Therapeutic Strategies
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Oncogene ◽  
2021 ◽  
Yujie Zhang ◽  
Yuxin Zhang ◽  
Bo Ai ◽  
Juejun Gong ◽  
Yichen Li ◽  

AbstractEsophageal squamous cell carcinoma (ESCC) is one of the most lethal gastrointestinal malignancies with high mortality. Recurrence develops within only a few years after curative resection and perioperative adjuvant therapy in 30–50% of these patients. Therefore, it is essential to identify postoperative recurrence biomarkers to facilitate selecting the following surveillance and therapeutic strategies. The general transcription factor IIE subunit beta (GTF2E2) is crucial for physiological and pathological functions, but its roles in the aggression and recurrence of ESCC remain ambiguous. In this study, we found that GTF2E2 was highly expressed in ESCC samples, and elevated GTF2E2 expression predicted early recurrence after surgery for ESCC patients. High expression of GTF2E2 associated with more aggressive clinic features and poor prognosis. GTF2E2 promoted the proliferation and mobility of ESCC cells in vitro and in vivo. We further revealed that miR-139-5p repressed GTF2E2 expression by downregulating its mRNA through binding with Argonaute 2 (Ago2). Rescue assays suggested that miR-139-5p affected GTF2E2-mediated ESCC progression. Moreover, GTF2E2 positively interacted with FUS promoter and regulated FUS expression, and the phenotype changes caused by GTF2E2 manipulation were recovered by rescuing FUS expression in ESCC cells. Additionally, we demonstrated that GTF2E2 promotes ESCC cells progression via activation of the AKT/ERK/mTOR pathway. In conclusion, GTF2E2 may serve as a novel biomarker for recurrence after surgery and a potential therapeutic target for ESCC patients, and it promotes ESCC progression via miR-139-5p/GTF2E2/FUS axis.

2021 ◽  
Vol 8 ◽  
Jinpeng Wang ◽  
Kuoyun Zhu ◽  
Yuchuan Xue ◽  
Guangfu Wen ◽  
Lin Tao

With the improvement in the understanding of COVID-19 and the widespread vaccination of COVID-19 vaccines in various countries, the epidemic will be brought under control soon. However, multiple viruses could result in the post-viral syndrome, which is also common among patients with COVID-19. Therefore, the long-term consequences and the corresponding treatment of COVID-19 should be the focus in the post-epidemic era. In this review, we summarize the therapeutic strategies for the complications and sequelae of eight major systems caused by COVID-19, including respiratory system, cardiovascular system, neurological system, digestive system, urinary system, endocrine system, reproductive system and skeletal complication. In addition, we also sorted out the side effects reported in the vaccine trials. The purpose of this article is to remind people of possible complications and sequelae of COVID-19 and provide robust guidance on the treatment. It is extremely important to conduct long-term observational prognosis research on a larger scale, so as to have a comprehensive understanding of the impact of the SARS-CoV-2 on the human body and reduce complications to the greatest extent.

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Joice de Faria Poloni ◽  
Thaiane Rispoli ◽  
Maria Lucia Rossetti ◽  
Cristiano Trindade ◽  
José Eduardo Vargas

Cystic fibrosis (CF) is an autosomal recessive disorder, caused by diverse genetic variants for the CF transmembrane conductance regulator (CFTR) protein. Among these, p.Phe508del is the most prevalent variant. The effects of this variant on the physiology of each tissue remains unknown. This study is aimed at predicting cell signaling pathways present in different tissues of fibrocystic patients, homozygous for p.Phe508del. The study involved analysis of two microarray datasets, E-GEOD-15568 and E-MTAB-360 corresponding to the rectal and bronchial epithelium, respectively, obtained from the ArrayExpress repository. Particularly, differentially expressed genes (DEGs) were predicted, protein-protein interaction (PPI) networks were designed, and centrality and functional interaction networks were analyzed. The study reported that p.Phe508del-mutated CFTR-allele in homozygous state influenced the whole gene expression in each tissue differently. Interestingly, gene ontology (GO) term enrichment analysis revealed that only “neutrophil activation” was shared between both tissues; however, nonshared DEGs were grouped into the same GO term. For further verification, functional interaction networks were generated, wherein no shared nodes were reported between these tissues. These results suggested that the p.Phe508del-mutated CFTR-allele in homozygous state promoted tissue-specific pathways in fibrocystic patients. The generated data might further assist in prediction diagnosis to define biomarkers or devising therapeutic strategies.

2021 ◽  
Vol 9 ◽  
Anneline S. J. M. te Riele ◽  
Cynthia A. James ◽  
Hugh Calkins ◽  
Adalena Tsatsopoulou

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of predominantly the right ventricular (RV) myocardium. Affected patients typically present as young adults with hemodynamically stable ventricular tachycardia, although pediatric cases are increasingly recognized. These young subjects often have a more severe phenotype with a high risk of sudden cardiac death (SCD) and progression toward heart failure. Diagnosis of ARVC is made by combining multiple sources of information as prescribed by the consensus-based Task Force Criteria. The description of Naxos disease, a fully penetrant autosomal recessive disorder that is associated with ARVC and a cutaneous phenotype of palmoplantar keratoderma and wooly hair facilitated the identification of the genetic cause of ARVC. At present, approximately 60% of patients are found to carry a pathogenic variant in one of five genes associated with the cardiac desmosome. The incomplete penetrance and variable expressivity of these variants however implies an important role for environmental factors, of which participation in endurance exercise is a strong risk factor. Since there currently is no definite cure for ARVC, disease management is directed toward symptom reduction, delay of disease progression, and prevention of SCD. This clinically focused review describes the spectrum of ARVC among children and adolescents, the genetic architecture underlying this disease, the cardio-cutaneous syndromes that led to its identification, and current diagnostic and therapeutic strategies in pediatric ARVC subjects.

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Nieves Martinez Chanza ◽  
Louisa Soukane ◽  
Philippe Barthelemy ◽  
Aurélien Carnot ◽  
Thierry Gil ◽  

Abstract Introduction Cisplatin-based neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for patients with non-metastatic muscle invasive bladder cancer (MIBC). Unfortunately, many patients are not candidates to receive cisplatin due to renal impairment. Additionally, no predictive biomarkers for pathological complete response (pCR) are currently validated in clinical practice. Studies evaluating immune checkpoint inhibitors in the peri-operative setting are emerging with promising results. Clinical trials are clearly required in the neoadjuvant setting in order to improve therapeutic strategies. Methods and analysis Oncodistinct 004 – AURA is an ongoing multicenter phase II randomized trial assessing the efficacy and safety of avelumab single-agent or combined to different NAC regimens in patients with non-metastatic MIBC. Patients are enrolled in two distinct cohorts according to their eligibility to receive cisplatin-based NAC. In the cisplatin eligible cohort, patients are randomized in a 1:1 fashion to receive avelumab combined with cisplatin-gemcitabine or with dose-dense methotrexate-vinblastine-doxorubicin-cisplatin. In the cisplatin ineligible cohort, patients are randomized at a 1:1 ratio to paclitaxel-gemcitabine associated to avelumab or avelumab alone. Primary endpoint is pCR. Secondary endpoints are pathological response and safety. Ethics and dissemination The study is approved by ethics committee from all participating centers. All participants provide informed consent prior inclusion to the study. Once completed, results will be published in peer-reviewed journals. Trial registration number (NCT03674424).

2021 ◽  
George garinis ◽  
Katerina Gkirtzimanaki ◽  
Edisona Tsakani ◽  
Ermioni Arvanitaki ◽  
Electra Nenedaki ◽  

Abstract Neurodegenerative disorders are a growing challenge for the elderly yet their etiology remains elusive. Here, we show that persistent DNA damage in tissue-resident macrophages carrying an ERCC1-XPF DNA repair defect leads to cerebellar ataxia in mice. We find that cytoplasmic chromatin fragments accumulate in the brain microglia of progeroid and naturally aged mice stimulating a type-I Interferon (IFN-I) response and are then packaged in extracellular vesicles (EVs) leading to Purkinje cell death and neurodegeneration in Er1CX/− animals. To reduce neuroinflammation, we developed an EV-based strategy to deliver recombinant DNase I specifically in inflamed Er1CX/− microglia in vivo. Our approach rapidly removes dsDNAs from the cytoplasm of microglial cells and in secreted EVs; it alleviates the IFN-I response, decreases Purkinje cell death and delays the onset of neuronal decline in Er1CX/− animals. Thus, brain microglia causally contribute to neurodegeneration allowing for the development of promising therapeutic strategies against age-related neuroinflammation.

Dharmendra Kumar Yadav

: Neurodegeneration is a syndrome that occurs through the loss of the neuronal system's structure and function. In the 21st century, major health issues are related to cognitive impairment and neurological disorders such as autism, learning disabilities, Huntington’s, cerebral palsy, schizophrenia, Alzheimer's, neuromuscular, lateral sclerosis, and Parkinson’s disease may be life-threatening. Various experimental and epidemiological studies reveal the risk factors associated with the disease, like oxidative stress, hypertension, antioxidant enzyme abnormalities, metabolic toxicity, advanced age, cytoskeletal abnormalities, genetic defects, autoimmunity, mineral deficiencies, and other vascular disorders. Various compounds have been screened for the treatment of neurodegenerative diseases (NDs), but, due to their side effects, they have solitary symptomatic benefits. Phytochemicals play a crucial role in maintaining the chemical balance of the brain by affecting the receptor function of specific inhibitory neurotransmitters. This review highlights the importance of phytochemicals for neurodegenerative diseases, in particular the possible mechanism of action of these natural compounds used for the treatment.

2021 ◽  
Vol 28 (12) ◽  
pp. 2041-2043
Benjamin H. Goldenson ◽  
Dan S. Kaufman

2021 ◽  
Vol 8 ◽  
Xueyan Zhao ◽  
Jingjing Xu ◽  
Xiaofang Tang ◽  
Keyong Huang ◽  
Jiawen Li ◽  

Background: Both Niemann-Pick C1-like 1 (NPC1L1) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) play a key role on dyslipidaemia. We aim to evaluate whether NPC1L1 and HMGCR genetic variants are associated with susceptibility of premature triple-vessel disease (PTVD).Methods: Four single-nucleotide polymorphisms (SNPs) (rs11763759, rs4720470, rs2072183, and rs2073547) of NPC1L1; and three SNPs (rs12916, rs2303151, and rs4629571) of HMGCR were genotyped in 872 PTVD patients (males ≤ 50 years old and females ≤ 60 years old), and 401 healthy controls.Results: After adjusting for age and sex, rs12916 of HMGCR was associated with the risk of PTVD in dominance model [odds ratio (OR) = 1.68, 95% confidence intervals (CI): 1.29–2.18, P < 0.001], recessive model (OR = 1.43, 95% CI: 1.08–1.90, P = 0.013) and codominant model (OR = 1.38, 95% CI: 1.17–1.63, P < 0.001); meanwhile, rs4720470 of NPC1L1 was related to increased risk of PTVD in recessive model (OR = 1.74, 95% CI: 1.14–2.74, P = 0.013). Patients who carried both variant rs4720470 and rs12916 also had the risk of PTVD (P < 0.001); however, there were no correlation between these SNPs and the SNYTAX score (all P > 0.05).Conclusions: This is the first report that rs4720470 is a novel polymorphism of the NPC1L1 gene associated with PTVD, and rs12916 of HMGCR gene appears to be a strong genetic marker of PTVD. Our study may improve the early warning, therapeutic strategies and drug development of PTVD.

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