Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class II BRAF Mutant Melanomas

The choice of an effective therapeutic strategy in the treatment of biofilm-related infections is a significant issue. Amyloids, which have been historically related to human diseases, are now considered to be prevailing structural components of the biofilm matrix in a wide range of bacteria. This assumption creates the potential for an exciting research area, in which functional amyloids are considered to be attractive targets for drug development to dissemble biofilm structures. The present review describes the best-characterized bacterial functional amyloids and focuses on anti-biofilm agents that target intrinsic and facultative amyloids. This study provides a better understanding of the different modes of actions of the anti-amyloid molecules to inhibit biofilm formation. This information can be further exploited to improve the therapeutic strategies to combat biofilm-related infections.

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Gene Editing and Modulation: the Holy Grail for the Genetic Epilepsies?

Neurotherapeutics ◽

10.1007/s13311-021-01081-y ◽

2021 ◽

Author(s):

Jenna C. Carpenter ◽

Gabriele Lignani

Keyword(s):

Precision Medicine ◽

Neurological Disorder ◽

Gene Editing ◽

Therapeutic Strategy ◽

Therapeutic Potential ◽

Single Gene ◽

Drug Resistant ◽

Holy Grail ◽

Effective Therapeutic Strategy ◽

Genetic Epilepsies

AbstractEpilepsy is a complex neurological disorder for which there are a large number of monogenic subtypes. Monogenic epilepsies are often severe and disabling, featuring drug-resistant seizures and significant developmental comorbidities. These disorders are potentially amenable to a precision medicine approach, of which genome editing using CRISPR/Cas represents the holy grail. Here we consider mutations in some of the most ‘common’ rare epilepsy genes and discuss the different CRISPR/Cas approaches that could be taken to cure these disorders. We consider scenarios where CRISPR-mediated gene modulation could serve as an effective therapeutic strategy and discuss whether a single gene corrective approach could hold therapeutic potential in the context of homeostatic compensation in the developing, highly dynamic brain. Despite an incomplete understanding of the mechanisms of the genetic epilepsies and current limitations of gene editing tools, CRISPR-mediated approaches have game-changing potential in the treatment of genetic epilepsy over the next decade.

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PS1226 DEVELOPMENT OF INNOVATIVE PRECLINICAL IN VITRO AND IN VIVO TOOLS FOR AN EFFECTIVE THERAPEUTIC STRATEGY IN PEDIATRIC ACUTE MYELOID LEUKEMIA

HemaSphere ◽

10.1097/01.hs9.0000563188.26522.47 ◽

2019 ◽

Vol 3 (S1) ◽

pp. 559

Author(s):

G. Borella ◽

V. Bisio ◽

A. Da Ros ◽

C. Tregnago ◽

M. Benetton ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Therapeutic Strategy ◽

Pediatric Acute Myeloid Leukemia ◽

Effective Therapeutic Strategy ◽

Acute Myeloid

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Emergent Uterine Arterial Embolization Using N-Butyl Cyanoacrylate in Postpartum Hemorrhage with Disseminated Intravascular Coagulation

BioMed Research International ◽

10.1155/2017/1562432 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Soichiro Obata ◽

Michi Kasai ◽

Junko Kasai ◽

Kazuo Seki ◽

Zenjiro Sekikawa ◽

...

Keyword(s):

Disseminated Intravascular Coagulation ◽

Postpartum Hemorrhage ◽

Uterine Artery Embolization ◽

Therapeutic Strategy ◽

Arterial Embolization ◽

Artery Embolization ◽

Intravascular Coagulation ◽

First Choice ◽

Uterine Arterial Embolization ◽

Effective Therapeutic Strategy

Although it is widely accepted that uterine artery embolization (UAE) is an effective therapeutic strategy for postpartum hemorrhage (PPH), no consensus has been reached regarding the efficacy of UAE in patients with PPH with disseminated intravascular coagulation (DIC). This single-center retrospective cohort study included patients treated with UAE using NBCA for PPH between 2010 and 2015. The patients were divided into DIC and non-DIC groups, according to the obstetrical DIC score and the overt DIC diagnostic criteria issued by the International Society of Thrombosis and Haemostasis (ISTH), and their clinical outcomes were compared. There were 28 patients treated with UAE using NBCA. Complete hemostasis was achieved by UAE in 19 of 28 patients. In eight of nine patients with unsuccessful hemostasis, surgical hemostatic interventions were performed after UAE, and hemostasis was achieved in seven patients. UAE using NBCA showed no significant intergroup differences in complete hemostasis according to the presence or absence of DIC based on obstetrical DIC score (70% versus 62.5%, P=1.000) or ISTH DIC score (54.5% versus 76.5%, P=0.409). UAE using NBCA may be a useful first-choice treatment for PPH with DIC.

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Excavating Anticonvulsant Compounds from Prescriptions of Traditional Chinese Medicine in the Treatment of Epilepsy

The American Journal of Chinese Medicine ◽

10.1142/s0192415x18500374 ◽

2018 ◽

Vol 46 (04) ◽

pp. 707-737 ◽

Cited By ~ 4

Author(s):

Zefeng Zhao ◽

Xirui He ◽

Cuixia Ma ◽

Shaoping Wu ◽

Ye Cuan ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Therapeutic Strategy ◽

In Vitro Models ◽

New Drugs ◽

Treatment Of Epilepsy ◽

Effective Therapeutic Strategy ◽

Promising Source

Traditional Chinese medicine (TCM) has a long history and been widely used in prevention and treatment of epilepsy in China. This paper is intended to review the advances in the active anticonvulsant compounds isolated from herbs in the prescription of TCM in the treatment of epilepsy. These compounds were introduced with the details including classification, CAS number specific structure and druggability data. Meanwhile, much of the research in these compounds in the last two decades has shown that they exhibited favorable pharmacological properties in treatment of epilepsy both in in vivo and in vitro models. In addition, in this present review, the evaluation of the effects of the anticonvulsant classical TCM prescriptions is discussed. According to these rewarding pharmacological effects and chemical substances, the prescription of TCM herbs could be an effective therapeutic strategy for epilepsy patients, and also could be a promising source for the development of new drugs.

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Dual BRAF/MEK blockade restores CNS responses in BRAF-mutant Erdheim–Chester disease patients following BRAF inhibitor monotherapy

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa024 ◽

2020 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Roei D Mazor ◽

Ran Weissman ◽

Judith Luckman ◽

Liran Domachevsky ◽

Eli L Diamond ◽

...

Keyword(s):

Disease Progression ◽

Therapeutic Strategy ◽

Braf Inhibitor ◽

Response To Therapy ◽

Cns Disease ◽

Erdheim Chester Disease ◽

Braf Mutant ◽

Erdheim Chester ◽

Chester Disease

Abstract Background Erdheim–Chester disease (ECD), a rare inflammatory myeloid neoplasm, is known to be fundamentally reliant on the constitutive activation of the MAPK signaling pathway in the majority of patients. Consequently, inhibition of the V600E-mutant BRAF kinase has proven to be a safe and efficacious long-term therapeutic strategy for BRAF-mutant ECD patients. Nevertheless, in a subset of patients with CNS disease, the efficacy of long-term treatment may diminish, facilitating suboptimal responses or disease progression. Methods We retrospectively describe 3 BRAF-mutant ECD patients whose treatment with Vemurafenib was upgraded to Vemurafenib/Cobimetinib due to either disease progression, insufficient response, or unacceptable toxicity. CNS response to therapy was evaluated using magnetic resonance imaging (MRI) and extra-cranial disease was monitored using 18F-fludeoxyglucose positron emission tomography/computed tomography (PET/CT). Results Three patients with a mean age of 52.6 years were treated with Vemurafenib for a mean duration of 26.6 months (range: 6–52). Monotherapies were upgraded to Vemurafenib/Cobimetinib dual therapy. The combination therapy was administered for a mean duration of 21 months (range: 19–23). All patients exhibited clinical and neurological improvement. Regression of lesions on MRI was noted in 2 patients. Both patients characterized by a PET-avid disease responded to the biological treatment regimen with complete metabolic remissions. Conclusion Dual inhibition of BRAF and downstream MEK may be a safe and effective therapeutic strategy for BRAF-mutant ECD patients for whom BRAF inhibitor therapy proved insufficient and as such appropriate for the long-term management of CNS disease in ECD.

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Mitochondrial dysfunction and the AKI-to-CKD transition

AJP Renal Physiology ◽

10.1152/ajprenal.00285.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. F1105-F1116

Author(s):

Mingzhu Jiang ◽

Mi Bai ◽

Juan Lei ◽

Yifan Xie ◽

Shuang Xu ◽

...

Keyword(s):

Therapeutic Strategy ◽

Kidney Diseases ◽

Kidney Injury ◽

Mitochondrial Homeostasis ◽

Cycle Arrest ◽

Persistent Inflammation ◽

Acute Injuries ◽

Nephron Loss ◽

Effective Therapeutic Strategy

Acute kidney injury (AKI) has been widely recognized as an important risk factor for the occurrence and development of chronic kidney disease (CKD). Even milder AKI has adverse consequences and could progress to renal fibrosis, which is the ultimate common pathway for various terminal kidney diseases. Thus, it is urgent to develop a strategy to hinder the transition from AKI to CKD. Some mechanisms of the AKI-to-CKD transition have been revealed, such as nephron loss, cell cycle arrest, persistent inflammation, endothelial injury with vascular rarefaction, and epigenetic changes. Previous studies have elucidated the pivotal role of mitochondria in acute injuries and demonstrated that the fitness of this organelle is a major determinant in both the pathogenesis and recovery of organ function. Recent research has suggested that damage to mitochondrial function in early AKI is a crucial factor leading to tubular injury and persistent renal insufficiency. Dysregulation of mitochondrial homeostasis, alterations in bioenergetics, and organelle stress cross talk contribute to the AKI-to-CKD transition. In this review, we focus on the pathophysiology of mitochondria in renal recovery after AKI and progression to CKD, confirming that targeting mitochondria represents a potentially effective therapeutic strategy for the progression of AKI to CKD.

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Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer

Cancers ◽

10.3390/cancers12102746 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2746

Author(s):

Hwa-Yong Lee ◽

In-Sun Hong

Keyword(s):

Stem Cell ◽

Liver Cancer ◽

Signaling Pathways ◽

Therapeutic Strategy ◽

Malignant Tumors ◽

Current Knowledge ◽

Therapeutic Approaches ◽

Effective Therapeutic Strategy ◽

Cancer Types ◽

The Brain

The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.

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