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Brain metastasis (BrM) is a major threat to the survival of melanoma, breast, and lung cancer patients. Circulating tumor cells (CTCs) cross the blood-brain barrier (BBB) and sustain in the brain microenvironment. Genetic mutations and epigenetic modifications have been found to be critical in controlling key aspects of cancer metastasis. Metastasizing cells confront inflammation and gradually adapt in the unique brain microenvironment. Currently, it is one of the major areas that has gained momentum. Researchers are interested in the factors that modulate neuroinflammation during BrM. We review here various epigenetic factors and mechanisms modulating neuroinflammation and how this helps CTCs to adapt and survive in the brain microenvironment. Since epigenetic changes could be modulated by targeting enzymes such as histone/DNA methyltransferase, deacetylases, acetyltransferases, and demethylases, we also summarize our current understanding of potential drugs targeting various aspects of epigenetic regulation in BrM.
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Neoplasias Encefálicas , Neoplasias Pulmonares , Humanos , Epigénesis Genética , Enfermedades Neuroinflamatorias , Neoplasias Encefálicas/genética , Inflamación/genética , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: Cystic fibrosis (CF) is a multisystem disorder that leads to abnormal transport of chloride and sodium across secretory epithelia resulting in thickened, viscous secretions in the bronchi, biliary tract, pancreas, intestine, and the reproductive system. Defects in the biliary tract can predispose to stone formation requiring endoscopic retrograde cholangiopancreatography (ERCP). However, there is a paucity of data assessing ERCP outcomes in patients with CF. METHODS: We identified patients from the Healthcare Cost and Utilization Project (HCUP)-National Inpatient Sample (NIS) between the years 2016 and 2020. Our study group included patients with CF of all ages who underwent an inpatient ERCP. We used ICD10 diagnostic and procedural codes to identify patients, procedures, and complications of the procedure. RESULTS: From 2016 to 2020, a total of 860,679 inpatient ERCPs were identified. Of these procedures, 535 (0.06%) were performed in patients with CF. The mean age of patients with CF undergoing ERCP was 60.62 years, of which 48% were males and 52% were females. Patients in the CF group had a higher incidence of post-ERCP pneumothorax (0.93%) than the patients in the non-CF group (0.15%). The occurrence of other ERCP-related adverse events was similar in both groups (P>0.05). On multivariate regression analysis, patients with CF were 1.75 times more likely to develop post-ERCP infections [odds ratio (OR): 1.75; 95% CI: 1.03-2.94; P=0.035) and 7.64 times more likely to develop post-ERCP pneumothorax (OR: 7.64; 95% CI: 1.03-56.5; P=0.046) compared to patients without CF after adjusting for confounders. The groups had no significant difference in mortality, post-ERCP pancreatitis, bleeding, perforation, pneumoperitoneum, and gas embolism. There was also no significant difference in the length of stay between the study and control groups. CONCLUSIONS: ERCP is a safe procedure in patients with CF with a comparable risk of postprocedural complications and mortality to those who do not have cystic fibrosis. However, patients with CF may experience a higher risk of post-ERCP infections and post-ERCP pneumothorax. Further studies are needed to prospectively evaluate outcomes of ERCP in patients with CF and to determine methods of mitigating adverse events.
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Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10-40 % of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM.
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Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/prevención & control , Quimiocinas , Células Madre Neoplásicas , Encéfalo , Microambiente Tumoral , Metástasis de la NeoplasiaRESUMEN
The diagnosis of brain metastasis (BrM) has historically been a dooming diagnosis that is nothing less than a death sentence, with few treatment options for palliation or prolonging life. Among the few treatment options available, brain radiotherapy (RT) and surgical resection have been the backbone of therapy. Within the past couple of years, immunotherapy (IT), alone and in combination with traditional treatments, has emerged as a reckoning force to combat the spread of BrM and shrink tumor burden. This review compiles recent reports describing the potential role of IT in the treatment of BrM in various cancers. It also examines the impact of the tumor microenvironment of BrM on regulating the spread of cancer and the role IT can play in mitigating that spread. Lastly, this review also focuses on the future of IT and new clinical trials pushing the boundaries of IT in BrM.
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Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/secundario , Inmunoterapia , Microambiente TumoralRESUMEN
BACKGROUND: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. METHODS: To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. RESULTS: A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. CONCLUSIONS: Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis.
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Neoplasias Pulmonares , MicroARNs , Carcinoma Pulmonar de Células Pequeñas , Humanos , Animales , Ratones , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Neoplasias Pulmonares/patología , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Proteína Forkhead Box M1/genética , Receptores CXCR4/genética , Receptores CXCR4/metabolismoRESUMEN
Brain metastasis (BrM) is a major problem associated with cancer-related mortality, and currently, no specific biomarkers are available in clinical settings for early detection. Liquid biopsy is widely accepted as a non-invasive method for diagnosing cancer and other diseases. We have reviewed the evidence that shows how the molecular alterations are involved in BrM, majorly from breast cancer (BC), lung cancer (LC), and melanoma, with an inception in how they can be employed for biomarker development. We discussed genetic and epigenetic changes that influence cancer cells to breach the blood-brain barrier (BBB) and help to establish metastatic lesions in the uniquely distinct brain microenvironment. Keeping abreast with the recent breakthroughs in the context of various biomolecules detections and identifications, the circulating tumor cells (CTC), cell-free nucleotides, non-coding RNAs, secretory proteins, and metabolites can be pursued in human body fluids such as blood, serum, cerebrospinal fluid (CSF), and urine to obtain potential candidates for biomarker development. The liquid biopsy-based biomarkers can overlay with current imaging techniques to amplify the signal viable for improving the early detection and treatments of occult BrM.
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Neoplasias Encefálicas , Neoplasias de la Mama , Células Neoplásicas Circulantes , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Femenino , Humanos , Biopsia Líquida/métodos , Células Neoplásicas Circulantes/patología , Microambiente TumoralRESUMEN
Nano-emulsions are defined as stable oil droplets sizing below 300 nm. Their singular particularity lies in the loading capabilities of their oily core, much higher than other kinds of carrier. On the other hand, functionalizing the dynamic oil/water interface, to date, has remained a challenge. To ensure the best anchoring of the reactive functions onto the surface of the droplets, we have designed specific amphiphilic polymers (APs) based on poly(maleic anhydride-alt-1-octadecene), stabilizing the nano-emulsions instead of surfactants. Aliphatic C18 chains of the APs are anchored in the droplet core, while the hydrophilic parts of the APs are poly(ethylene glycol) (PEG) chains. In addition, PEG chains are terminated with reactive (i) azide functions in order to prove the concept of the droplet decoration with clickable rhodamine (Rh-DBCO, specifically synthesized for this study), or (ii) biotin functions to verify the potential droplet functionalization with fluorescent streptavidin (streptavidin-AF-488). This study describes AP synthesis, physico-chemical characterization of the functional droplets (electron microscopy), and finally fluorescence labeling and droplet decoration. To conclude, these APs constitute an interesting solution for the stable functionalization of nano-emulsion droplets, paving a new way for the applications of nano-emulsions in targeting drug delivery.
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Polímeros , Tensoactivos , Emulsiones , Interacciones Hidrofóbicas e Hidrofílicas , PolietilenglicolesRESUMEN
Endothelial senescence has been identified as an early event in the development of endothelial dysfunction, a hallmark of cardiovascular disease. This study developed theranostic nanocarriers (NC) decorated with VCAM-1 antibodies (NC-VCAM-1) in order to target cell surface VCAM-1, which is overexpressed in senescent endothelial cells (ECs) for diagnostic and therapeutic purposes. Incubation of Ang II-induced premature senescent ECs or replicative senescent ECs with NC-VCAM-1 loaded with lipophilic fluorescent dyes showed higher fluorescence signals than healthy EC, which was dependent on the NC size and VCAM-1 antibodies concentration, and not observed following masking of VCAM-1. NC loaded with omega 3 polyunsaturated fatty acid (NC-EPA:DHA6:1) were more effective than native EPA:DHA 6:1 to prevent Ang II-induced VCAM-1 and p53 upregulation, and SA-ß-galactosidase activity in coronary artery segments. These theranostic NC might be of interest to evaluate the extent and localization of endothelial senescence and to prevent pro-senescent endothelial responses.
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Senescencia Celular , Portadores de Fármacos , Endotelio Vascular/citología , Colorantes Fluorescentes/química , Molécula 1 de Adhesión Celular Vascular/metabolismo , Animales , Autoanticuerpos/inmunología , Proliferación Celular , Endotelio Vascular/metabolismo , Medicina de Precisión , Porcinos , Molécula 1 de Adhesión Celular Vascular/inmunologíaRESUMEN
BACKGROUND: Runt related transcription factor3 (RUNX3) is considered as a tumor suppressor gene (TSG) that functions through the TGF-ß dependent apoptosis. Promoter methylation of the CpG islands of RUNX3 and overexpression of enhancer of zeste homolog 2 (EZH2) has been suggested to downregulate RUNX3 in cancer. METHODS: Here, we studied the expression of RUNX3 and EZH2 in 58 esophageal tumors along with paired adjacent normal tissue. mRNA levels, protein expressions and cellular localizations of EZH2 and RUNX3 were analyzed using real-time PCR and immunohistochemistry, respectively. DNA methylation was further assessed by the methylation specific-PCR. RESULTS: Compared to normal tissue, a significant increase in expression of RUNX3 mRNA in 31/57 patient's tumor tissue (p < 0.04) was observed. The expression of EZH2 was found to be upregulated compared to normal, and a significant positive correlation between EZH2 and RUNX3 expression was observed (p = 0.002). 22 of the 27 unmethylated cases at the promoter region of the RUNX3 had elevated RUNX3 protein expression (p < 0.001). CONCLUSION: The data presented in this study provide new insights into the biology of RUNX3 and highlights the need to revisit our current understanding of the role of RUNX3 in cancer.
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Currently, most nonviral nucleic acid vectors are in the form of colloidal suspensions administered primarily parenterally. This type of formulation and the mode of administration impose strong constraints such as the size of the administered vectors or the production of sterile preparations. The tablet form provides access to easy oral administration, well accepted by patients; As regards nucleic acid vectors, a dry form represents an advance in terms of stability. Using an optimized lipid-based small interfering RNA-delivery system, we studied the tabletability of a liquid suspension of these vectors. We optimized the conditions of freeze-drying by choosing excipients and process, allowing for the conservation of both the gene-silencing efficacy of the formulated siRNAs and the supramolecular structure of the lipid particulate system. Gene-silencing efficacy was assayed on luciferase-expressing cells and the structure of the siRNA vector in freeze-dried and tablet forms was examined using small-angle X-ray scattering (SAXS) synchrotron radiation. The freeze-dried powders were then mixed with excipients necessary for the good progress of the compression by allowing for a regular supply of the matrix and the reduction of friction. The compression was carried out using a rotary press simulator that allows for complete monitoring of the compression conditions. After compression, formulated siRNAs retained more than 60% of their gene-silencing efficacy. Within the tablets, a specific SAXS signal was detectable and the lamellar and cubic phases of the initial liquid suspension were restored after resuspension of siRNA vectors by disintegration of the tablets. These results show that the bilayer lipid structures of the particles were preserved despite the mechanical constraints imposed by the compression. If such a result could be expected after the freeze-drying step, it was never shown, to our knowledge, that siRNA-delivery systems could retain their efficacy and structure after mechanical stress such as compression. This opens promising perspectives to oral administration of siRNA as an alternative to parenteral administration.
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Lípidos/química , ARN Interferente Pequeño/química , Comprimidos/química , Administración Oral , Animales , Línea Celular , Excipientes/química , Liofilización/métodos , Silenciador del Gen/efectos de los fármacos , Ratones , Ácidos Nucleicos/química , Tamaño de la Partícula , Polvos/química , Dispersión del Ángulo Pequeño , Difracción de Rayos X/métodosRESUMEN
Delivery systems able to coencapsulate both hydrophilic and hydrophobic species are of great interest in both fundamental research and industrial applications. Water-in-oil-in-water (w1/O/W2) emulsions are interesting systems for this purpose, but they suffer from limited stability. In this study, we propose an innovative approach to stabilize double emulsions by the synthesis of a silica membrane at the water/oil interface of the primary emulsion (i.e., inner w1/O emulsion). This approach allows the formulation of stable double emulsions through a two-step process, enabling high encapsulation efficiencies of model hydrophilic dyes encapsulated in the internal droplets. This approach also decreases the scale of the double droplets up to the nanoscale, which is not possible without silica stabilization. Different formulation and processing parameters were explored in order to optimize the methodology. Physicochemical characterization was performed by dynamic light scattering, encapsulation efficiency measurements, release profiles, and optical and transmission electron microscopies.
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BACKGROUND: YAP, a potent oncogene and major downstream effector of the mammalian Hippo tumor suppressor pathway can act as either oncogene or tumor suppressor gene based on the type of tissue involved. Despite various studies, the role and mechanism through which YAP mediates its tumor suppressor or oncogenic effects are not yet fully understood. Therefore in the present study we aimed to investigate YAP at DNA, mRNA and protein level and also attempted to correlate our molecular findings with various clinicopathological variables of the patients. METHODS: The study comprised of a total 137 genetically unrelated women with sporadic breast cancer cases and normal adjacent tissues not infiltrated with tumor. Mutation of YAP gene was analyzed by automated DNA sequencing. YAP promoter methylation was studied using MS-PCR. Expression at mRNA and protein level was studied using qPCR and IHC respectively. RESULTS: In our study YAP mRNA expression was found to be 8.65 ± 6.17 fold downregulated in 67.15% cases. The expression of YAP when analyzed at the protein level by IHC was found to be absent in 78.83% cases. Results from MS-PCR analysis showed that YAP promoter methylation plays an important role in declining the expression of YAP protein. The absence of YAP protein coincided with 86.60% methylated cases thereby showing a very strong correlation (p = 0.001). We also investigated YAP mutation at the major check point sites in the Hippo pathway and observed no mutation. A significant association was observed on correlating mRNA expression with clinical stages (p = 0.038) and protein expression with ER status (p = 0.018) among Indian breast cancer patients. CONCLUSION: The expression of YAP was found to be downregulated in response to aberrant promoter methylation. The downregulation of YAP are consistent with previous studies suggesting it to have a tumor suppressive role in breast cancer. We did not observe any mutation at the major check point sites in the Hippo pathway.
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Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias de la Mama/genética , Metilación de ADN , Fosfoproteínas/genética , Regiones Promotoras Genéticas , Proteínas Adaptadoras Transductoras de Señales/análisis , Adulto , Anciano , Neoplasias de la Mama/patología , Regulación hacia Abajo , Femenino , Humanos , Persona de Mediana Edad , Mutación , Fosfoproteínas/análisis , ARN Mensajero/análisis , Factores de Transcripción , Proteínas Señalizadoras YAPRESUMEN
O-6-methylguanine-DNA methyltransferase, DNA repair gene, has been found to be involved with the pathogenesis of the esophageal cancer. DNA hypermethylation and other factors have been suggested to downregulate O-6-methylguanine-DNA methyltransferase. In this communication, the methylation status of O-6-methylguanine-DNA methyltransferase gene and the corresponding O-6-methylguanine-DNA methyltransferase protein expression in esophageal cancer from North India has been studied. In all, 80 samples of tumor tissue along with adjacent normal tissue as controls were analyzed for messenger RNA level of O-6-methylguanine-DNA methyltransferase gene, protein expression, and subcellular localization. The messenger RNA expression was studied using real-time quantitative polymerase chain reaction, protein expression, and its subcellular localization by Western blotting and immunohistochemistry. DNA methylation was assessed through methylation-specific polymerase chain reaction. Clinicopathological parameters were recorded and correlated with the O-6-methylguanine-DNA methyltransferase expression. O-6-methylguanine-DNA methyltransferase messenger RNA expression was found to be downregulated in 65% cases (52/80). The expression of O-6-methylguanine-DNA methyltransferase at the protein level was also found to be absent in 65% (52/80) cases. In all, 52 cases had low or no expression of the protein, whereas out of those 28 remaining cases, 11.25% (09/80) cases had high O-6-methylguanine-DNA methyltransferase protein expression. The absence of O-6-methylguanine-DNA methyltransferase protein coincided with the methylated cases in 84% (38/45), whereas in 07 cases, out of the 45 methylated, O-6-methylguanine-DNA methyltransferase protein was present. The aggressive esophageal cancer patients having methylated O-6-methylguanine-DNA methyltransferase had more than 50% cases with no/mild expression of the O-6-methylguanine-DNA methyltransferase protein ( p > 0.001). Loss of O-6-methylguanine-DNA methyltransferase protein was very frequent in the incidence of esophageal cancer from North Indian patients, and methylation of the promoter region of O-6-methylguanine-DNA methyltransferase was significantly associated in its downregulation.
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Biomarcadores de Tumor/genética , Metilación de ADN/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Neoplasias Esofágicas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Biomarcadores de Tumor/biosíntesis , Metilasas de Modificación del ADN/biosíntesis , Enzimas Reparadoras del ADN/biosíntesis , Neoplasias Esofágicas/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , India , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Regiones Promotoras Genéticas , ARN Mensajero/biosíntesis , Proteínas Supresoras de Tumor/biosíntesisRESUMEN
Promoter methylation reflects in the inactivation of different genes like O6-methylguanine-DNA methyltransferase DNA repair gene and runt-related transcription factor 3, a known tumor suppressor gene in various cancers such as esophageal cancer. The promoter methylation was evaluated for O6-methylguanine-DNA methyltransferase and runt-related transcription factor 3 in CpG, CHH, and CHG context (where H is A, T, or C) by next-generation sequencing. The methylation status was correlated with quantitative messenger RNA expression. In addition, messenger RNA expression was correlated with different risk factors like tobacco, alcohol, betel nut consumption, and smoking habit. CpG methylation of O6-methylguanine-DNA methyltransferase promoter had a positive association in the development of esophageal cancer (p < 0.05), whereas runt-related transcription factor 3 promoter methylation showed no significant association (p = 1.0) to develop esophageal cancer. However, the non-CpG methylation, CHH, and CHG were significantly correlated with O6-methylguanine-DNA methyltransferase (p < 0.05) and runt-related transcription factor 3 (p < 0.05) promoters in the development of esophageal cancer. The number of cytosine converted to thymine (CâT) in O6-methylguanine-DNA methyltransferase promoter showed a significant correlation between cases and controls (p < 0.05), but in runt-related transcription factor 3 no such significant correlation was observed. Besides, messenger RNA expression was found to be significantly correlated with promoter hypermethylation of O6-methylguanine-DNA methyltransferase and runt-related transcription factor 3 in the context of CHG and CHH (p < 0.05). The CpG hypermethylation in O6-methylguanine-DNA methyltransferase showed positive (p < 0.05) association, whereas in runt-related transcription factor 3, it showed contrasting negative association (p = 0.23) with their messenger RNA expression. Tobacco, betel nut consumption, and smoking habits were associated with altered messenger RNA expression of O6-methylguanine-DNA methyltransferase (p < 0.05) and betel nut consumption and smoking habits were associated with runt-related transcription factor 3 (p < 0.05). There was no significant association between messenger RNA expression of O6-methylguanine-DNA methyltransferase and runt-related transcription factor 3 with alcohol consumption (p = 0.32 and p = 0.15). In conclusion, our results suggest that an aberrant messenger RNA expression may be the outcome of CpG, CHG, and CHH methylation in O6-methylguanine-DNA methyltransferase, whereas outcome of CHG and CHH methylation in runt-related transcription factor 3 promoters along with risk factors such as consumption of tobacco, betel nut, and smoking habits in esophageal cancer from Northeast India.
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Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Metilación de ADN/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Neoplasias Esofágicas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Consumo de Bebidas Alcohólicas/efectos adversos , Areca/efectos adversos , Subunidad alfa 3 del Factor de Unión al Sitio Principal/biosíntesis , Islas de CpG/genética , Metilasas de Modificación del ADN/biosíntesis , Enzimas Reparadoras del ADN/biosíntesis , Neoplasias Esofágicas/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Guanina/análogos & derivados , Guanina/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Regiones Promotoras Genéticas , ARN Mensajero/genética , Factores de Riesgo , Fumar/efectos adversos , Proteínas Supresoras de Tumor/biosíntesisRESUMEN
BACKGROUND: Posterior urethral valve (PUV) is life-threatening congenital anomaly of the urinary tract that results in vesicoureteric reflux, recurrent UTI, voiding dysfunction and renal insufficiency if not treat timely. Endoscopic ablation of posterior urethral valves using cold knife or laser is the current gold standard therapy. Many urologists go for repeat cystoscopy to see residual valve or stricture while others repeat VCUG to measure the posterior to anterior urethral ratio for residual obstruction. In this study, we have standardized by regularly doing re-look cystoscopy at 3 months whether the child is symptomatic or not to see justification for re-look cystoscopy after PUV ablation. METHODS: In this prospective study, first 50 cases that underwent posterior urethral valve fulguration were included. Diagnosis of posterior urethral valve was made by voiding symptoms, ultrasonography and confirmed by voiding cysto-urethrogram (VCUG). All children were treated by endoscopic fulguration of posterior urethral valves (PUV) using cold knife as urethral valvotome and were followed clinically for voiding symptoms and with ultrasonography and laboratory test at 3 and 6 months. All patients underwent re-look cystoscopy at three months to see residual valves irrespective of their clinical improvement. RESULTS: Mean age at presentation was 4.9±3.2 years. The most common symptoms were poor stream (76%), straining at voiding (72%), dribbling of urine (54%), fever (42%) and urinary retention (14%). Residual valves on re-look cystoscopy were seen in 78%. Four (8%) patients had urethral stricture on re-look cystoscopy. CONCLUSIONS: We suggest routine re-look cystoscopy after primary fulguration of PUV to pick more residual obstructive valves.
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Cistoscopía , Electrocoagulación , Reoperación , Estrechez Uretral , Niño , Preescolar , Humanos , Estudios Prospectivos , Uretra/fisiopatología , Uretra/cirugía , Estrechez Uretral/fisiopatología , Estrechez Uretral/cirugíaRESUMEN
Isolated female epispadias without bladder exstrophy is a rare congenital anomaly. Patients present with total or partial urinary incontinence. The diagnosis can only be made on careful genitalia examination by separating the labia majora. That is why it is often missed by most physicians even after being extensively investigated. The physical findings include patulous urethra, flattened mons pubis, and bifid clitoris with lack of anterior labial commissure. In most of the cases, single stage reconstruction of urethra, labia minora and clitoris is enough to achieve urinary continence with cosmetically acceptable genitalia.
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Epispadias/diagnóstico , Epispadias/cirugía , Niño , Clítoris/cirugía , Femenino , Humanos , Uretra/cirugía , Vulva/cirugíaRESUMEN
To address the gap of extant literature and to assess employees' in-role and innovative performance, a model was developed and tested through organizational justice facets- procedural, distributive, and interactional justice with knowledge hiding facets, well-being facets and professional commitment. The purpose of the present research is to inspect the role of justice facets in shaping knowledge hiding behavior through optimistic role of well-being toward employee performance with the remedial role of professional commitment under the shadow of Psychological Ownership Knowledge Theory (POKT) and Social Exchange Theory (SET). For that persistence, present research acknowledged the practices and connotations of knowledge hiding because limited research is prevailed on the contrasting influence of knowledge hiding practice. Data were collected through random sampling via dual-wave survey questionnaire from 613 employees working in Kuala Terengganu, Malaysia. Structural Equation Modeling was carried out through AMOS (24.0) and SPSS (25.0). Findings reveal that the association with in-role and innovative performance with justice is positively associated through well-being, and the relationship between knowledge hiding and job performance was also positively associated. This study argued that knowledge sharing reshapes knowledge hiding behavior that plays a negative role in organizational performance. This study suggested the notable contribution in the direction of organizational context of developing realm settings by revealing the predecessor character of knowledge hiding and endorses the organizational justice to persuade top management for in-role and innovative performance enhancement.
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This paper determines the effect of international remittances on the healthcare utilization of childbearing mothers in Pakistan using the Pakistan Social and Living Standards Measurement (PSLM) survey, 2018-19. The study reports a significant and positive effect of international remittances on the healthcare outcomes of childbearing mothers. Importantly, the remittance-receiving households have 0.615, 0.208 and 0.306 times the odds of the non-receiving households, utilizing prenatal healthcare, postnatal healthcare, and healthcare decision making, respectively, and all of them are statistically significant. Consequently, the analysis confirms that remittance receiving-households do in fact influence and increase the likelihood of utilizing prenatal healthcare, postnatal healthcare and decisions about medical treatment for women. As regression-based estimation of remittances is prone to selection bias due to the nature of the non-experimental data set, we also used propensity score matching methods, which also confirmed a significant and positive effect of international remittances on healthcare outcomes of the childbearing mothers. Thus, financial support or social development programs by the government or non-governmental organization are pivotal in enhancing the healthcare outcomes and ultimately the living standards of childbearing mothers.
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Aceptación de la Atención de Salud , Salud Reproductiva , Atención a la Salud , Femenino , Humanos , Pakistán , Embarazo , Factores SocioeconómicosRESUMEN
COVID-19 rapidly spread across the world, constituting a public health disaster unlike any other experienced in decades. The impact exerted on workplaces and their employees was dramatic, and an immense burden fell on healthcare provision globally. Along with "front-line" healthcare staff, sanitation workers at hospitals also had to cope with additional workloads, making them vulnerable to psychological trauma and affecting their quality of life at establishments. This study investigated how the factors of occupational stress, self-efficacy (belief in the capacity to carry out a task well) and mental health altered the WRQoL (Work-Related Quality of Life) of employees carrying out sanitation duties at hospitals in Malaysia. To this end, a survey translated into the Malay language was conducted among 449 such workers during a so-called "recovery movement control order", i.e. quarantine and control measures pertaining to an outbreak of Coronavirus disease. Research involved co-variance-based structural equation modeling, performed in IBM-AMOS-26 software, in order to discern the causal relationship of the aforementioned factors on WRQoL. Results revealed a high level of occupational stress, diminished self-efficacy and poor mental health among the employees surveyed. Such stress directly impacted the WRQoL of the second factor alongside an indirect effect on that of the third, i.e. anxiety stemming from potentially catching the virus and the experience of having to disinfect facilities for treating patients, undertake cleaning duties, and move corpses.
Asunto(s)
COVID-19 , Estrés Laboral , COVID-19/epidemiología , Hospitales , Humanos , Malasia/epidemiología , Salud Mental , Estrés Laboral/epidemiología , Pandemias , Calidad de Vida , Saneamiento , AutoeficaciaRESUMEN
The unsettling fear of COVID-19 infections has caused a new trend in consumer behavior in the food and beverage industry. The unprecedented COVID-19 pandemic has shifted consumers' preferences from eat-in to online delivery. This research aims to measure the impact of consumers' motivation to protect themselves from contracting COVID-19, which explains why people switch from eat-in to online food delivery. We adopted the theory of protection motivation (PMT) to explain consumer switching behavior during the COVID-19 pandemic. The present study investigated the mediating effect of switching intention on the relationship between vulnerability, altruistic fear, anticipated regret, and switching behavior. Simultaneously, we examined the role of brand awareness as a moderator of behavioral choices of consumers switching from eat-in to online delivery. We collected data from 681 eatery consumers in Kuala Terengganu, Malaysia, using scenario-based survey questionnaires (327 eat-in respondents and 354 online delivery respondents). Then, the data were analyzed using structural equation modeling (SEM). This new generation analysis was conducted using the analysis of moment structure (AMOS) (v.24.0) and the statistical package for social science (SPSS-version 25.0). The results indicated that consumer vulnerability, altruistic fear, and anticipated regret of COVID-19 increased consumers' propensity to shift from eat-in to online food delivery. Allegedly, consumer behavioral control and intention of switching toward online delivery were pointedly affected by switching behavior. The results indicated that consumer vulnerability, altruistic fear, and anticipated regret of COVID-19 increased the shifting of restaurant dine-in patterns and made the intention to switch to online delivery. Consumers' alleged behavioral control and their intention of switching toward online delivery were pointedly affected by switching behavior. We also found that brand awareness moderately affects switching behavior toward restaurant settings. The present research contributes to developing the consumer behavior model of switching from eat-in to online delivery. This study also provides eatery customers and the business community with a safer and healthier proposition of shifting to online food delivery during the pandemic.