer RNA synthetase 1 (MARS1) immunofluorescence (IF) staining in such cytologic specimens. METHODS: During ERCP, endobiliary brushings were obtained from patients with extrahepatic biliary strictures prospectively enrolled at 6 tertiary hospitals. Using liquid-based cytologic preparations of these samples, we performed Pap and MARS1 IF staining. RESULTS: In total, 240 patients were eligible; of these, we compared the Pap and MARS1 IF staining results of 218 (malignant, 157; benign, 61). By conventional Pap staining, the diagnoses were distributed as follows: malignant, 55; suspicious of malignancy, 60; atypical, 45; negative for malignancy, 58. MARS1 IF staining was strongly positive in malignant biliary stricture but not so in specimens negative for malignancy. The diagnostic parameters (sensitivity, specificity, positive predictive value, negative predictive value, and accuracy) of the MARS1 IF (93.6%, 96.7%, 98.7%, 85.5%, and 94.5%, respectively) and conventional Pap (73.2%, 100%, 100%, 59.2%, and 80.7%, respectively) staining methods differed significantly (P < .0001). CONCLUSIONS: The high sensitivity and accuracy of MARS1 IF staining enabled the detection of malignancy in patients with biliary strictures. Further prospective studies are needed to validate our findings. (Clinical trial registration number: NCT03708445.).
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Neoplasias dos Ductos Biliares , Colestase , Metionina tRNA Ligase , Colangiopancreatografia Retrógrada Endoscópica , Constrição Patológica , Humanos , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND AND AIM: Endoscopic ultrasound (EUS) is the most accurate diagnostic modality for polypoid lesions of the gallbladder (GB), but is limited by subjective interpretation. Deep learning-based artificial intelligence (AI) algorithms are under development. We evaluated the diagnostic performance of AI in differentiating polypoid lesions using EUS images. METHODS: The diagnostic performance of the EUS-AI system with ResNet50 architecture was evaluated via three processes: training, internal validation, and testing using an AI development cohort of 1039 EUS images (836 GB polyps and 203 gallstones). The diagnostic performance was verified using an external validation cohort of 83 patients and compared with the performance of EUS endoscopists. RESULTS: In the AI development cohort, we developed an EUS-AI algorithm and evaluated the diagnostic performance of the EUS-AI including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. For the differential diagnosis of neoplastic and non-neoplastic GB polyps, these values for EUS-AI were 57.9%, 96.5%, 77.8%, 91.6%, and 89.8%, respectively. In the external validation cohort, we compared diagnostic performances between EUS-AI and endoscopists. For the differential diagnosis of neoplastic and non-neoplastic GB polyps, the sensitivity and specificity were 33.3% and 96.1% for EUS-AI; they were 74.2% and 44.9%, respectively, for the endoscopists. Besides, the accuracy of the EUS-AI was between the accuracies of mid-level (66.7%) and expert EUS endoscopists (77.5%). CONCLUSIONS: This newly developed EUS-AI system showed favorable performance for the diagnosis of neoplastic GB polyps, with a performance comparable to that of EUS endoscopists.
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Inteligência Artificial , Neoplasias da Vesícula Biliar , Pólipos , Aprendizado Profundo , Endossonografia , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Humanos , Pólipos/diagnóstico por imagem , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: Non-surgical methods have high success rates for treating benign biliary strictures (BBSs), but treatment of proximal strictures is difficult. Recent studies have reported that fully covered self-expandable metal stents (FCSEMSs) are useful for treating refractory BBSs. We investigated the efficacy of a short and removable FCSEMS with an anti-migration design for treatment of proximal BBSs. METHODS: Fully covered self-expandable metal stents were inserted endoscopically in patients with BBSs after living donor liver transplantation (LDLT). Each FCSEMS was initially maintained for 3 months and subsequently exchanged every 3 months until the stricture resolved. Adverse events and stricture recurrence after FCSEMS removal were assessed during follow-up. RESULTS: A total of 63 patients with a median age of 57 years were enrolled in this study; 50 were male. The most common underlying disease was hepatocellular carcinoma and the previous operation was LDLT. The mean duration from surgery to diagnosis of stricture was 8.5 months, and the mean stent indwelling time was 4.2 months. The technical success and stricture resolution rate were 100%. The recurrence rate was 23.8% and the adverse event rate was 12.7%. All stents were removable, and asymptomatic stent migration was observed in four patients (6.4%). CONCLUSIONS: The newly designed FCSEMS is effective in the treatment of proximal BBSs after LDLT.
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Transplante de Fígado , Doadores Vivos , Colangiopancreatografia Retrógrada Endoscópica , Constrição Patológica/cirurgia , Remoção de Dispositivo , Humanos , Recém-Nascido , Transplante de Fígado/efeitos adversos , Masculino , Recidiva Local de Neoplasia , Stents , Resultado do TratamentoRESUMO
Solution-processed Cu(In,Ga)(S,Se)2 (CIGS) has a great potential for the production of large-area photovoltaic devices at low cost. However, CIGS solar cells processed from solution exhibit relatively lower performance compared to vacuum-processed devices because of a lack of proper composition distribution, which is mainly instigated by the limited Se uptake during chalcogenization. In this work, a unique potassium treatment method is utilized to improve the selenium uptake judiciously, enhancing grain sizes and forming a wider bandgap minimum region. Careful engineering of the bandgap grading structure also results in an enlarged space charge region, which is favorable for electron-hole separation and efficient charge carrier collection. Besides, this device processing approach has led to a linearly increasing electron diffusion length and carrier lifetime with increasing the grain size of the CIGS film, which is a critical achievement for enhancing photocurrent yield. Overall, 15% of power conversion efficiency is achieved in solar cells processed from environmentally benign solutions. This approach offers critical insights for precise device design and processing rules for solution-processed CIGS solar cells.
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BACKGROUND AND AIMS: Identifying malignant biliary strictures using endobiliary brushing cytology specimens is important for treatment decision-making and prognosis prediction. The sensitivity of brushing cytology specimens based on Papanicolaou (Pap) staining is low, which hampers accurate diagnosis of indeterminate strictures. Here, we assessed the diagnostic value of immunohistochemical (IHC) and immunofluorescence (IF) staining for methionyl-tRNA synthetase 1 (MARS1). METHODS: Endobiliary brushing cytology specimens were obtained during ERCP from 80 patients with an extrahepatic biliary stricture. Pap and MARS1 IF staining were performed on liquid-based cytology slides derived from these specimens. Sections of bile duct adenocarcinoma and normal bile duct tissue were obtained from 45 patients who underwent surgery for malignant biliary stricture, and MARS1 levels were evaluated by IHC staining. RESULTS: MARS1 IF staining was applied to brushing cytology specimens, and the results showed strong signals in malignant biliary structures but not in the negative for malignancy specimens. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 70.4%, 96.2%, 97.4%, 56.8%, and 78.8%, respectively, for conventional Pap staining and 98.1%, 96.1%, 98.1%, 96.2%, and 97.5%, respectively, for MARS1 IF (P < .0001). When IHC staining was used, MARS1 was detected in 45 bile duct adenocarcinoma sections but not in 15 normal bile duct sections. Moreover, MARS1 mRNA and protein levels were significantly higher in bile duct adenocarcinoma sections according to polymerase chain reaction and Western blot, respectively. CONCLUSIONS: The high sensitivity and accuracy of MARS1 IF staining enabled detection of malignancy in patients with indeterminate biliary stricture. Further prospective studies are needed to validate our findings. (Clinical trial registration number: KCT 0003285.).
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Neoplasias dos Ductos Biliares , Metionina tRNA Ligase , Neoplasias dos Ductos Biliares/diagnóstico , Ductos Biliares , Ductos Biliares Intra-Hepáticos , Colangiopancreatografia Retrógrada Endoscópica , Humanos , Estudos Prospectivos , Sensibilidade e Especificidade , Coloração e RotulagemRESUMO
The efficient delivery of small interfering RNAs (siRNAs) to the target cells is critical for the pharmaceutical success of RNA interference (RNAi) drugs. One of the possible strategies to improve siRNA delivery is to identify auxiliary molecules that augment their cellular uptake. Herein, we performed a chemical library screening in an effort to discover small molecules that enhance the potency of cholesterol-conjugated, cell-penetrating asymmetric siRNAs (cp-asiRNAs). Interestingly, three compounds identified from the screen share a common dihydropyridine (DHP) core and function as L-type calcium channel blockers (CCBs). Using confocal microscopy and quantitative analysis of small RNAs, we demonstrated that the L-type CCBs increased the endocytic cellular uptake of cp-asiRNAs. Furthermore, these small molecules substantially improved the potency of cp-asiRNAs, not only in vitro but also in vivo on rat skin. Collectively, our study provides an alternative pharmacological approach for the identification of small molecules that potentiate the effects of therapeutic siRNAs.
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Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacocinética , Canais de Cálcio Tipo L/metabolismo , Di-Hidropiridinas/farmacocinética , Interferência de RNA , RNA Interferente Pequeno/farmacocinética , Animais , Biópsia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Colesterol/química , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Di-Hidropiridinas/administração & dosagem , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/farmacocinética , Células HeLa , Humanos , Injeções Intradérmicas , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Pele/metabolismo , Pele/patologia , Bibliotecas de Moléculas Pequenas , TransfecçãoRESUMO
BACKGROUNDS AND AIM: Multiple insertions of self-expandable metal stents (SEMS) for advanced malignant hilar obstruction (MHO) are now considered to be an effective palliative method for adequate drainage of liver volume. However, the efficacy of endoscopic reintervention in technically and clinically successful bilateral SEMS is limited. This study investigated the endoscopic revision efficacy in patients who underwent bilateral SEMS in MHO. METHODS: Primary endoscopic revision using plastic or metal stents or an alternative percutaneous approach followed by secondary endoscopic revision was performed in patients who underwent clinically successful deployment of bilateral SEMS. The primary outcome was a technical success. Secondary outcomes were clinical success, adverse events, and patency duration after reintervention. RESULTS: A total of 55 patients (83.3%) out of 66 enrolled patients underwent reintervention: primary endoscopic reintervention (n = 47) and secondary endoscopic revision following percutaneous drainage (n = 8). Intended technical success rates of primary and secondary endoscopic reintervention were 93.6% (44/47) and 87.5% (7/8), respectively (P = 0.47). Clinical success rates were 72.3% and 50%, respectively (P = 0.23). Stent malfunction rate after reintervention was 48.9% (23/47) and 37.5% (3/8) (P = 0.70) during follow up, and median cumulative stent patency duration was 119 and 55 days, respectively (log-rank P = 0.68). Stent patent rate after reintervention was not different according to the time interval. In univariate and multivariate analysis for stent patency duration-related factors after reintervention, there were no meaningful factors. CONCLUSION: Primary endoscopic reintervention for bilateral SEMS in MHO was feasible technically and clinically. However, there were no statistically meaningful factors for stent patency duration after reintervention.
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Colestase Intra-Hepática/cirurgia , Endoscopia do Sistema Digestório/métodos , Ducto Hepático Comum/cirurgia , Reoperação/métodos , Stents Metálicos Autoexpansíveis , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/complicações , Colestase Intra-Hepática/etiologia , Estudos de Viabilidade , Feminino , Neoplasias da Vesícula Biliar/complicações , Humanos , Tumor de Klatskin/complicações , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Distal biliary strictures (DBS) are common and may be caused by both malignant and benign pathologies. While endoscopic procedures play a major role in their management, a comprehensive review of the subject is still lacking. Our consensus statements were formulated by a group of expert Asian pancreatico-biliary interventional endoscopists, following a proposal from the Digestive Endoscopy Society of Taiwan, the Thai Association for Gastrointestinal Endoscopy, and the Tokyo Conference of Asian Pancreato-biliary Interventional Endoscopy. Based on a literature review utilizing Medline, Cochrane library, and Embase databases, a total of 19 consensus statements on DBS were made on diagnosis, endoscopic drainage, benign biliary stricture, malignant biliary stricture, and management of recurrent biliary obstruction and other complications. Our consensus statements provide comprehensive guidance for the endoscopic management of DBS.
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Procedimentos Cirúrgicos do Sistema Biliar/métodos , Procedimentos Cirúrgicos do Sistema Biliar/normas , Sistema Biliar/patologia , Colestase/cirurgia , Consenso , Endoscopia do Sistema Digestório/métodos , Endoscopia do Sistema Digestório/normas , Gastroenterologia/organização & administração , Cooperação Internacional , Sociedades Médicas/organização & administração , Povo Asiático , Colestase/etiologia , Constrição Patológica/diagnóstico , Constrição Patológica/etiologia , Constrição Patológica/cirurgia , Humanos , Taiwan , TóquioRESUMO
Solar water splitting using photoelectrochemical cells (PECs) has emerged as one of the most promising routes to produce hydrogen as a clean and renewable fuel source. Among various semiconductors that have been considered as photoelectrodes for use in PECs, oxide-based photoanodes are particularly attractive because of their stability in aqueous media in addition to inexpensive and facile processing compared to other types of semiconductors. However, they typically suffer from poor charge carrier separation and transport. In the past few years, there has been tremendous progress in developing ternary oxide-based photoelectrodes, specifically, photoanodes. The use of ternary oxides provides more opportunities to tune the composition and electronic structure of the photoelectrode compared to binary oxides, thus providing more freedom to tune the photoelectrochemical properties. In this article, we outline the important characteristics to analyze when evaluating photoanodes and review the major recent progress made on the development of ternary oxide-based photoanodes. For each system, we highlight the favorable and unfavorable features and summarize the strategies utilized to address the challenges associated with each material. Finally, by combining our analyses of all the photoanodes surveyed in this review, we provide possible future research directions for each compound and an outlook for constructing more efficient oxide-based PECs. Overall, this review will provide a critical overview of current ternary oxide-based photoanodes and will serve as a platform for the design of future oxide-based PECs.
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Gemcitabine is clinically used to treat certain types of cancers, including pancreatic and biliary cancer. We investigated the signal transduction pathways underlying the local antitumor effects of gemcitabine-eluting membranes (GEMs) implanted in pancreatic/biliary tumor-bearing nude mice. Here, we report that GEMs increased the E3 ubiquitin ligase c-CBL protein level, leading to degradation of epidermal growth factor receptor (EGFR) in SCK and PANC-1 cells. GEMs decreased the RAS and PI3K protein levels, leading to a reduction in the protein levels of active forms of downstream signaling molecules, including PDK, AKT, and GSK3ß. GEM reduced proliferation of cancer cells by upregulating cell cycle arrest proteins, particularly p53 and p21, and downregulating cyclin D1 and cyclin B. Moreover, GEMs reduced the levels of proangiogenic factors, including VEGF, VEGFR2, CD31, and HIF-1α, and inhibited tumor cell migration and invasion by inducing the expression of E-cadherin and reducing that of N-cadherin, snail, and vimentin. We demonstrated that local delivery of gemcitabine using GEM implants inhibited tumor cell growth by promoting c-CBL-mediated degradation of EGFR and inhibiting the proliferation, angiogenesis, and epithelial-mesenchymal transition of pancreatic/biliary tumors. Use of gemcitabine-eluting stents can improve stent patency by inhibiting the ingrowth of malignant biliary obstructions.
Assuntos
Colangiocarcinoma/tratamento farmacológico , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Receptores ErbB/metabolismo , Pâncreas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antígenos CD , Caderinas/metabolismo , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Ciclina B/metabolismo , Ciclina D1/metabolismo , Desoxicitidina/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
BACKGROUNDS: The placement of a self-expandable metal stent (SEMS) is widely used in patients with unresectable malignant biliary obstructions, but SEMSs are susceptible to occlusion by tumor ingrowth or overgrowth. The efficacy and safety of a novel paclitaxel-eluting biliary metal stent incorporating sodium caprate (MSCPM-III) were compared prospectively with those of a covered metal stent (CMS) in patients with malignant biliary obstructions. METHODS: Patients with unresectable distal malignant biliary obstructions (nâ=â106) were prospectively enrolled in this study at multiple treatment centers. Stents were placed endoscopically: MSCPM-III in 54 patients and CMS in 51 patients. The patients received systemic chemotherapy regimens according to their disease characteristics. RESULTS: The two groups did not differ significantly in basic characteristics or mean follow-up period. Stent occlusion occurred in 14 patients who received MSCPM-III and in 11 patients who received CMS.âTime to recurrent biliary obstruction (RBO) and survival time did not differ significantly between the two groups (P â=â0.84 and Pâ=â0.29, respectively). However, tumor size at 2 months after stent insertion was significantly decreased in patients in the MSCPM-III group with bile duct cancers or those who experienced stent migration compared with the CMS group.âComplications, including cholangitis and pancreatitis, were found to be acceptable in both groups. CONCLUSIONS: Although compared with a CMS the MSCPM-III did not significantly influence time to RBO or survival duration in patients with malignant biliary obstructions, MSCPM-III reduced tumor volume and was used safely in humans.
Assuntos
Antifúngicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Colestase/cirurgia , Ácidos Decanoicos/administração & dosagem , Stents Farmacológicos , Paclitaxel/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Colestase/etiologia , Neoplasias do Sistema Digestório/patologia , Humanos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Endoscopic papillary large balloon dilation (EPLBD) without prior endoscopic sphincterotomy (EST) produces excellent outcomes for the treatment of large common bile duct (CBD) stones. However, it remains unclear how the outcomes of EPLBD alone compare with those of EPLBD with EST. In this study, we assessed the safety and therapeutic outcomes of EPLBD with vs. without EST for the removal of large bile duct stones. METHODS: This prospective, multicenter study was conducted on 200 patients with bile duct stones of ≥â10âmm in diameter. Patients were randomly assigned to an EPLBD alone group (nâ=â100) or an EPLBD with EST group (nâ=â100). These two groups were compared with respect to overall procedure-related adverse events, overall stone removal success rate, number of endoscopic sessions required for complete stone removal, need for mechanical lithotripsy, and total procedure time. RESULTS: The incidence of adverse events was not significantly different between the groups (EPLBD alone vs. EPLBD with EST: overall adverse events 6â% vs. 4â%, Pâ=â0.75; pancreatitis 1â% vs. 3â%, Pâ=â0.62). Overall success (Pâ=â0.35), initial success (Pâ=â0.28), and the need for mechanical lithotripsy (Pâ=â0.39) were also similar between groups. Median total procedure time tended to be greater in the EPLBD alone group (20.5 minutes) than in the EPLBD with EST group (18 minutes; Pâ=â0.08). CONCLUSION: The therapeutic outcomes and adverse events of EPLBD alone for the removal of large bile duct stones were comparable to those of EPLBD with EST.