RESUMO
Lung cancer is the leading cause of cancer mortality worldwide. KRAS oncogenes are responsible for at least a quarter of lung adenocarcinomas, the main subtype of lung cancer. After four decades of intense research, selective inhibitors of KRAS oncoproteins are finally reaching the clinic. Yet, their effect on overall survival is limited due to the rapid appearance of drug resistance, a likely consequence of the high intratumoral heterogeneity characteristic of these tumors. In this study, we have attempted to identify those functional alterations that result from KRAS oncoprotein expression during the earliest stages of tumor development. Such functional changes are likely to be maintained during the entire process of tumor progression regardless of additional co-occurring mutations. Single-cell RNA sequencing analysis of murine alveolar type 2 cells expressing a resident Kras oncogene revealed impairment of the type I interferon pathway, a feature maintained throughout tumor progression. This alteration was also present in advanced murine and human tumors harboring additional mutations in the p53 or LKB1 tumor suppressors. Restoration of type I interferon (IFN) signaling by IFN-ß or constitutive active stimulator of interferon genes (STING) expression had a profound influence on the tumor microenvironment, switching them from immunologically "cold" to immunologically "hot" tumors. Therefore, enhancement of the type I IFN pathway predisposes KRAS mutant lung tumors to immunotherapy treatments, regardless of co-occurring mutations in p53 or LKB1.
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Inibidores de Checkpoint Imunológico , Interferon Tipo I , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais , Animais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Camundongos , Interferon Tipo I/metabolismo , Interferon Tipo I/genética , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Linhagem Celular Tumoral , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Proteínas Quinases Ativadas por AMPRESUMO
Nucleolar stress (NS) has been associated with age-related diseases such as cancer or neurodegeneration. To investigate how NS triggers toxicity, we used (PR)n arginine-rich peptides present in some neurodegenerative diseases as inducers of this perturbation. We here reveal that whereas (PR)n expression leads to a decrease in translation, this occurs concomitant with an accumulation of free ribosomal (r) proteins. Conversely, (PR)n-resistant cells have lower rates of r-protein synthesis, and targeting ribosome biogenesis by mTOR inhibition or MYC depletion alleviates (PR)n toxicity in vitro. In mice, systemic expression of (PR)97 drives widespread NS and accelerated aging, which is alleviated by rapamycin. Notably, the generalized accumulation of orphan r-proteins is a common outcome of chemical or genetic perturbations that induce NS. Together, our study presents a general model to explain how NS induces cellular toxicity and provides in vivo evidence supporting a role for NS as a driver of aging in mammals.
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Neoplasias , Ribossomos , Camundongos , Animais , Ribossomos/metabolismo , Envelhecimento/genética , Peptídeos/metabolismo , Sirolimo/farmacologia , Neoplasias/metabolismo , Nucléolo Celular/genética , MamíferosRESUMO
OBJECTIVE: To compare the long-term effectiveness, complications, and outcomes of primary obstructive megaureter (POM) treated by endoscopic balloon dilation under fluoroscopic guidance versus not using radioscopy during the procedure. PATIENTS AND METHODS: A comparative study between POM cases treated at our institution by endoscopic balloon dilation (EBD) under fluoroscopic guidance (FG) (n = 43) vs no fluoroscopic guidance (NFG) (n = 48) between the years 2004 and 2018 was conducted. The procedure in FG consisted of performing a retrograde pyelography before dilation. Then, a guidewire is introduced to the renal pelvis, and the dilation of the vesicoureteral junction is performed using high-pressure balloon catheters under fluoroscopic vision. Finally, a double-J stent is placed between the renal pelvis and bladder. The procedure in NFG was performed exclusively under cystoscopic vision without radiological exposure. Complications, outcomes, and success rates were analyzed using Spearman's correlation test. Mean follow-up was 12.5 ± 2.2 years in FG and 6.4 ± 1.3 years in NFG. RESULTS: MAG-3 showed significant differences in renal drainage before and after endoscopic treatment in both groups (p < 0.001 T-test). Statistical analysis did not reveal differences between groups in initial technical failure (r: - 0.035, p = 0.74), early postoperative complications (r: - 0.029, p = 0.79), secondary VUR (r: 0.033, p = 0.76), re-stenosis (r: 0.022, p = 0.84), long-term ureteral reimplantation (r: 0.065, p = 0.55), and final outcome (r: - 0.054, p = 0.61). The endoscopic approach of POM had a long-term success rate of 86.5% in FG VS 89.6% in NFG. CONCLUSIONS: Endoscopic balloon dilation of POM can be done with no radiation exposure with similar results, effectiveness, and outcomes.
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Ureter , Obstrução Ureteral , Humanos , Obstrução Ureteral/diagnóstico por imagem , Obstrução Ureteral/cirurgia , Obstrução Ureteral/etiologia , Dilatação/métodos , Endoscopia/métodos , Ureter/diagnóstico por imagem , Ureter/cirurgia , Fluoroscopia/efeitos adversos , Resultado do Tratamento , Estudos RetrospectivosRESUMO
The biallelic pathogenic repeat (AAGGG)400-2000 intronic expansion in the RFC1 gene has been recently described as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and as a major cause of late-onset ataxia. Since then, many heterozygous carriers have been identified, with an estimated allele frequency of 0.7% to 4% in the healthy population. Here, we describe in two affected CANVAS sisters the presence of the nonsense c.724C > T p.(Arg242*) variant in compound heterozygosity with the pathogenic repeat expansion in the RFC1 gene. Further RNA analysis demonstrated a reduced expression of the p.Arg242* allele in patients confirming an efficient nonsense-mediated mRNA decay. We also highlight the importance of considering the sequencing of the RFC1 gene for the diagnosis, especially in patients with CANVAS diagnosis carriers of the AAGGG repeat expansion.
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Vestibulopatia Bilateral , Ataxia Cerebelar , Doenças do Sistema Nervoso Periférico , Proteína de Replicação C , Neuronite Vestibular , Humanos , Ataxia/genética , Vestibulopatia Bilateral/genética , Ataxia Cerebelar/genética , Ataxia Cerebelar/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/genética , Síndrome , Doenças Vestibulares/genética , Neuronite Vestibular/genética , Proteína de Replicação C/genéticaRESUMO
FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses found an upregulation of mitochondrial factors as a hallmark of FBXW7 deficiency, which has been previously linked to chemotherapy resistance. Despite this increased expression of mitochondrial factors, functional analyses revealed that mitochondria are under stress, and genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. Mechanistically, the toxicity of therapies targeting mitochondrial translation such as the antibiotic tigecycline relates to the activation of the integrated stress response (ISR) in a GCN2 kinase-dependent manner. Furthermore, the discovery of additional drugs that are toxic for FBXW7-deficient cells showed that all of them unexpectedly activate a GCN2-dependent ISR regardless of their accepted mechanism of action. Our study reveals that while one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, it renders cells vulnerable to ISR-activating drugs.
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Biossíntese de Proteínas , Proteômica , Linhagem Celular Tumoral , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Mutação , Regulação para CimaRESUMO
Purpose: To analyze the effectiveness, complications and long-term outcome of the patients with ureteropelvic junction obstruction (UPJO) treated by endoscopic retrograde balloon dilatation (ERBD) in the largest series reported. Materials and Methods: Between years 2004 and 2018, 112 patients with primary unilateral UPJO were treated by ERBD. Endoscopic treatment consisted on a retrograde balloon dilatation of the ureteropelvic junction (UPJ), through cystoscopy and under fluoroscopic guidance, using high-pressure balloon catheters. In case of persistence in the balloon notch, a Cutting Balloon™ catheter was used. Double-J stent was placed after dilatation. Results: Mean age at surgery was 13.1 ± 21.3 months, 92 cases being younger than 18 months. Mean operative time was 24.4 ± 10.3 min; hospital stay was 1 day in 82% of patients. No intraoperative complications occurred. UPJ was calibrated at time of stent removal with cystoscopy 39.1 ± 13.7 days after dilatation. ERBD was not possible in 11 cases. An additional procedure was needed in 24 cases: second ERBD (n = 11, seven during the stent withdrawal), a third dilatation (n = 3) due to persistent hydronephrosis, and percutaneous endopyelotomy (n = 3) or open pyeloplasty (n = 7) in cases of technical failure. Significant improvement in postoperative ultrasound measures were observed (p < 0.05, T-test). Long-term success rate was 76.8% after one dilatation, and 86.6% in those who required up to 2 dilatations. Mean follow-up was 66.7 ± 37.5 months. Conclusions: ERBD is a feasible and safe option for the minimally invasive treatment of UPJ obstruction in infants. Long-term outcome is acceptable with a very low complication rate.
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The ongoing COVID-19 pandemic is one of the biggest health challenges of recent decades. Among the causes of mortality triggered by SARS-CoV-2 infection, the development of an inflammatory "cytokine storm" (CS) plays a determinant role. Here, we used transcriptomic data from the bronchoalveolar lavage fluid (BALF) of COVID-19 patients undergoing a CS to obtain gene-signatures associated to this pathology. Using these signatures, we interrogated the Connectivity Map (CMap) dataset that contains the effects of over 5000 small molecules on the transcriptome of human cell lines, and looked for molecules which effects on transcription mimic or oppose those of the CS. As expected, molecules that potentiate immune responses such as PKC activators are predicted to worsen the CS. In addition, we identified the negative regulation of female hormones among pathways potentially aggravating the CS, which helps to understand the gender-related differences in COVID-19 mortality. Regarding drugs potentially counteracting the CS, we identified glucocorticoids as a top hit, which validates our approach as this is the primary treatment for this pathology. Interestingly, our analysis also reveals a potential effect of MEK inhibitors in reverting the COVID-19 CS, which is supported by in vitro data that confirms the anti-inflammatory properties of these compounds.
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Anti-Inflamatórios/uso terapêutico , Tratamento Farmacológico da COVID-19 , COVID-19/complicações , Simulação por Computador , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Glucocorticoides/uso terapêutico , Pandemias , Inibidores de Proteínas Quinases/uso terapêutico , SARS-CoV-2 , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/virologia , COVID-19/sangue , COVID-19/epidemiologia , Síndrome da Liberação de Citocina/mortalidade , Citocinas/sangue , Feminino , Perfilação da Expressão Gênica/métodos , Glucocorticoides/farmacologia , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Inibidores de Proteínas Quinases/farmacologia , Fatores Sexuais , Transcriptoma/genéticaRESUMO
INTRODUCTION: Surgical management of children with Prune-belly syndrome (PBS) can be divided into three categories: urinary tract reconstruction, abdominal wall reconstruction, and orchidopexy. Adequate repair of the abdominal wall by abdominoplasty at an early age, allows an adequate aesthetic appearance, but also allows a correct development of walking, breathing, defecation and urination. OBJECTIVE: To present a novel surgical technique for abdominal wall reconstruction, which combines plication with complete overlap of the fascia and neoumbilicoplasty with an island flap rotated on itself. STUDY DESIGN: A retrospective review of the patients with PBS who underwent surgery in our center between 2009 and 2020. A new abdominoplasty technique was performed, which consists of plication with complete overlap of the fascia, as well as a neoumbilicoplasty with an island flap rotated on itself. The skin is then well freed from the rest of planes, and the plication is performed with complete overlapping of the muscle-aponeurotic plane from one side to the other. At this time, the interposition of some type of reinforcement material (mesh) may be required in the event of complete absence or insufficient presence of the fascia and muscle. RESULTS: Abdominoplasty was performed in four patients. In all patients, bilateral orchidopexy was performed in the same surgical procedure for intra-abdominal testicles. The mean age of the patients at the time of surgery was 10,5 years and the average admission time was 4 days. There were no short-term or long-term complications. Average follow-up time was 7 years. All patients and their families are satisfied with the aesthetic result obtained. DISCUSSSION: Abdominoplasty in patients with PBS in addition to aesthetic reconstruction, brings significant improvements to wandering, breathing, urination and defecation, improving the quality of life of the patient. Compared to the techniques described, the abdominoplasty we propose makes it possible to easily improve the abdominal wall support by means of meshes or synthetic devices if necessary and allows the evaluation and correction of cryptorchidism or other associated renal abnormalities in the same surgical act, as it allows full abdominal exposure. Likewise our modified abdominoplasty allows the creation of the new umbilicus in a more anatomical way, rectifying its natural position. CONCLUSION: In our experience, this modified surgical technique for abdominal wall repair is a novel procedure in the PBS approach, easily reproducible, which provides good aesthetic results in our series of cases.
Assuntos
Parede Abdominal , Abdominoplastia , Síndrome do Abdome em Ameixa Seca , Parede Abdominal/cirurgia , Criança , Humanos , Masculino , Síndrome do Abdome em Ameixa Seca/cirurgia , Qualidade de Vida , Estudos RetrospectivosRESUMO
Aim: Miniaturization of endoscopic instruments has allowed to improve the efficacy of kidney stone treatment in young children. Aim of the study is to evaluate the usefulness of microureteroscopy with 4.85F sheath in the treatment of renal stones in children. M&M: We present 4 cases of microureteroscopy in 3 younger than 3 years patients with renal pelvic stones. Lithiasis was unilateral in 2 female patients and bilateral in 1 male patient. Microureteroscopy was performed using a MicroPerc set 4.85F sheath, without placing a safety guide or dilating the meatus in 3 procedures. The lithotripter system used was Ho:YAG Laser with 200-µm fiber in all cases. Results: Mean operating time was 100 ± 16 min. There were no intraoperative complications. In all procedures, complete pulverization of the lithiasis was achieved, except in the coraliform lithiasis in which 5 mm residual lithiasis remained in the lower calyx. All patients were discharged 24 h after the intervention. Conclusion: Microureteroscopy can be considered a new alternative for treatment of selected cases of renal pelvic stones in infants and children.
Assuntos
Neoplasias Pulmonares/genética , Mutação/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Neoplasias Pulmonares/patologia , Fosforilação/genética , Proteínas Proto-Oncogênicas/genéticaRESUMO
BACKGROUND: The evidence for the efficacy of glucocorticoids combined with tocilizumab (TCZ) in COVID-19 comes from observational studies or subgroup analysis. Our aim was to compare outcomes between hospitalized COVID-19 patients who received high-dose corticosteroid pulse therapy and TCZ and those who received TCZ. METHODS: A retrospective single-center study was performed on consecutive hospitalized patients with severe COVID-19 between 1 March and 23 April 2020. Patients treated with either TCZ (400-600 mg, one to two doses) and methylprednisolone pulses (MPD-TCZ group) or TCZ alone were analyzed for the occurrence of a combined endpoint of death and need for invasive mechanical ventilation during admission. The independence of both treatment groups was tested using machine learning classifiers, and relevant variables that were potentially different between the groups were measured through a mean decrease accuracy algorithm. RESULTS: An earlier date of admission was significantly associated with worse outcomes regardless of treatment type. Twenty patients died (27.0%) in the TCZ group, and 33 (44.6%) died or required intubation (n = 74), whereas in the MPD-TCZ group, 15 (11.0%) patients died and 29 (21.3%) patients reached the combined endpoint (n = 136; p = 0.006 and p < 0.001, respectively). Machine learning methodology using a random forest classifier confirmed significant differences between the treatment groups. CONCLUSIONS: MPD and TCZ improved outcomes (death and invasive mechanical ventilation) among hospitalized COVID-19 patients, but confounding variables such as the date of admission during the COVID-19 pandemic should be considered in observational studies.
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Introduction: Congenital ureteral valves are a rare cause of ureteral obstruction that may lead to renal function deterioration. We present two clinical cases treated endoscopically by monopolar electrocautery and laser fiber ablation. Presentation of Case: The first case is a 13-year-old male with several episodes of abdominal pain and was found to have severe left hydronephrosis. Ultrasonography showed a dilated ureter and pelvicaliceal system with an obstructive renogram curve. We performed a retrograde pyelogram, finding a dilated ureter 5 cm up from the vesicoureteral junction with ureteral valves in that place. Ablation of the valves was conducted using monopolar electrocautery. The second case is a 2-year-old male with left ureterohydronephrosis shown in abdominal ultrasonography. In the radiologic findings, a high-risk pyelocaliceal dilatation with renal parenchyma thinning and a diameter of 3.3 cm for the left ureter is described, with an obstructive renogram. We performed a cystoscopy, observing the presence of valves in the ureter at 3 cm that conditioned an obstruction. The complete section of the valves was performed through a 270µm holmium laser fiber. Our patients made an uneventful postoperative recovery and continue to remain completely asymptomatic. A significant decrease in renal dilation was observed and renal function recovered in both cases. Conclusion: Ureteral valves are an uncommon cause of ureteral obstruction. Advances in endourologic techniques allow us to give a minimally invasive approach to these diseases, obtaining good long-term results in our small series of patients.
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KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.
Assuntos
Adenocarcinoma de Pulmão/genética , Quinase 4 Dependente de Ciclina/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Inativação Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Proteínas Proto-Oncogênicas c-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
INTRODUCTION: The management of recurrent pyeloureteral junction obstruction (PUJO) is controversial, as there is no suitable technique for its correction. Percutaneous endopyelotomy shows better results in recurrent PUJO compared to primary PUJO. Micro-percutaneous approaches reduce damage to renal parenchyma and facilitate access to renal pelvis. OBJETIVE: To present our experience in the use of this minimally invasive technique for the treatment of recurrent PUJO. STUDY DESIGN: A retrospective study was performed collecting data of patients with recurrent PUJO treated in our hospital using the percutaneous approach between July 2014 and January 2018. Micropercutaneous access was performed in all patients. In Valdivia position, a 5 or 6 mm high-pressure ballon is placed in the renal pelvis under cystoscopic and fluoroscopic guidance. The 4.8 or 8 Fr microperc puncture needle is placed into the pelvicalyceal system. Endopyelotomy is performed with a laser fiber or monopolar hook on a high-pressure balloon. To improve the exposure of the cutting area, the high-pressure balloon is placed at the pyeloureteral junction. Double J stent is left for weeks. RESULTS: The ages of the patients were 4, 8 and 18 months, and 2 and 4 years. All patients had previously undergone pyeloplasty due to pyeloureteral junction obstruction. Operative time was 50 ± 21 min. Hospital stay after surgery was 24 h and hematuria disappeared within the 24 postoperative hours. DISCUSSION: The number of patients with recurrent PUJO is small, making it difficult to establish a standard surgical approach for failed pyeloplasty. Redo pyeloplasty is considered the gold standard by some authors but alternative methods, such as endourological techniques, may also have a role in the treatment of failed pyeloplasty. The percutaneous approach has shown very good results in this treatment and the miniaturization of percutaneous surgery has improved with the micropercutaneus access. We consider micropercutaneous approach helped with a high pressure balloon in the pyeloureteral junction is an alternative and minimally invasive technique that has shown good results in our small cases series. However, we must take into account the limitation of the study considering the low number of patients. We need prospective studies to support our results. CONCLUSION: Micropercutaneous endopyelotomy is a fairly effective technique to treat recurrent UPJO after failed pyeloplasty in children. In our experience, it reduces kidney damage without increasing complications.
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Obstrução Ureteral , Procedimentos Cirúrgicos Urológicos , Criança , Humanos , Pelve Renal/cirurgia , Estudos Prospectivos , Estudos Retrospectivos , Obstrução Ureteral/cirurgiaRESUMO
In this study, a restoration process was developed with potassium hydroxide (KOH), in order to improve each of the structures for their posterior fixation, through the use of new methods such as the Chilean conservative fixative solution (SFCCh), with exceptional results. Restore anatomical pieces corresponding to corpse and organs, being these last set with the SFCCh. In this work dealt with processes of restoration with potassium hydroxide, sodium chloride, and sodium hypochlorite, the process began with the cleanliness and suture of the structures for subsequent fixing in Chilean conservative fixative solution, making use of a corpse and different anatomical parts. Work based on items found in the database, Elsevier, Science Direct, ProQuest, and MEDLINE. At the end of the process of restoration and conservation of the anatomical pieces, was observed an improvement in muscle pigment with decrease of rigidity in the specimen, additionally a recovery of appearance in the vascular-nervous elements was achieved. The organs were much more malleable and the structures facilitate the identification of specific details, its subsequent immersion in SFCCh allows the longer preservation of the obtained results. The restoration with potassium hydroxide allows the improvement in the appearance of the different anatomical structures and simultaneously to facilitate its study. The SFCCh is an alternative that replaces partially the use of formaldehyde. In addition, it presents toxicity reduction.
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Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.
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Carcinoma Ductal Pancreático/tratamento farmacológico , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Gefitinibe/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas c-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A biological aerated filter (BAF) pilot plant consisting of two reactors (aerobic and anoxic one) was used to determine a strategy to remove nitrogen via nitrite. RNA/DNA analysis was performed to assess microbial activity and support chemical results. In less than 13 days the pilot plant was able to remove COD and suspended solids. Nitrogen removal via nitrite pathway could not be observed until day 130 when the empty bed contact time (EBCT) was set at 0.71 h. Nitrite was detected in the aerated BAF effluent but never nitrate. qPCR of amoA gene from RNA and DNA extracts of the aerobic biofilm confirmed that ammonia oxidizing bacteria (AOB) were present from the beginning of the operation but not active. AOB activity increased with time, reaching stability from operational day 124. The combination of both, low EBCT together with high OLR, has been demonstrated to be a feasible strategy to startup a BAF to achieve nitrogen removal via nitrite.
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Reatores Biológicos/microbiologia , Nitritos/química , Nitrogênio/química , Poluentes Químicos da Água/isolamento & purificação , Purificação da Água/métodos , Amônia/química , Compostos de Amônio/química , Biofilmes , DNA Bacteriano , Oxigênio/química , Reação em Cadeia da Polimerase , RNA Bacteriano , Eliminação de Resíduos LíquidosRESUMO
Aim: To assess long-term effectiveness, complications, and outcomes of primary obstructive megaureter (POM) treated by endoscopic balloon dilation (EBD) in the largest series reported. Patients and Methods: Hundred POM in 92 consecutive patients were treated by EBD between years 2004 and 2016. A total of 79 POM (73 patients) with more than 18 months of follow-up after treatment have been analyzed. EBD of the vesicoureteral junction was performed with semicompliant high-pressure balloon catheters (2.7FG) with minimum balloon diameter of 5 mm, followed by temporary Double-J stent placement. Follow-up protocol included periodical clinical reviews, US and MAG-3 renogram scans. Results: Median age at surgery was 4 months (15 days-3.6 years), with median operating time of 20 min (10-60) and hospital stay of 1 day (1-7). Initial renal function was preserved in all patients with significant improvement in renal drainage on the MAG-3 diuretic renogram after endoscopic treatment (p < 0.001 T-test). Significant post-operative differences were observed in hydronephrosis grade and ureteral diameter that were maintained in the long-term (p < 0.001 T-test). Endoscopic approach of POM had a long-term success rate of 87.3%, with a mean follow-up of 6.4 ± 3.8 years. Secondary VUR was found in 17 cases (21.5%), being successfully treated by endoscopic subureteral injection in 13 (76.4%). Nine cases developed long-term re-stenosis (12.2%) that were successfully treated with a new EBD in 8. Endoscopic management of POM failed in 10 cases (12.7%) that required ureteral reimplantation. Five were early failures (4 intraoperative technical problems and 1 double-J stent migration with severe re-stenosis), and 5 long-term (4 persistent VUR and 1 re-stenosis recurrence). Conclusion: EBD has shown to be an effective treatment of POM with few complications and good outcomes at long-term follow up. Main complication was secondary VUR that could also be treated endoscopically with a high success rate. In our opinion, EBD may be considered first-line treatment in POM.
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Resumen El objetivo de este trabajo fue analizar las vivencias de adolescentes con respecto a su paso por la escuela, caracterizando la contradicción cultural al interior del aula en contextos de vulnerabilidad social y pobreza económica. Desde un enfoque biográfico se entrevistaron 42 estudiantes de octavo año básico de siete escuelas de la provincia de Concepción (Chile). Los resultados muestran características de un sentido de identidad cultural y de diferenciación respecto del rol y la posición del estudiante en la escuela, la cultura escolar y la forma en que se expresa en el aula, a través de sus profesores. Para algunos estudiantes la escuela es complementaria a "proyectos de vida". Para otros, la cultura de la escuela representa el lugar donde no se sienten libres, generando interpretaciones contradictorias a su identidad cultural.
Abstract The objective of this work was to analyze the experiences of adolescent students with respect to their schooling by characterizing the cultural contradiction within the classroom in those that operate in the contexts of social vulnerability and economic poverty. 42 eighth-grade students from seven educational establishments from the area of Concepción, Chile, were interviewed with a focus on utilizing the biographical method. The results show characteristic features of a sense of cultural identity, as well as a sense of differentiation regarding the role and position of the student at the school, the culture which that position represents, and how it manifests itself in the classroom via the teachers. For some students, the school as complementary to "life projects". For other students, school represents some misinterpretations with respect to their cultural identity.