Nanomedicine Targeting Cuproplasia in Cancer: Labile Copper Sequestration Using Polydopamine Particles Blocks Tumor Growth through Altering Metabolism and Redox Homeostasis.

Copper plays critical roles as a metal active site cofactor and metalloallosteric signal for enzymes involved in cell proliferation and metabolism, making it an attractive target for cancer therapy. In this study, we investigated the efficacy of polydopamine nanoparticles (PDA NPs), classically applied for metal removal from water, as a therapeutic strategy for depleting intracellular labile copper pools in triple-negative breast cancer models through the metal-chelating groups present on the PDA surface. By using the activity-based sensing probe FCP-1, we could track the PDA-induced labile copper depletion while leaving total copper levels unchanged and link it to the selective MDA-MB-231 cell death.

The E1a Adenoviral Gene Upregulates the Yamanaka Factors to Induce Partial Cellular Reprogramming.

The induction of pluripotency by enforced expression of different sets of genes in somatic cells has been achieved with reprogramming technologies first described by Yamanaka's group. Methodologies for generating induced pluripotent stem cells are as varied as the combinations of genes used. It has previously been reported that the adenoviral E1a gene can induce the expression of two of the Yamanaka factors (c-Myc and Oct-4) and epigenetic changes.

Coating an adenovirus with functionalized gold nanoparticles favors uptake, intracellular trafficking and anti-cancer therapeutic efficacy.

Adenoviral (Ad) vectors have proven to be important tools for gene and cell therapy, although some issues still need to be addressed, such as undesired interactions with blood components and off-target sequestration that ultimately hamper efficacy. In the past years, several organic and inorganic materials have been developed to reduce immunogenicity and improve biodistribution of Ad vectors. Here we investigated the influence of the functionalization of 14 nm PEGylated gold nanoparticles (AuNPs) with quaternary ammonium groups and an arginine-glycine-aspartic acid (RGD)-motif on the uptake and biodistribution of Ad vectors.

Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive nutrient signaling to mTORC1 by means of genetic activation of RagA (expression of GTP-locked RagA, or RagA) in mice resulted in a fatal energetic crisis at birth. Herein, we rescue neonatal lethality in RagA mice and find morphometric and metabolic alterations that span glucose, lipid, ketone, bile acid and amino acid homeostasis in adults, and a median lifespan of nine months.

Oncogenic Rag GTPase signaling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR.

The humoral immune response demands that B cells undergo a sudden anabolic shift and high cellular nutrient levels which are required to sustain the subsequent proliferative burst. Follicular lymphoma (FL) originates from B cells that have participated in the humoral response, and 15% of FL samples harbor point, activating mutations in , an essential activator of mTORC1 downstream of the sensing of cellular nutrients. The impact of recurrent mutations in B cell function and lymphoma is unexplored.

Plk1 overexpression induces chromosomal instability and suppresses tumor development.

Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression results in abnormal chromosome segregation and cytokinesis, generating polyploid cells with reduced proliferative potential.

Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies.

Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown. We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts.

Safety study of intravitreal and suprachoroidal Laponite clay in rabbit eyes.

Purpose: To study the safety and biocompatibility of Laponite clay (LAP) within an intravitreal and suprachoroidal administration in rabbit eyes.

Methods: Thirty-two New Zealand albino rabbits were divided into two experimental groups to test intravitreal (IVT group) and suprachoroidal (SCS group) administration of a 100-μl and 50-μl Laponite suspension respectively. Following injection, the eyes were monitored by ocular tonometry, slit-lamp eye examination and indirect ophthalmoscopy, at 24 h, 1, 4, 12, and 14 weeks post administration.

Senescence promotes in vivo reprogramming through p16 and IL-6.

Cellular senescence is a damage response aimed to orchestrate tissue repair. We have recently reported that cellular senescence, through the paracrine release of interleukin-6 (IL6) and other soluble factors, strongly favors cellular reprogramming by Oct4, Sox2, Klf4, and c-Myc (OSKM) in nonsenescent cells. Indeed, activation of OSKM in mouse tissues triggers senescence in some cells and reprogramming in other cells, both processes occurring concomitantly and in close proximity.

In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias.

Mammalian DNA replication origins are "licensed" by the loading of DNA helicases, a reaction that is mediated by CDC6 and CDT1 proteins. After initiation of DNA synthesis, CDC6 and CDT1 are inhibited to prevent origin reactivation and DNA overreplication before cell division. CDC6 and CDT1 are highly expressed in many types of cancer cells, but the impact of their deregulated expression had not been investigated in vivo.

Tissue damage and senescence provide critical signals for cellular reprogramming in vivo.

Reprogramming of differentiated cells into pluripotent cells can occur in vivo, but the mechanisms involved remain to be elucidated. Senescence is a cellular response to damage, characterized by abundant production of cytokines and other secreted factors that, together with the recruitment of inflammatory cells, result in tissue remodeling. Here, we show that in vivo expression of the reprogramming factors OCT4, SOX2, KLF4, and cMYC (OSKM) in mice leads to senescence and reprogramming, both coexisting in close proximity.

Acetylsalicylic Acid Exhibits Antitumor Effects in Esophageal Adenocarcinoma Cells In Vitro and In Vivo.

Background And Aim: Recent observational studies have shown therapeutic benefits of acetylsalicylic acid (ASA) in several types of cancer. We examined whether ASA exerts antitumor activity in esophageal adenocarcinoma (EAC).

Methods: Human EAC cells (OE33) were treated with ASA (0-5 mM) to evaluate proliferation, apoptosis, and migration.

K-Ras(V14I) -induced Noonan syndrome predisposes to tumour development in mice.

The Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. A significant proportion of NS patients may also develop myeloproliferative disorders (MPDs), including juvenile myelomonocytic leukaemia (JMML). Surprisingly, scarce information is available in relation to other tumour types in these patients.

Aurora B Overexpression Causes Aneuploidy and p21Cip1 Repression during Tumor Development.

Aurora kinase B, one of the three members of the mammalian Aurora kinase family, is the catalytic component of the chromosomal passenger complex, an essential regulator of chromosome segregation in mitosis. Aurora B is overexpressed in human tumors although whether this kinase may function as an oncogene in vivo is not established. Here, we report a new mouse model in which expression of the endogenous Aurkb locus can be induced in vitro and in vivo.

Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction.

Coronary heart disease is one of the main causes of death in the developed world, and treatment success remains modest, with high mortality rates within 1 year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases, including heart disease.

Jagunal homolog 1 is a critical regulator of neutrophil function in fungal host defense.

Neutrophils are key innate immune effector cells that are essential to fighting bacterial and fungal pathogens. Here we report that mice carrying a hematopoietic lineage-specific deletion of Jagn1 (encoding Jagunal homolog 1) cannot mount an efficient neutrophil-dependent immune response to the human fungal pathogen Candida albicans. Global glycobiome analysis identified marked alterations in the glycosylation of proteins involved in cell adhesion and cytotoxicity in Jagn1-deficient neutrophils.

Angiogenesis and proliferation markers in adjacent cirrhotic tissue could predict hepatocellular carcinoma outcome after liver transplantation.

Introduction: The current staging systems for hepatocellular carcinoma (HCC) do not sufficiently predict outcomes after liver transplantation (LT). The present study assessed whether some tissue markers related to proliferation and angiogenesis have prognostic value.

Patients And Methods: The expression of CD34, vascular endothelial growth factor (VEGF), VEGFR2, VEGFR1, angiopoietin-1, angiopoietin-2, TIE2, COX-2, and proliferating cell nuclear antigen (PCNA) in tumor and adjacent cirrhotic tissue samples from 36 patients with HCC (n=10 with tumor recurrence after LT) was determined by immunochemistry.

Single-walled carbon nanotubes (SWCNTs) enhance KCl-, acetylcholine-, and serotonin-induced contractions and evoke oxidative stress on rabbit ileum.

We examined the effects of intravenous administration of purified arc-discharge single-walled carbon nanotubes (SWCNTs) on rabbit ileum to establish the possibility of using these SWCNTs as cell markers or drug carriers for the treatment of intestinal diseases. The SWCNT purification process eliminated carbonaceous impurities and decreased the amount of metals. SWCNTs increased the contractile responses induced by KCl, acetylcholine (ACh), and serotonin (5-HT) in rabbit ileum.

MMP-10 is required for efficient muscle regeneration in mouse models of injury and muscular dystrophy.

Matrix metalloproteinases (MMPs), a family of endopeptidases that are involved in the degradation of extracellular matrix components, have been implicated in skeletal muscle regeneration. Among the MMPs, MMP-2 and MMP-9 are upregulated in Duchenne muscular dystrophy (DMD), a fatal X-linked muscle disorder. However, inhibition or overexpression of specific MMPs in a mouse model of DMD (mdx) has yielded mixed results regarding disease progression, depending on the MMP studied.

Attenuated Mycobacterium tuberculosis SO2 vaccine candidate is unable to induce cell death.

It has been proposed that Mycobacterium tuberculosis virulent strains inhibit apoptosis and trigger cell death by necrosis of host macrophages to evade innate immunity, while non-virulent strains induce typical apoptosis activating a protective host response. As part of the characterization of a novel tuberculosis vaccine candidate, the M. tuberculosis phoP mutant SO2, we sought to evaluate its potential to induce host cell death.

Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites.

Hyperhomocysteinemia has been reported in human reproduction as a risk factor for early pregnancy loss, preeclampsia, and congenital birth defects like spina bifida. Female infertility was also observed in cystathionine beta synthase-deficient mice (Cbs-KO) as an animal model for severe hyperhomocysteinemia. The aim for the present research was to elucidate the time-point of pregnancy loss and to pinpoint gene and cellular changes involved in the underlying pathological mechanism.

Course of infection with the emergent pathogen Brucella microti in immunocompromised mice.

A new Brucella species, Brucella microti, has been isolated from wild rodents and found to be pathogenic in mice. The biological relevance of this new mouse pathogen is clear, as it allows us to study Brucella infection in a species-specific model. The course of infection in wild-type (wt) and immunodeficient mice that lack B (Jh), T and B (SCID), or T, B, and NK (SCID.

Biocompatibility, inflammatory response, and recannalization characteristics of nonradioactive resin microspheres: histological findings.

Intra-arterial radiotherapy with yttrium-90 microspheres (radioembolization) is a therapeutic procedure exclusively applied to the liver that allows the direct delivery of high-dose radiation to liver tumors, by means of endovascular catheters, selectively placed within the tumor vasculature. The aim of the study was to describe the distribution of spheres within the precapillaries, inflammatory response, and recannalization characteristics after embolization with nonradioactive resin microspheres in the kidney and liver. We performed a partial embolization of the liver and kidney vessels in nine white pigs.

Comparative study of four different spherical embolic particles in an animal model: a morphologic and histologic evaluation.

Purpose: To perform a study in a porcine model comparing four different spherical embolic particles in terms of postembolization patency, deformation, and potential for recanalization, with a focus on a relatively new agent--HepaSphere.

Materials And Methods: Partial embolization of both kidneys was performed in 18 pigs. Nine animals were sacrificed at 48 hours and nine at 4 weeks.