AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells

In the past years, we have learnt that tumors co-evolve with their microenvironment, and that the active interaction between cancer cells and stromal cells plays a pivotal role in cancer initiation, progression and treatment response. Among the players involved, the pathways regulating mitochondrial functions have been shown to be crucial for both cancer and stromal cells. This is perhaps not surprising, considering that mitochondria in both cancerous and non-cancerous cells are decisive for vital metabolic and bioenergetic functions and to elicit cell death. The central part played by mitochondria also implies the existence of stringent mitochondrial quality control mechanisms, where a specialized autophagy pathway (mitophagy) ensures the selective removal of damaged or dysfunctional mitochondria. Although the molecular underpinnings of mitophagy regulation in mammalian cells remain incomplete, it is becoming clear that mitophagy pathways are intricately linked to the metabolic rewiring of cancer cells to support the high bioenergetic demand of the tumor. In this review, after a brief introduction of the main mitophagy regulators operating in mammalian cells, we discuss emerging cell autonomous roles of mitochondria quality control in cancer onset and progression. We also discuss the relevance of mitophagy in the cellular crosstalk with the tumor microenvironment and in anti-cancer therapy responses.

https://www.mdpi.com/2073-4409/8/5/493/pdf

Mitophagy in Cancer: A Tale of Adaptation

Minor spliceosome and disease.

Alzheimer's disease (AD) is the most common form of dementia worldwide, being characterized by the deposition of senile plaques, neurofibrillary tangles (enriched in the amyloid beta (Aβ) peptide and hyperphosphorylated tau (p-tau), respectively) and memory loss. Aging, type 2 diabetes (T2D) and female sex (especially after menopause) are risk factors for AD, but their crosslinking mechanisms remain unclear. Most clinical trials targeting AD neuropathology failed and it remains incurable. However, evidence suggests that effective anti-T2D drugs, such as the GLP-1 mimetic and neuroprotector liraglutide, can be also efficient against AD. Thus, we aimed to study the benefits of a peripheral liraglutide treatment in AD female mice. We used blood and brain cortical lysates from 10-month-old 3xTg-AD female mice, treated for 28 days with liraglutide (0.2 mg/kg, once/day) to evaluate parameters affected in AD (e.g., Aβ and p-tau, motor and cognitive function, glucose metabolism, inflammation and oxidative/nitrosative stress). Despite the limited signs of cognitive changes in mature female mice, liraglutide only reduced their cortical Aβ1-42 levels. Liraglutide partially attenuated brain estradiol and GLP-1 and activated PKA levels, oxidative/nitrosative stress and inflammation in these AD female mice. Our results support the earlier use of liraglutide as a potential preventive/therapeutic agent against the accumulation of the first neuropathological features of AD in females.

Liraglutide Protects Against Brain Amyloid-β1-42 Accumulation in Female Mice with Early Alzheimer's Disease-Like Pathology by Partially Rescuing Oxidative/Nitrosative Stress and Inflammation.

The mercapturic acid pathway is a major route for the biotransformation of xenobiotic and endobiotic electrophilic compounds and their metabolites. Mercapturic acids (N-acetyl-l-cysteine S-conjugates) are formed by the sequential action of the glutathione transferases, γ-glutamyltransferases, dipeptidases, and cysteine S-conjugate N-acetyltransferase to yield glutathione S-conjugates, l-cysteinylglycine S-conjugates, l-cysteine S-conjugates, and mercapturic acids; these metabolites constitute a "mercapturomic" profile. Aminoacylases catalyze the hydrolysis of mercapturic acids to form cysteine S-conjugates. Several renal transport systems facilitate the urinary elimination of mercapturic acids; urinary mercapturic acids may serve as biomarkers for exposure to chemicals. Although mercapturic acid formation and elimination is a detoxication reaction, l-cysteine S-conjugates may undergo bioactivation by cysteine S-conjugate β-lyase. Moreover, some l-cysteine S-conjugates, particularly l-cysteinyl-leukotrienes, exert significant pathophysiological effects. Finally, some enzymes of the mercapturic acid pathway are described as the so-called "moonlighting proteins," catalytic proteins that exert multiple biochemical or biophysical functions apart from catalysis.

The mercapturic acid pathway

Numerous factors impact on the prognosis of acute myeloid leukemia (AML), among which molecular genetic abnormalities are developed increasingly, however, accurate prediction for newly diagnosed AML patients remains unsatisfied. For further improving the prognosis evaluation system, we investigated the transcripts levels of PDCD7, FIS1, FAM3A, CA6, APP, KLRF1, ATCAY, GGT5 and Ang2 in 97 AML patients and 30 non-malignant controls, and validated using the published microarray data from 225 cytogenetically normal AML (CN-AML) patients treated according to the German AMLCG-1999 protocol. Real-time quantitative polymerase chain reaction and western blot were carried out, and clinical data were collected and analyzed. High Ang2 and FIS1 expression discriminated the CR rate of AML patients (62.5% versus 82.9% for Ang2, P = 0.011; 61.4% versus 82.2% for FIS1, P = 0.029). In CN-AML, patients with high FIS1 expression were more likely to be resistant to two courses of induction (P = 0.035). Overall survival (OS) and relapse-free survival (RFS) were shorter in CN-AML patients with high PDCD7 expression (P<0.001; P = 0.006), and PDCD7 was revealed to be an independent risk factor for OS in CN-AML (P = 0.004). In the analysis of published data from 225 CN-AML patients, PDCD7 remained independently predicting OS in CN-AML (P = 0.039). As a conclusion, Ang2 and FIS1 seem related to decreased CR rate of AML patients, and PDCD7 is associated with shorter OS and RFS in CN-AML. Hence, PDCD7, Ang2 and FIS1 may indicate a more aggressive form and poor prognosis of AML.

/pdf/identification-of-novel-molecular-markers-for-prognosis-4s4g43dyqa.pdf

Identification of novel molecular markers for prognosis estimation of acute myeloid leukemia: over-expression of PDCD7, FIS1 and Ang2 may indicate poor prognosis in pretreatment patients with acute myeloid leukemia.

Treatment choices for the “severe acute respiratory syndrome‐related coronavirus‐2 (SARS‐CoV‐2)” are inadequate, having no clarity on efficacy and safety profiles. Currently, no established intervention has lowered the mortality rate in the “coronavirus disease 2019 (COVID‐19)” patients. Recently, 2-deoxy-D-glucose (2-DG) has evaluated as a polypharmacological agent for COVID-19 therapy owing to its influence on the glycolytic pathway, interaction with viral proteins, and anti-inflammatory action. In May 2020, the Indian drug regulatory authority approved 2-DG as an emergency adjunct therapy in mild to severe COVID-19 patients. Clinical studies of 2-DG corroborate that it aids in faster recovery of hospitalized patients and decreases supplemental oxygen. Herein, we describe the development process, synthesis, mechanism of viral eradication, and preclinical and clinical development of 2-DG and its derivatives as molecularly targeted therapeutics for COVID-19 treatment.

2-Deoxy-D-Glucose and its Derivatives for the COVID-19 Treatment: An Update

Exosomes are small endosomal derived membrane extracellular vesicles that contain cell-specific cargos such as lipid, protein, DNA, RNA, miRNA, long non-coding RNA, and some other cell components that are released into surrounding body fluids upon the fusion of multivesicular bodies (MVB) and the plasma membrane. Exosomes are a one-of-a-kind cell-to-cell communication mechanism that might pave the way for target therapy. The use of exosomes as a therapeutic potential in a variety of cancers has been and is still being investigated. One of the most important of these has been the use of exosomes in brain tumors therapy. Exosome contents play a crucial role in brain tumor progression by providing a favorable niche for tumor cell proliferation. Also, exosomes that are secreted from tumor cells, lead to the protection of tumor cells and their proliferation in the tumor environment by reducing the inflammatory response and suppression of the immune system. Although some treatment protocols such as surgery, chemotherapy, and radiotherapy are common in brain tumors, they do not result in complete remission in the treatment of some malignant and metastatic brain tumors. Identifying, targeting, and blocking exosomes involved in the progression of brain tumors could be a promising way to reduce brain tumor progression. On the other way, brain tumor therapy with effective therapeutic components such as siRNAs, mRNAs, proteins, could be developed. Finally, our research suggested that exosomes of nanoscale sizes might be a useful tool for crossing the blood-brain barrier and delivering effective content. However, further research is needed to fully comprehend the potential involvement of the exosome in brain tumor therapy protocols.

/pdf/the-potential-role-of-exosomes-in-the-treatment-of-brain-1awwwdcc.pdf

The Potential Role of Exosomes in the Treatment of Brain Tumors, Recent Updates and Advances

Abstract Mantle cell lymphoma (MCL) is a subtype of Non-Hodgkin lymphoma (NHL) of mature B-cells characterized by translocation, which is typically due to excess expression of Cyclin D1. Although with the progress in our knowledge of the causes for MCL and available treatments for MCL, this cancer is still incurable. Age, male gender, rapid advancement, significant nodal involvement, elevated serum lactate dehydrogenase level, and prognostic indications including increased expression of Ki-67 and presence of TP53 mutation, are symbols of poor outcome. Advanced immunotherapy using chimeric antigen receptor (CAR)-T cells is advantageous for patients suffering from B-cell malignancies and MCL. Targeting B-cell antigens on the cell surface is a feasible approach in re-occurring (R/R) MCL because of significant responses obtained in other B-cell cancers. USFDA has approved brexucabtagene autoleucel (Tecartus, KTE-X19), a novel CAR T-cell therapy to be used in patients with MCL who have not responded to previous treatments or have relapsed. The FDA approved this new treatment depending on the outcomes of the ZUMA-2 clinical trial. Serious adverse reactions, moderate anti-tumor activity, allergen withdrawal, antigen escape, limited tumor infiltration, and trafficking are major barriers to successful CAR T-cell therapy. This review is a brief synopsis of the development of CAR T-cell therapy for MCL. 

/pdf/car-t-cell-therapy-for-the-management-of-mantle-cell-1781ogpr.pdf

CAR T-Cell therapy for the management of mantle cell lymphoma

Abstract Malignant brain tumors rank among the most challenging type of malignancies to manage. The current treatment protocol commonly entails surgery followed by radiotherapy and/or chemotherapy, however, the median patient survival rate is poor. Recent developments in immunotherapy for a variety of tumor types spark optimism that immunological strategies may help patients with brain cancer. Chimeric antigen receptor (CAR) T cells exploit the tumor-targeting specificity of antibodies or receptor ligands to direct the cytolytic capacity of T cells. Several molecules have been discovered as potential targets for immunotherapy-based targeting, including but not limited to EGFRvIII, IL13Rα2, and HER2. The outstanding clinical responses to CAR T cell-based treatments in patients with hematological malignancies have generated interest in using this approach to treat solid tumors. Research results to date support the astounding clinical response rates of CD19-targeted CAR T cells, early clinical experiences in brain tumors demonstrating safety and evidence for disease-modifying activity, and the promise for further advances to ultimately assist patients clinically. However, several variable factors seem to slow down the progress rate regarding treating brain cancers utilizing CAR T cells. The current study offers a thorough analysis of CAR T cells’ promise in treating brain cancer, including design and delivery considerations, current strides in clinical and preclinical research, issues encountered, and potential solutions. 

/pdf/car-t-cells-engineered-immune-cells-to-treat-brain-cancers-1r468cuj.pdf

Zoufang Huang

Papers

Identification of novel molecular markers for prognosis estimation of acute myeloid leukemia: over-expression of PDCD7, FIS1 and Ang2 may indicate poor prognosis in pretreatment patients with acute myeloid leukemia.

2-Deoxy-D-Glucose and its Derivatives for the COVID-19 Treatment: An Update

The Potential Role of Exosomes in the Treatment of Brain Tumors, Recent Updates and Advances

CAR T-Cell therapy for the management of mantle cell lymphoma

CAR T cells: engineered immune cells to treat brain cancers and beyond