The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas.

Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation.

The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control.

Thioredoxin-interacting protein (TXNIP) is commonly considered a master regulator of cellular oxidation, regulating the expression and function of Thioredoxin (Trx). Recent work has identified that TXNIP has a far wider range of additional roles: from regulating glucose and lipid metabolism, to cell cycle arrest and inflammation. Its expression is increased by stressors commonly found in neoplastic cells and the wider tumor microenvironment (TME), and, as such, TXNIP has been extensively studied in cancers.

Exosomal transfer leads to chemoresistance through oxidative phosphorylation-mediated stemness phenotype in colorectal cancer.

Recently years have seen the increasing evidence identifying that OXPHOS is involved in different processes of tumor progression and metastasis and has been proposed to be a potential therapeutical target for cancer treatment. However, the exploration in oxidative phosphorylation-mediated chemoresistance is still scarce. In our study, we identify exosomal transfer leads to chemoresistance by reprogramming metabolic phenotype in recipient cells.

Serum-derived extracellular vesicles from breast cancer patients contribute to differential regulation of T-cell-mediated immune-escape mechanisms in breast cancer subtypes.

Background: Intracellular communication within the tumour is complex and extracellular vesicles (EVs) have been identified as major contributing factors for the cell-to-cell communication in the local and distant tumour environments. Here, we examine the differential effects of breast cancer (BC) subtype-specific patient serum and cell-line derived EVs in the regulation of T cell mediated immune responses.

Methods: Ultracentrifugation was used to isolate EVs from sera of 63 BC patients, 15 healthy volunteers and 4 human breast cancer cell lines.

Predicting progression-free survival after systemic therapy in advanced head and neck cancer: Bayesian regression and model development.

Background: Advanced head and neck squamous cell carcinoma (HNSCC) is associated with a poor prognosis, and biomarkers that predict response to treatment are highly desirable. The primary aim was to predict progression-free survival (PFS) with a multivariate risk prediction model.

Methods: Experimental covariates were derived from blood samples of 56 HNSCC patients which were prospectively obtained within a Phase 2 clinical trial (NCT02633800) at baseline and after the first treatment cycle of combined platinum-based chemotherapy with cetuximab treatment.

Exosomal transfer of miR-181b-5p confers senescence-mediated doxorubicin resistance via modulating BCLAF1 in breast cancer.

Background: Doxorubicin resistance represents a major clinical challenge for treating patients with advanced breast cancer (BC). Exosomes, exchanging genetic cargo between heterogeneous populations of tumour cells, have been proposed to mediate drug resistance and cancer progression in other cancer types. However, their specific role in mediating doxorubicin resistance in BC remains unclear.

Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury through a sirtuin-3 mediated increase in fatty acid oxidation.

Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury (IRI) but the mechanisms are unknown. Here, we investigate the role of the mitochondrial NAD-dependent deacetylase, Sirtuin-3 (SIRT3), which has been shown to influence fatty acid oxidation and cardiac outcomes, as a potential mediator of this effect. Fasting was shown to shift metabolism from glucose towards fatty acid oxidation.

Genome editing in animals with minimal PAM CRISPR-Cas9 enzymes.

The requirement for Cas nucleases to recognize a specific PAM is a major restriction for genome editing. SpCas9 variants SpG and SpRY, recognizing NGN and NRN PAMs, respectively, have contributed to increase the number of editable genomic sites in cell cultures and plants. However, their use has not been demonstrated in animals.

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs.

Evaluation of a Novel Zonular Tension Restoring Accommodating Silicone IOL Design: Pilocarpine and Cyclopentolate-Induced Effect 20 Months after Implantation.

Purpose: To investigate a novel zonular-stress restoring accommodating 1-piece silicone IOL. . Angeles City, Philippines.

A Living Organism in your CRISPR Toolbox: Is a Rapid and Efficient Model for Developing CRISPR-Cas Technologies.

The Cas9 nuclease from (SpCas9) is the most popular enzyme for CRISPR technologies. However, considering the wide diversity of microorganisms (discovered and still unknown), a massive number of CRISPR effectors are being and will be identified and characterized in the search of optimal Cas variants for each of the many applications of CRISPR. In this context, a versatile and efficient multicellular system for CRISPR editing such as would be of great help in the development of these effectors.

Efficient Generation of Endogenous Fluorescent Reporters by Nested CRISPR in .

CRISPR-based genome-editing methods in model organisms are evolving at an extraordinary speed. Whereas the generation of deletion or missense mutants is quite straightforward, the production of endogenous fluorescent reporters is more challenging. We have developed Nested CRISPR, a cloning-free ribonucleoprotein-driven method that robustly produces endogenous fluorescent reporters with EGFP, mCherry or wrmScarlet in This method is based on the division of the fluorescent protein (FP) sequence in three fragments.

Endothelial cells release cardioprotective exosomes that may contribute to ischaemic preconditioning.

Extracellular vesicles (EVs) such as exosomes are nano-sized vesicles that carry proteins and miRNAs and can transmit signals between cells. We hypothesized that exosomes from endothelial cells can transmit protective signals to cardiomyocytes. Co-culture of primary adult rat cardiomyocytes with normoxic HUVEC cells separated by a cell-impermeable membrane reduced the percentage of cardiomyocyte death following simulated ischaemia and reperfusion (sIR) from 80 ± 11% to 51 ± 4% (P < 0.

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers.

Background: Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer with approximately half a million cases diagnosed each year worldwide. HNSCC has a poor survival rate which has not improved for over 30 years. The molecular pathogenesis of HNSCCs remains largely unresolved; there is high prevalence of p53 mutations and EGFR overexpression; however, the contribution of these molecular changes to disease development and/or progression remains unknown.

ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation.

The immunosuppressive transmembrane protein PD-L1 was shown to traffic via the multivesicular body (MVB) and to be released on exosomes. A high-content siRNA screen identified the endosomal sorting complexes required for transport (ESCRT)-associated protein ALIX as a regulator of both EGFR activity and PD-L1 surface presentation in basal-like breast cancer (BLBC) cells. ALIX depletion results in prolonged and enhanced stimulation-induced EGFR activity as well as defective PD-L1 trafficking through the MVB, reduced exosomal secretion, and its redistribution to the cell surface.

Cardioprotection mediated by exosomes is impaired in the setting of type II diabetes but can be rescued by the use of non-diabetic exosomes in vitro.

Many patients with ischaemic heart disease also have diabetes. As myocardial infarction is a major cause of mortality and morbidity in these patients, treatments that increase cell survival in response to ischaemia and reperfusion are needed. Exosomes-nano-sized, lipid vesicles released from cells-can protect the hearts of non-diabetic rats.

Therapeutic targeting of autophagy in myocardial infarction and heart failure.

Introduction: Myocardial infarction (MI) is the leading cause of death. When MI is not lethal, heart failure (HF) is a major consequence with high prevalence and poor prognosis. The targeting of autophagy represents a potentially therapeutic approach for the treatment of both pathologies.

Two complementary strategies to improve cell engraftment in mesenchymal stem cell-based therapy: Increasing transplanted cell resistance and increasing tissue receptivity.

Over the past 2 decades, therapies based on mesenchymal stem cells (MSC) have been tested to treat several types of diseases in clinical studies, due to their potential for tissue repair and regeneration. Currently, MSC-based therapy is considered a biologically safe procedure, with the therapeutic results being very promising. However, the benefits of these therapies are not stable in the long term, and the final outcomes manifest with high inter-patient variability.

Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction.

Mitochondria alter their shape by undergoing cycles of fusion and fission. Changes in mitochondrial morphology impact on the cellular response to stress, and their interactions with other organelles such as the sarcoplasmic reticulum (SR). Inhibiting mitochondrial fission can protect the heart against acute ischemia/reperfusion (I/R) injury.

Microvesicles and exosomes: new players in metabolic and cardiovascular disease.

The past decade has witnessed an exponential increase in the number of publications referring to extracellular vesicles (EVs). For many years considered to be extracellular debris, EVs are now seen as novel mediators of endocrine signalling via cell-to-cell communication. With the capability of transferring proteins and nucleic acids from one cell to another, they have become an attractive focus of research for different pathological settings and are now regarded as both mediators and biomarkers of disease including cardio-metabolic disease.

Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism.

The alpha2-adrenergic receptor agonist Dexmedetomidine (Dex) is a sedative medication used by anesthesiologists. Dex protects the heart against ischemia-reperfusion (IR) and can also act as a preconditioning mimetic. The mechanisms involved in Dex-dependent cardiac preconditioning, and whether this action occurs directly or indirectly on cardiomyocytes, still remain unclear.

Plasma exosomes protect the myocardium from ischemia-reperfusion injury.

Background: Exosomes are nanometer-sized vesicles released from cells into the blood, where they can transmit signals throughout the body. Shown to act on the heart, exosomes' composition and the signaling pathways they activate have not been explored. We hypothesized that endogenous plasma exosomes can communicate signals to the heart and provide protection against ischemia and reperfusion injury.