The carcinogenic capacity of arsenic in normal epithelial breast cells and double-positive breast cancer cells.

Background and aims: The carcinogenic effect of arsenic is a subject of controversy in relation to breast cancer. In our current research, we aimed to simulate the effects of chronic low-level arsenic exposure on breast cells by intoxicating MCF-10A and MCF-7 cells with 1 µM Arsenic trioxide (As2O3) for 3 weeks (3w) and 6 weeks (6w), respectively. Methods: We assessed the cellular responses to As2O3 through various assays, including confocal fluorescence microscopy, flow cytometry for cell cycle analysis, Transwell invasion assay, scratch assay, and colony assay. Additionally, we analyzed the mutation burden in all the exposed cells by using the next generation sequencing technology. Results: Our findings indicate that As2O3 has a minor carcinogenic effect in normal cells, with no definitive evidence of malignant transformation observed after 6 weeks of exposure. In the case of breast cancer cells, As2O3 exhibits a dual effect, both inhibitory and stimulatory. It leads to reduced colony formation ability at 6 weeks, while enhancing the cells' ability for invasion. The mutations triggered by As2O3 exposure are distributed across genes with both tumor-suppressive and oncogenic functions. Five mutations are common to both cell lines, involving the following genes: Kinase Insert Domain Receptor (KDR) (c.798+54G>A), Colony Stimulating Factor 1 Receptor (CSF1R) (c.*37AC>C, c.*35C>TC), SWI/SNF-Related Matrix-Associated Actin-Dependent Regulator of Chromatin Subfamily B Member 1 (SMARCB1) (c.1119-41C>T), and Fms-like Tyrosine Kinase 3 (FLT3) (c.1310-3T>C). Additionally, Human Epidermal Growth Factor Receptor 4 (ERBB4/HER4) (c.421+58A>G) and Human Epidermal Growth Factor Receptor 2 (HER2/ERBB2) (c.2307+46A>G) mutations were exclusively found in MCF-10A cells exposed to As2O3. Furthermore, MCF-7 cells exhibited unique mutations in the KIT Proto-Oncogene (KIT) (c.1594G>A) and TP53 (c.215C>G). Conclusion: In summary, our study reveals that a 6-weeks exposure to arsenic has a limited carcinogenic effect in normal breast cells and a dual role in breast cancer cells.

Differential effect of the duration of exposure on the carcinogenicity of cadmium in MCF10A mammary epithelial cells.

The carcinogenic role of cadmium (Cd2+) in breast cancer is still debatable. Current data points to duration of exposure as the most important element. In our study, we designed an in vitro model to investigate the effects of 3 weeks versus 6 weeks of low-level CdCl2 exposure on MCF10A cells. Our results demonstrated that after 3 weeks of CdCl2 exposure the cells displayed significant changes in the DNA integrity, but there was no development of malignant features. Interestingly, after 6 weeks of exposure, the cells significantly increased their invasion, migration and colony formation capacities. Additionally, MCF10A cells exposed for 6 weeks to CdCl2 had many dysregulated genes (4905 up-regulated and 4262 down-regulated). As follows, Cd-induced phenotypical changes are accompanied by a profound modification of the transcriptomic landscape. Furthermore, the molecular alterations driving carcinogenesis in MCF10A cells exposed to CdCl2 were found to be influenced by the duration of exposure, as in the case of MEG8. This long non-coding RNA was down-regulated at 3 weeks, but up-regulated at 6 weeks of exposure. In conclusion, even very low levels of Cd (0.5 µM) can have significant carcinogenic effects on breast cells in the case of subchronic exposure.

The Role of Epigenetic Modifier Mutations in Peripheral T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a group of diseases with a low incidence, high degree of heterogeneity, and a dismal prognosis in most cases. Because of the low incidence of these diseases, there have been few therapeutic novelties developed over time. Nevertheless, this fact is changing presently as epigenetic modifiers have been shown to be recurrently mutated in some types of PTCLs, especially in the cases of PTCLs not otherwise specified (PTCL-NOS), T follicular helper (TFH), and angioimmunoblastic T-cell lymphoma (AITL). These have brought about more insight into PTCL biology, especially in the case of PTCLs arising from TFH lymphocytes. From a biological perspective, it has been observed that ten-eleven translocators (TET2) mutated T lymphocytes tend to polarize to TFH, while Tregs lose their inhibitory properties. IDH2 R172 was shown to have inhibitory effects on TET2, mimicking the effects of TET2 mutations, as well as having effects on histone methylation. DNA methyltransferase 3A (DNMT3A) loss-of-function, although it was shown to have opposite effects to TET2 from an inflammatory perspective, was also shown to increase the number of T lymphocyte progenitors. Aside from bringing about more knowledge of PTCL biology, these mutations were shown to increase the sensitivity of PTCLs to certain epigenetic therapies, like hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDACis). Thus, to answer the question from the title of this review: We found the Achilles heel, but only for one of the Achilles.

Design and preclinical testing of an anti-CD41 CAR T cell for the treatment of acute megakaryoblastic leukaemia.

Acute megakaryoblastic leukaemia (AMkL) is a rare subtype of acute myeloid leukaemia (AML) representing 5% of all reported cases, and frequently diagnosed in children with Down syndrome. Patients diagnosed with AMkL have low overall survival and have poor outcome to treatment, thus novel therapies such as CAR T cell therapy could represent an alternative in treating AMkL. We investigated the effect of a new CAR T cell which targets CD41, a specific surface antigen for M7-AMkL, against an in vitro model for AMkL, DAMI Luc2 cell line. The performed flow cytometry evaluation highlighted a percentage of 93.8% CAR T cells eGFP-positive and a limited acute effect on lowering the target cell population. However, the interaction between effector and target (E:T) cells, at a low ratio, lowered the cell membrane integrity, and reduced the M7-AMkL cell population after 24 h of co-culture, while the cytotoxic effect was not significant in groups with higher E:T ratio. Our findings suggest that the anti-CD41 CAR T cells are efficient for a limited time spawn and the cytotoxic effect is visible in all experimental groups with low E:T ratio.

Hybrid Material Based on Vaccinium myrtillus L. Extract and Gold Nanoparticles Reduces Oxidative Stress and Inflammation in Hepatic Stellate Cells Exposed to TGF-ß.

(1) Background: The study aimed to investigate the impact of gold nanoparticles capped with Cornus sanguinea (NPCS) and mixed with a fruit extract (Vaccinum myrtillus L.-VL) on human hepatic stellate cells (LX-2) exposed to TGF-ß. (2) Methods: NPCS were characterized by UV-Vis, transmission electron microscopy (TEM), zeta potential measurement, X-ray diffraction (XRD) and energy dispersive spectroscopy (EDX). The cytotoxic effects of VL, NPCS and of the hybrid compounds obtained by mixing the two components in variable proportions (NPCS-VL) were assessed. LDH activity, MDA levels, secretion of inflammation markers, the expression of fibrogenesis markers and collagen I synthesis were estimated after treating the cells with a mixture of 25:25 µg/mL NPCS and VL. (3) Results: TEM analysis showed that NPCS had spherical morphology and homogenous distribution, while their formation and elemental composition were confirmed by XRD and EDX analysis. TGF-ß increased cell membrane damage as well as secretion of IL-1ß, IL-1α and TLR4. It also amplified the expression of α-SMA and type III collagen and induced collagen I deposition. NPCS administration reduced the inflammation caused by TGF-ß and downregulated α-SMA expression. VL diminished LDH activity and the secretion of proinflammatory cytokines. The NPCS-VL mixture maintained IL-1ß, IL-1α, TLR4 and LDH at low levels after TGF-ß exposure, but it enhanced collagen III expression. (4) Conclusions: The mixture of NPCS and VL improved cell membrane damage and inflammation triggered by TGF-ß and mitigated collagen I deposition, but it increased the expression of collagen III, suggestive of a fibrogenetic effect of the hybrid material.

Optimization of Tyrosine Kinase Inhibitor-Loaded Gold Nanoparticles for Stimuli-Triggered Antileukemic Drug Release.

Tyrosine kinase inhibitor (TKI) therapy is gaining attraction in advanced cancer therapeutics due to the ubiquity of kinases in cell survival and differentiation. Great progress was made in the past years in identifying tyrosine kinases that can function as valuable molecular targets and for the entrapment of their corresponding inhibitors in delivery compounds for triggered release. Herein we present a class of drug-delivery nanocompounds based on TKI Midostaurin-loaded gold nanoparticles that have the potential to be used as theranostic agents for the targeting of the FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia. We optimized the nanocompounds' formulation with loading efficiency in the 84-94% range and studied the drug release behavior in the presence of stimuli-responsive polymers. The therapeutic activity of MDS-loaded particles, superior to that of the free drug, was confirmed with toxicities depending on specific dosage ranges. No effect was observed on FLT3-negative cells or for the unloaded particles. Beyond druggability, we can track this type of nanocarrier inside biological structures as demonstrated via dark field microscopy. These properties might contribute to the facilitation of personalized drug dosage administration, critical for attaining a maximal therapeutic effect.

RNA sequencing suggests that non-coding RNAs play a role in the development of acquired haemophilia.

Acquired haemophilia (AH) is a rare disorder characterized by bleeding in patients with no personal or family history of coagulation/clotting-related diseases. This disease occurs when the immune system, by mistake, generates autoantibodies that target FVIII, causing bleeding. Small RNAs from plasma collected from AH patients (n = 2), mild classical haemophilia (n = 3), severe classical haemophilia (n = 3) and healthy donors (n = 2), for sequencing by Illumina, NextSeq500. Based on bioinformatic analysis, AH patients were compared to all experimental groups and a significant number of altered transcripts were identified with one transcript being modified compared to all groups at fold change level. The Venn diagram shows that haemoglobin subunit alpha 1 was highlighted to be the common upregulated transcript in AH compared to classical haemophilia and healthy patients. Non-coding RNAs might play a role in AH pathogenesis; however, due to the rarity of HA, the current study needs to be translated on a larger number of AH samples and classical haemophilia samples to generate more solid data that can confirm our findings.

Flow Cytometry of CD5-Positive Hairy Cell Leukemia.

BACKGROUND AND OBJECTIVE: Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder for which diagnosis is typically straightforward, based on bone marrow morphology and flow cytometry (FC) or immunohistochemistry. Nevertheless, variants present atypical expressions of cell surface markers, as is the case of CD5, for which the differential diagnosis can be more difficult. The aim of the current paper was to describe diagnosis of HCL with atypical CD5 expression, with an emphasis on FC. METHODS: The detailed diagnostic methodology for HCL with atypical CD5 expression is presented, including differential diagnosis from other lymphoproliferative diseases with similar pathologic features, by FC analysis of the bone marrow aspirate. RESULTS: Diagnosis of HCL by means of FC started by gating all events based on side scatter (SSC) versus CD45 and B lymphocytes were selected from the lymphocytes gate as CD45/CD19 positive. The gated cells were positive for CD25, CD11c, CD20, and CD103, while CD10 proved to be dim to negative. Moreover, cells positive for CD3, CD4, and CD8, the three pan-T markers, as well as CD19, showed a bright expression of CD5. The atypical CD5 expression is usually correlated with a negative prognosis and thus chemotherapy with cladribine should be initiated. CONCLUSION: HCL is an indolent chronic lymphoproliferative disorder and diagnosis is usually straightforward. However, atypical expression of CD5 renders its differential diagnosis more difficult, but FC is a useful tool that allows an optimal classification of the disease and allows initiation of timely satisfactory therapy.

The Effect of Different Anesthetic Techniques on Proliferation, Apoptosis, and Gene Expression in Colon Cancer Cells: A Pilot In Vitro Study.

BACKGROUND: Colorectal cancer is highly common and causes high mortality rates. Treatment for colorectal cancer is multidisciplinary, but in most cases the main option remains surgery. Intriguingly, in recent years, a number of studies have shown that a patient's postoperative outcome may be influenced by certain anesthetic drugs. Our main objective was to compare the effect of propofol-total intravenous anesthesia (TIVA) with sevoflurane anesthesia and to investigate the potential role of intravenous lidocaine on colon cancer cell functions. We tested the effects of serum from colorectal cancer patients undergoing TIVA vs. sevoflurane anesthesia with or without lidocaine on HCT 116 cell lines; on proliferation, apoptosis, migration, and cell cycles; and on cancer-related gene expressions. METHODS: 60 patients who were scheduled for colorectal cancer surgery were randomized into four different groups (two groups with TIVA and two groups with sevoflurane anesthesia with or without intravenous lidocaine). Blood samples were collected at the start and at the end of surgery. HCT 116 cells were exposed to the patients' serum. RESULTS: 15 patients were included in each of the study groups. We did not find any significant difference on cell viability or apoptosis between the study groups. However, there was an increased apoptosis in propofol groups, but this result was not statistically significant. A significant increase in the expression profile of the TP53 gene in the propofol group was registered (p = 0.029), while in the other study groups, no significant differences were reported. BCL2 and CASP3 expressions increased in the sevoflurane-lidocaine group without statistical significance. CONCLUSIONS: In our study, serum from patients receiving different anesthetic techniques did not significantly influence the apoptosis, migration, and cell cycle of HCT-116 colorectal carcinoma cells. Viability was also not significantly influenced by the anesthetic technique, except the sevoflurane-lidocaine group where it was increased. The gene expression of TP53 was significantly increased in the propofol group, which is consistent with the results of similar in vitro studies and may be one of the mechanisms by which anesthetic agents may influence the biology of cancer cells. Further studies that investigate the effects of propofol and lidocaine in different plasma concentrations on different colon cancer cell lines and assess the impacts of these findings on the clinical outcome are much needed.

Low-Molecular-Weight Heparins (LMWH) and Synthetic Factor X Inhibitors Can Impair the Osseointegration Process of a Titanium Implant in an Interventional Animal Study.

Background and objectives: Cementless total hip arthroplasty is a common surgical procedure and perioperative thromboprophylaxis is used to prevent deep vein thrombosis or pulmonary embolism. Osseointegration is important for long-term implant survival, and there is no research on the effect of different thromboprophylaxis agents on the process of osseointegration. Materials and Methods: Seventy rats were allocated as follows: Group I (control group), Group II (enoxaparin), Group III (nadroparin), and Group IV (fondaparinux). Ovariectomy was performed on all subjects, followed by the introduction of an intramedullary titanium implant into the femur. Thromboprophylaxis was administered accordingly to each treatment group for 35 days postoperatively. Results: Group I had statistically significantly lower anti-Xa levels compared to treatment groups. Micro-CT analysis showed that nadroparin had lower values compared to control in bone volume (0.12 vs. 0.21, p = 0.01) and percent bone volume (1.46 vs. 1.93, p = 0.047). The pull-out test showed statistically significant differences between the control group (8.81 N) compared to enoxaparin, nadroparin, and fondaparinux groups (4.53 N, 4 N and 4.07 N, respectively). Nadroparin had a lower histological cortical bone tissue and a higher width of fibrous tissue (27.49 µm and 86.9 µm) at the peri-implant area, compared to control (43.2 µm and 39.2 µm), enoxaparin (39.6 µm and 24 µm), and fondaparinux (36.2 µm and 32.7 µm). Conclusions: Short-term administration of enoxaparin, nadroparin, and fondaparinux can reduce the osseointegration of titanium implants, with nadroparin having the most negative effect. These results show that enoxaparin and fondaparinux are preferred to be administered due to a lesser negative impact on the initial implant fixation.

Hybrid Lipid Nanoformulations for Hepatoma Therapy: Sorafenib Loaded Nanoliposomes-A Preliminary Study.

Sorafenib is a multikinase inhibitor that has received increasing attention due to its high efficacy in hepatocellular carcinoma treatment. However, its poor pharmacokinetic properties (limited water solubility, rapid elimination, and metabolism) still represent major bottlenecks that need to be overcome in order to improve Sorafenib's clinical application. In this paper, we propose a nanotechnology-based hybrid formulation that has the potential to overcome these challenges: sorafenib-loaded nanoliposomes. Sorafenib molecules have been incorporated into the hydrophobic lipidic bilayer during the synthesis process of nanoliposomes using an original procedure developed in our laboratory and, to the best of our knowledge, this is the first paper reporting this type of analysis. The liposomal hybrid formulations have been characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), and nanoparticle tracking analysis (NTA) that provided useful information concerning their shape, size, zeta-potential, and concentration. The therapeutic efficacy of the nanohybrids has been evaluated on a normal cell line (LX2) and two hepatocarcinoma cell lines, SK-HEP-1 and HepG2, respectively.

Phytochemicals as Regulators of Tumor Glycolysis and Hypoxia Signaling Pathways: Evidence from In Vitro Studies.

The full understanding of the complex nature of cancer still faces many challenges, as cancers arise not as a result of a single target disruption but rather involving successive genetic and epigenetic alterations leading to multiple altered metabolic pathways. In this light, the need for a multitargeted, safe and effective therapy becomes essential. Substantial experimental evidence upholds the potential of plant-derived compounds to interfere in several important pathways, such as tumor glycolysis and the upstream regulating mechanisms of hypoxia. Herein, we present a comprehensive overview of the natural compounds which demonstrated, in vitro studies, an effective anticancer activity by affecting key regulators of the glycolytic pathway such as glucose transporters, hexokinases, phosphofructokinase, pyruvate kinase or lactate dehydrogenase. Moreover, we assessed how phytochemicals could interfere in HIF-1 synthesis, stabilization, accumulation, and transactivation, emphasizing PI3K/Akt/mTOR and MAPK/ERK pathways as important signaling cascades in HIF-1 activation. Special consideration was given to cell culture-based metabolomics as one of the most sensitive, accurate, and comprising approaches for understanding the response of cancer cell metabolome to phytochemicals.

Targeting Cell Death Mechanism Specifically in Triple Negative Breast Cancer Cell Lines.

Triple negative breast cancer (TNBC) is currently associated with a lack of treatment options. Arsenic derivatives have shown antitumoral activity both in vitro and in vivo; however, their mode of action is not completely understood. In this work we evaluate the response to arsenate of the double positive MCF-7 breast cancer cell line as well as of two different TNBC cell lines, Hs578T and MDA-MB-231. Multimodal experiments were conducted to this end, using functional assays and microarrays. Arsenate was found to induce cytoskeletal alteration, autophagy and apoptosis in TNBC cells, and moderate effects in MCF-7 cells. Gene expression analysis showed that the TNBC cell lines' response to arsenate was more prominent in the G2M checkpoint, autophagy and apoptosis compared to the Human Mammary Epithelial Cells (HMEC) and MCF-7 cell lines. We confirmed the downregulation of anti-apoptotic genes (MCL1, BCL2, TGFß1 and CCND1) by qRT-PCR, and on the protein level, for TGFß2, by ELISA. Insight into the mode of action of arsenate in TNBC cell lines it is provided, and we concluded that TNBC and non-TNBC cell lines reacted differently to arsenate treatment in this particular experimental setup. We suggest the future research of arsenate as a treatment strategy against TNBC.

Relation Between Plasma Proteomics Analysis and Major Adverse Cardiovascular Events in Patients With Stable Coronary Artery Disease.

OBJECTIVE: Despite the advances in the control of traditional risk factors, coronary artery disease (CAD) remains the greatest cause of morbidity and mortality. Our aim was to establish the relation between plasma proteomics analysis and the risk of cardiovascular events in patients with stable CAD. MATERIALS AND METHODS: Patients with stable CAD and documented coronary atherosclerosis were screened for inclusion. Using proximity extension assays, 177 plasma proteins were simultaneously measured. The endpoint consisted of the first major adverse cardiovascular event (MACE) and was the composite of cardiovascular death, acute coronary syndrome, stroke, transient ischemic attack, or acute limb ischemia at 18 months follow-up. Cox proportional-hazards regression with adjustment for multiple comparisons was used to identify biomarkers for the outcomes of interest. RESULTS: The cohort consisted of 229 patients. Six mediators were associated with MACE (p < 0.001). For these markers, the risk of MACE was calculated: tumor necrosis factor receptor superfamily member 13B (HR = 1.65; 95% CI: 1.30-2.10), C-C motif chemokine-3 (HR = 1.57; 95% CI: 1.23-1.98), decorin (HR = 1.65; 95% CI: 1.26-2.16), fibroblast growth factor-23 (HR = 1.56; 95% CI: 1.23-1.99), tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) (HR = 1.61; 95% CI: 1.23-2.11), and tumor necrosis factor receptor superfamily member 10A (HR = 1.69; 95% CI: 1.25-2.29). Except for TRAIL-R2, the other proteins were associated with MACE independent of age, sex, diabetes mellitus, or estimated glomerular filtration rate. CONCLUSIONS: In patients with stable CAD, five novel biomarkers were identified as independent risk factors for adverse outcomes. Novel biomarkers could represent pharmacological targets for the prevention of adverse cardiovascular events.

Natural compounds modulate the crosstalk between apoptosis- and autophagy-regulated signaling pathways: Controlling the uncontrolled expansion of tumor cells.

Due to the high number of annual cancer-related deaths, and the economic burden that this malignancy affects today's society, the study of compounds isolated from natural sources should be encouraged. Most cancers are the result of a combined effect of lifestyle, environmental factors, and genetic and hereditary components. Recent literature reveals an increase in the interest for the study of phytochemicals from traditional medicine, this being a valuable resource for modern medicine to identify novel bioactive agents with potential medicinal applications. Phytochemicals are components of traditional medicine that are showing promising application in modern medicine due to their antitumor activities. Recent studies regarding two major mechanisms underlying cancer development and regulation, apoptosis and autophagy, have shown that the signaling pathways of both these processes are significantly interconnected through various mechanisms of crosstalk. Phytochemicals are able to activate pro-autophagic and pro-apoptosis mechanisms. Understanding the molecular mechanism involved in apoptosis-autophagy relationship modulated by phytochemicals plays a key role in development of a new therapeutic strategy for cancer treatment. The purpose of this review is to outline the bioactive properties of the natural phytochemicals with validated antitumor activity, focusing particularly on their role in the regulation of apoptosis and autophagy crosstalk that triggers the uncontrolled expansion of tumor cells. Furthermore, we have also critically discussed the limitations and challenges of existing research strategies and the prospective research directions in this field.

Quantifying Cytosolic Cytochrome c Concentration Using Carbon Quantum Dots as a Powerful Method for Apoptosis Detection.

BACKGROUND: Cytochrome c (Cyt c) is a key biomarker for early apoptosis, and many methods were designed to detect its release from mitochondria. For a proper evaluation of these programed cell death mechanisms, fluorescent nanoparticles are excellent candidates due to their valuable optical properties. Among all classes of nanoparticles developed thus far, carbon-based quantum dots bring qualitative and efficient imaging strategies for biomedical applications as a consequence of their biocompatibility and low cytotoxicity. METHODS: In this study, we synthesized carbon quantum dots smaller than 5 nm from sodium citrate and polyethylene imine. These nanoparticles were rigorously characterized, and their quenching capacity in apoptotic events was assessed in A549 cells treated with staurosporine and etoposide. For the evaluation of Cyt c release, a phenomenon directly correlated with apoptotic events, we ran a semiquantitative analysis using confocal laser scanning microscopy. RESULTS: Carbon quantum dots were synthesized and were successfully employed for Cyt c detection by means of fluorescence microscopy. Significant drops in fluorescence intensity were observed in the case of cells treated with apoptosis-inducing therapeutic compounds compared to untreated cells, confirming Cyt c release from mitochondria to cytosol. CONCLUSION: Considering these results, we strongly believe this method can contribute to an indirect in vitro evaluation of apoptosis.

B Cells versus T Cells in the Tumor Microenvironment of Malignant Lymphomas. Are the Lymphocytes Playing the Roles of Muhammad Ali versus George Foreman in Zaire 1974?

Malignant lymphomas are a heterogeneous group of malignancies that develop both in nodal and extranodal sites. The different tissues involved and the highly variable clinicopathological characteristics are linked to the association between the lymphoid neoplastic cells and the tissues they infiltrate. The immune system has developed mechanisms to protect the normal tissue from malignant growth. In this review, we aim to explain how T lymphocyte-driven control is linked to tumor development and describe the tumor-suppressive components of the resistant framework. This manuscript brings forward a new insight with regard to intercellular and intracellular signaling, the immune microenvironment, the impact of therapy, and its predictive implications. A better understanding of the key components of the lymphoma environment is important to properly assess the role of both B and T lymphocytes, as well as their interplay, just as two legendary boxers face each other in a heavyweight title final, as was the case of Ali versus Foreman.

Transforming growth factor ß-mediated micromechanics modulates disease progression in primary myelofibrosis.

Primary myelofibrosis (PMF) is a Ph-negative myeloproliferative neoplasm (MPN), characterized by advanced bone marrow fibrosis and extramedullary haematopoiesis. The bone marrow fibrosis results from excessive proliferation of fibroblasts that are influenced by several cytokines in the microenvironment, of which transforming growth factor-ß (TGF-ß) is the most important. Micromechanics related to the niche has not yet been elucidated. In this study, we hypothesized that mechanical stress modulates TGF-ß signalling leading to further activation and subsequent proliferation and invasion of bone marrow fibroblasts, thus showing the important role of micromechanics in the development and progression of PMF, both in the bone marrow and in extramedullary sites. Using three PMF-derived fibroblast cell lines and transforming growth factor-ß receptor (TGFBR) 1 and 2 knock-down PMF-derived fibroblasts, we showed that mechanical stress does stimulate the collagen synthesis by the fibroblasts in patients with myelofibrosis, through the TGFBR1, which however seems to be activated through alternative pathways, other than TGFBR2.

An Emerging Class of Long Non-coding RNA With Oncogenic Role Arises From the snoRNA Host Genes.

The small nucleolar RNA host genes (SNHGs) are a group of long non-coding RNAs, which are reported in many studies as being overexpressed in various cancers. With very few exceptions, the SNHGs (SNHG1, SNHG3, SNHG5, SNHG6, SNHG7, SNHG12, SNHG15, SNHG16, SNHG20) are recognized as inducing increased proliferation, cell cycle progression, invasion, and metastasis of cancer cells, which makes this class of transcripts a viable biomarker for cancer development and aggressiveness. Through our literature research, we also found that silencing of SNHGs through small interfering RNAs or short hairpin RNAs is very effective in both in vitro and in vivo experiments by lowering the aggressiveness of solid cancers. The knockdown of SNHG as a new cancer therapeutic option should be investigated more in the future.

Nanoscale delivery systems for microRNAs in cancer therapy.

Concomitant with advances in research regarding the role of miRNAs in sustaining carcinogenesis, major concerns about their delivery options for anticancer therapies have been raised. The answer to this problem may come from the world of nanoparticles such as liposomes, exosomes, polymers, dendrimers, mesoporous silica nanoparticles, quantum dots and metal-based nanoparticles which have been proved as versatile and valuable vehicles for many biomolecules including miRNAs. In another train of thoughts, the general scheme of miRNA modulation consists in inhibition of oncomiRNA expression and restoration of tumor suppressor ones. The codelivery of two miRNAs or miRNAs in combination with chemotherapeutics or small molecules was also proposed. The present review presents the latest advancements in miRNA delivery based on nanoparticle-related strategies.