protein overexpression
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Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 79
Author(s):  
Hiroyuki Shimada ◽  
Naohiko Ikegaki

Peripheral neuroblastic tumors (neuroblastoma, ganglioneuroblastoma and ganglioneuroma) are heterogeneous and their diverse and wide range of clinical behaviors (spontaneous regression, tumor maturation and aggressive progression) are closely associated with genetic/molecular properties of the individual tumors. The International Neuroblastoma Pathology Classification, a biologically relevant and prognostically significant morphology classification distinguishing the favorable histology (FH) and unfavorable histology (UH) groups in this disease, predicts survival probabilities of the patients with the highest hazard ratio. The recent advance of neuroblastoma research with precision medicine approaches demonstrates that tumors in the UH group are also heterogeneous and four distinct subgroups—MYC, TERT, ALT and null—are identified. Among them, the first three subgroups are collectively named extremely unfavorable histology (EUH) tumors because of their highly aggressive clinical behavior. As indicated by their names, these EUH tumors are individually defined by their potential targets detected molecularly and immunohistochemically, such as MYC-family protein overexpression, TERT overexpression and ATRX (or DAXX) loss. In the latter half on this paper, the current status of therapeutic targeting of these EUH tumors is discussed for the future development of effective treatments of the patients.


2021 ◽  
Vol 14 (12) ◽  
pp. 1300
Author(s):  
Ioannis A. Vathiotis ◽  
Andriani Charpidou ◽  
Niki Gavrielatou ◽  
Konstantinos N. Syrigos

While human epidermal growth factor receptor 2 (HER2) aberrations have long been described in patients with non-small cell lung cancer (NSCLC), they have only recently been effectively targeted. Unlike patients with breast cancer, NSCLC patients can harbor either HER2-activating mutations or HER2 amplification coupled with protein overexpression. The latter has also been the case for patients with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). As preclinical data continue to accumulate, clinical trials evaluating novel agents that target HER2 have produced promising preliminary results. Here, we review existing data on HER2 aberrations in NSCLC. Starting from HER2 biology in normal and disease processes, we summarize discrepancies in HER2 diagnostic assays between breast cancer and NSCLC. Finally, to dissect the therapeutic implications of HER2-activating mutations versus gene amplification and/or protein overexpression, we present data from prospective clinical trials that have employed distinct classes of agents to target HER2 in patients with NSCLC.


2021 ◽  
Vol 22 (23) ◽  
pp. 12872
Author(s):  
Mourad Assidi ◽  
Fatimah M. Yahya ◽  
Maryam H. Al-Zahrani ◽  
Razan Elkhatib ◽  
Ali Zari ◽  
...  

Ovarian cancer (OC) is the deadliest among all gynecological cancers. Epidemiological studies showed that obesity might influence many cancers including OC. One of the key factors that may link obesity and OC is leptin (LEP), known as an adipokine with pleiotropic effects on body homeostasis. This study aims to investigate the expression pattern of LEP, assess the methylation profiles of LEP and their associations with clinicopathological features including survival outcomes of OC patients. The protein expression of LEP was evaluated in 208 samples using both tissue microarray and immunohistochemistry techniques. The methylation profiles of LEP were measured in 63 formalin-fixed, paraffin-embedded tumor tissues by quantitative polymerase chain reaction using a MethyLight assay. Our results showed a significant association of LEP protein overexpression with several clinicopathological variables, mainly tumor subtype, LVI, age of menarche, tumor size and stage (p < 0.04). Kaplan–Meier analysis (using low expression versus high expression as a discriminator) indicated that LEP protein overexpression is a powerful positive prognosticator of both OC recurrence (DFS) and disease-specific survival (DSS) in our OC cohort (log-rank p = 0.01 and p = 0.002, respectively). This implies that patients with high LEP expression profiles live longer with less recurrence rates. Methylation analysis results demonstrated a clear association between no/low LEP protein expression pattern (38%) and LEP promoter CpG island hypermethylation (43%). Results of this study suggest that LEP is a powerful prognosticator of OC recurrence and DSS. LEP expression in OC seems to be regulated by its promoter hypermethylation through gene partial/total silencing. Further multi-institutional studies using larger cohorts are required to demystify the intricate molecular functions of this leptin-driven effects in OC pathophysiology and to accurately assess its theranostic potential and validate its prognostic/predictive power in OC onset, progression towards more effective and personalized management of OC patients.


2021 ◽  
Vol 2 (5) ◽  
pp. 6793-6800
Author(s):  
Oscar de Jesus Reyes Delgado ◽  
Bibiana Moreno Carranza

Introducción: La enterocolitis necrotizante (ECN) es la patología gastrointestinal de las más comunes y devastadoras en recién nacido con muy bajo peso al nacer (rango entre 500-1500g) y se caracteriza por inflamación y necrosis intestinal. Los objetivos de este estudio fueron desarrollar un modelo murino de ECN así como un modelo de sobreexpresión de proteínas en el intestino mediante la administración enteral mediante sonda de vectores lentivirales. Métodos: Para el modelo de ECN se utilizaron cepas de ratón C57BL6 y CD1 a los cuales se les trató por 6 veces cada dos horas con una dosis de anoxia con CO2 al 100% durante 10 o 7.5 minutos seguida una reoxigenación mediante hiperoxia al 95% por 5 minutos. Además, para activar el sistema inmune se administró LPS en las primeras dos dosis. Para la sobreexpresión de prolactina (PRL) en el intestino se administraron vectores lentivirales que sobreexpresan GFP (como control) o PRL por vía enteral a ratones CD1 en edades postnatales P2 y P3. Posteriormente se analizó la presencia de GFP y prolactina de las muestras de intestino mediante visualización por microscopia de fluorescencia y Western blot, respectivamente. Resultados: Se obtuvo una mortalidad del 45% y una eficiencia de desarrollo de ECN entre los animales vivos del 100% en ratones CD1 de edad postnatal P1, en contraste con la mortalidad de 85% y la eficiencia de desarrollo de ECN entre los animales vivos del 0% en ratones C57Bl6 de P1. En relación al modelo de sobreexpresión de proteínas en el intestino, se detectó GFP en el intestino de ratones administrados con 106 TU/ml vectores lentivirales para la sobreexpresión de GFP en el día P2 y evaluados 24 horas después. No se observó la sobreexpresión de PRL en el intestino de ratones administrados con 106 y 108 TU/ml vectores lentivirales para la sobreexpresión de PRL en los días P2 y P3 y evaluados 48 horas después. Conclusión: El modelo de ECN en ratones CD1 de P1 tuvo una efectividad del 100% a pesar de una mortalidad elevada. Además, se logró estandarizar el método para la sobreexpresión de proteínas en el intestino de ratones en P2 24 horas después de la administración de vectores lentivirales por la via enteral. La determinación de sobreexpresión de PRL en el intestino no fue conclusiva.     Background: Necrotizating enterocolitis (NEC) is one of the most common and devastating gastrointestinal disease in newborns with very low weight birth (range among 500 -1500 g). NEC is characterized by intestinal inflammation and necrosis. Our aims of this study were to develop a NEC murine model and a intestinal protein expression model by means of enteral administration of lentiviral vectors. Method: For the NEC model were used C57BL6 and CD1 mice which were treated with anoxia with 100% CO2 for 10 or 7.5 minutes followed by 95% O2 for 5 minutes. This treatment was repeated six times with a 2 hours interval. Moreover, to activate the immune system, LPS was administrated orally in the first two doses. For the overexpression of prolactin (PRL) in the intestine, lentiviral vectors that overexpress GFP (as a control) or PRL were administered by orally to CD1 mice at postnatal ages P2 and P3. Then, the presence of GFP and prolactin in the intestine samples was analyzed by fluorescence microscopy and Western blot, respectively. Result: Mortality of 45% and a NEC development efficiency of 100% was obtained among live animals in CD1 mice of P1 postnatal age, in contrast to the mortality of 85% and development efficiency of 0% among live animals in C57BL6 mice of P1 age. In relation to the protein overexpression model in the intestine, GFP was detected in the mice gut administrated with 106 lentiviral vectors for the GFP overexpression on P2 evaluated 24 hours later. PRL overexpression was not observed in mice that received on day P1 postnatal 106 and 108 TU/ml of lentiviral vectors for the overexpression of PRL and evaluated on days P2 and P3. Conclusion: NEC model had an effectiveness of 100% in CD1 mice of 1 day of life, despite the high mortality. Moreover, a method for protein overexpression in the intestine was standardized. Lenviral vectors were orally administered 24 hours after birth and the expression of the protein was detected 24 hours later. Prolactin overexpression determination was not conclusive.


2021 ◽  
Author(s):  
Haley M. Geertsma ◽  
Terry R Suk ◽  
Konrad M Ricke ◽  
Kyra Horsthuis ◽  
Jean-Louis A Parmasad ◽  
...  

Background A growing body of evidence suggests that nuclear alpha-synuclein (aSyn) plays a role in the pathogenesis of Parkinson's disease (PD). However, this question has been difficult to address as controlling the localization of aSyn in experimental systems often requires protein overexpression, which results in aggregation. Methods We engineered SncaNLS mice which localize endogenous aSyn to the nucleus. We characterized these mice on a behavioral, histological, and biochemical level to determine whether the increase of nuclear aSyn is sufficient to elicit disease phenotypes. Results SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to aSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of SncaNLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signaling, namely Darpp-32, which we further confirmed was decreased in cortical samples of the SncaNLS mice compared to controls via immunoblotting. Conclusions These results suggest that chronic endogenous nuclear aSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of aSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis.


2021 ◽  
pp. 109352662110433
Author(s):  
Mikako Warren ◽  
Nishant Tiwari ◽  
Sabrina Sy ◽  
Gordana Raca ◽  
Ryan J Schmidt ◽  
...  

Background The hallmark of lipoblastoma is a PLAG1 fusion. PLAG1 protein overexpression has been reported in sporadic PLAG1-rearranged lipoblastomas. Methods We evaluated the utility of PLAG1 immunohistochemical staining (IHC) in 34 pediatric lipomatous tumors, correlating the results with histology and conventional cytogenetics, FISH and/or next generation sequencing (NGS) results. Results The study included 24 lipoblastomas, divided into 2 groups designated as “Lipoblastoma 1” with both lipoblastoma histology and PLAG1 rearrangement (n = 16) and “Lipoblastoma 2” with lipoblastoma histology but without PLAG1 cytogenetic rearrangement (n = 8), and 10 lipomas with neither lipoblastoma histology nor a PLAG1 rearrangement. Using the presence of a fusion as the “gold standard” for diagnosing lipoblastoma (Lipoblastoma 1), the sensitivity of PLAG1 IHC was 94%. Using histologic features alone (Lipoblastoma 1 + 2), the sensitivity was 96%. Specificity, as defined by the ability to distinguish lipoma from lipoblastoma, was 100%, as there were no false positives in the lipoma group. Conclusions Cytogenetics/molecular testing is expensive and may not be ideal for detecting PLAG1 fusions because PLAG1 fusions are often cytogenetically cryptic and NGS panels may not include all partner genes. PLAG1 IHC is an inexpensive surrogate marker of PLAG1 fusions and may be useful in distinguishing lipoblastomas from lipomas.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Abdulkadir Elmas ◽  
Serena Tharakan ◽  
Suraj Jaladanki ◽  
Matthew D. Galsky ◽  
Tao Liu ◽  
...  

AbstractIdentifying genomic alterations of cancer proteins has guided the development of targeted therapies, but proteomic analyses are required to validate and reveal new treatment opportunities. Herein, we develop a new algorithm, OPPTI, to discover overexpressed kinase proteins across 10 cancer types using global mass spectrometry proteomics data of 1,071 cases. OPPTI outperforms existing methods by leveraging multiple co-expressed markers to identify targets overexpressed in a subset of tumors. OPPTI-identified overexpression of ERBB2 and EGFR proteins correlates with genomic amplifications, while CDK4/6, PDK1, and MET protein overexpression frequently occur without corresponding DNA- and RNA-level alterations. Analyzing CRISPR screen data, we confirm expression-driven dependencies of multiple currently-druggable and new target kinases whose expressions are validated by immunochemistry. Identified kinases are further associated with up-regulated phosphorylation levels of corresponding signaling pathways. Collectively, our results reveal protein-level aberrations—sometimes not observed by genomics—represent cancer vulnerabilities that may be targeted in precision oncology.


Animals ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 2406
Author(s):  
Juliana Moreira Rozolen ◽  
Tamires Goneli Wichert Teodoro ◽  
Renata Afonso Sobral ◽  
Felipe Augusto Ruiz Sueiro ◽  
Renee Laufer-Amorim ◽  
...  

Splenic hemangiosarcoma (HSA) is a malignant tumor of endothelial cells that affects middle-aged and elderly dogs and is characterized by the formation of new blood vessels, commonly associated with necrotic and hemorrhagic areas. Despite its importance in veterinary medicine, few studies have identified markers with prognostic value for canine HSA. Thus, this study aimed to associate the clinicopathological findings (prostate-specific membrane antigen [PSMA], Claudin-5, and Ki67 gene and protein expression) with overall survival in HSA-affected patients. Fifty-three formalin-fixed and paraffin-embedded canine splenic HSA samples, previously diagnosed by histopathological examination, were used in this study. Claudin-5, PSMA, and Ki67 protein expression levels were evaluated by immunohistochemistry, and gene expression was evaluated by quantitative polymerase chain reaction. Claudin-5 protein overexpression was observed in patients with metastasis (p = 0.0078) and with stage III tumors compared to those with stage I and II tumors (p = 0.0451). In patients treated with surgery alone, low PSMA gene and protein expression (p = 0.05 and p = 0.0355, respectively) were associated with longer survival time. Longer survival time was observed in patients with a low Ki67 index (p = 0.0488). Our results indicate that Claudin-5 protein expression is associated with metastatic status, and PSMA gene and protein expression, and Ki67 index are associated with survival time.


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