MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors

DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exosomes in obesity, airway epithelium-derived exosomes generated by smoking and pollution, diet-related exosomes and inflammation-induced exosomes, which may synergistically increase the exosomal miR-21 burden of the melanocyte, the transformed MM cell and its tumor environment. Several therapeutic agents that suppress MM cell growth and proliferation attenuate miR-21 expression. These include miR-21 antagonists, metformin, kinase inhibitors, beta-blockers, vitamin D, and plant-derived bioactive compounds, which may represent new options for the prevention and treatment of MM.

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The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-021-84117-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hiroaki Kanzaki ◽

Tetsuhiro Chiba ◽

Junjie Ao ◽

Keisuke Koroki ◽

Kengo Kanayama ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Progression Free Survival ◽

Erk Signaling ◽

Enzyme Linked Immunosorbent Assay ◽

Antitumor Effects ◽

The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

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The malaria burden of Amerindian groups of three Venezuelan states: a descriptive study based on programmatic data

Malaria Journal ◽

10.1186/s12936-021-03819-7 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Juan C. Gabaldón-Figueira ◽

Carlos Chaccour ◽

Jorge Moreno ◽

Maria Villegas ◽

Leopoldo Villegas

Keyword(s):

Risk Factors ◽

Plasmodium Falciparum ◽

Malaria Incidence ◽

Hot Spot ◽

Public Health Problem ◽

Epidemiological Data ◽

Descriptive Study ◽

Malaria Burden ◽

Indigenous Groups ◽

The Impact

Abstract Background Fifty-three percent of all cases of malaria in the Americas in 2019 came from Venezuela, where the epidemic is heavily focused south of the Orinoco river, and where most of the country’s Amerindian groups live. Although the disease is known to represent a significant public health problem among these populations, little epidemiological data exists on the subject. This study aims to provide information on malaria incidence, geospatial clustering, and risk factors associated to Plasmodium falciparum infection among these groups. Methods This is a descriptive study based on the analysis of published and unpublished programmatic data collected by Venezuelan health authorities and non-government organizations between 2014 and 2018. The Annual Parasite Index among indigenous groups (API-i) in municipalities of three states (Amazonas, Bolivar, and Sucre) were calculated and compared using the Kruskal Wallis test, risk factors for Plasmodium falciparum infection were identified via binomial logistic regression and maps were constructed to identify clusters of malaria cases among indigenous patients via Moran’s I and Getis-Ord’s hot spot analysis. Results 116,097 cases of malaria in Amerindian groups were registered during the study period. An increasing trend was observed between 2014 and 2016 but reverted in 2018. Malaria incidence remains higher than in 2014 and hot spots were identified in the three states, although more importantly in the south of Bolivar. Most cases (73.3%) were caused by Plasmodium vivax, but the Hoti, Yanomami, and Eñepa indigenous groups presented higher odds for infection with Plasmodium falciparum. Conclusion Malaria cases among Amerindian populations increased between 2014 and 2018 and seem to have a different geographic distribution than those among the general population. These findings suggest that tailored interventions will be necessary to curb the impact of malaria transmission in these groups.

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Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13133375 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3375

Author(s):

Annabelle Vogt ◽

Farsaneh Sadeghlar ◽

Tiyasha H. Ayub ◽

Carlo Schneider ◽

Christian Möhring ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Dendritic Cells ◽

Tumor Regression ◽

Combined Therapy ◽

Term Survival ◽

Effector Cells ◽

Tumor Environment ◽

The Impact

Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-fetoprotein (AFP) for immunotherapy of hepatocellular carcinoma (HCC). However, a strong immunosuppressive tumor environment limits their efficacy in patients. The co-stimulation with CD40Ligand (CD40L) is critical in the maturation of DC and T-cell priming. In this study, the impact of intratumoral (i.t.) CD40L-expressing DC to improve vaccination with murine (m)AFP-transduced DC (Ad-mAFP-DC) was analyzed in subcutaneous (s.c.) and orthotopic murine HCC. Murine DC were adenovirally transduced with Ad-mAFP or Ad-CD40L. Hepa129-mAFP-cells were injected into the right flank or the liver of C3H-mice to induce subcutaneous (s.c.) and orthotopic HCC. For treatments, 106 Ad-mAFP-transduced DC were inoculated s.c. followed by 106 CD40L-expressing DC injected intratumorally (i.t.). S.c. inoculation with Ad-mAFP-transduced DC, as vaccine, induced a delay of tumor-growth of AFP-positive HCC compared to controls. When s.c.-inoculation of Ad-mAFP-DC was combined with i.t.-application of Ad-CD40L-DC synergistic antitumoral effects were observed and complete remissions and long-term survival in 62% of tumor-bearing animals were achieved. Analysis of the tumor environment at different time points revealed that s.c.-vaccination with Ad-mAFP-DC seems to stimulate tumor-specific effector cells, allowing an earlier recruitment of effector T-cells and a Th1 shift within the tumors. After i.t. co-stimulation with Ad-CD40L-DC, production of Th1-cytokines was strongly increased and accompanied by a robust tumor infiltration of mature DC, activated CD4+-, CD8+-T-cells as well as reduction of regulatory T-cells. Moreover, Ad-CD40L-DC induced tumor cell apoptosis. Intratumoral co-stimulation with CD40L-expressing DC significantly improves vaccination with Ad-mAFP-DC in pre-established HCC in vivo. Combined therapy caused an early and strong Th1-shift in the tumor environment as well as higher tumor apoptosis, leading to synergistic tumor regression of HCC. Thus, CD40L co-stimulation represents a promising tool for improving DC-based immunotherapy of HCC.

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Impact of Extreme Weather on Healthcare Utilization by People with HIV in Metropolitan Miami

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18052442 ◽

2021 ◽

Vol 18 (5) ◽

pp. 2442

Author(s):

Daniel Samano ◽

Shubhayu Saha ◽

Taylor Corbin Kot ◽

JoNell E. Potter ◽

Lunthita M. Duthely

Keyword(s):

Relative Risk ◽

The United States ◽

Extreme Weather ◽

South Florida ◽

Heat Index ◽

Extreme Weather Events ◽

Weather Data ◽

Steady Increase ◽

Daily Weather Data ◽

The Impact

Extreme weather events (EWE) are expected to increase as climate change intensifies, leaving coastal regions exposed to higher risks. South Florida has the highest HIV infection rate in the United States, and disruptions in clinic utilization due to extreme weather conditions could affect adherence to treatment and increase community transmission. The objective of this study was to identify the association between EWE and HIV-clinic attendance rates at a large academic medical system serving the Miami-Dade communities. The following methods were utilized: (1) Extreme heat index (EHI) and extreme precipitation (EP) were identified using daily observations from 1990–2019 that were collected at the Miami International Airport weather station located 3.6 miles from the studied HIV clinics. Data on hurricanes, coastal storms and flooding were collected from the National Oceanic and Atmospheric Administration Storms Database (NOAA) for Miami-Dade County. (2) An all-HIV clinic registry identified scheduled daily visits during the study period (hurricane seasons from 2017–2019). (3) Daily weather data were linked to the all-HIV clinic registry, where patients’ ‘no-show’ status was the variable of interest. (4) A time-stratified, case crossover model was used to estimate the relative risk of no-show on days with a high heat index, precipitation, and/or an extreme natural event. A total of 26,444 scheduled visits were analyzed during the 383-day study period. A steady increase in the relative risk of ‘no-show’ was observed in successive categories, with a 14% increase observed on days when the heat index was extreme compared to days with a relatively low EHI, 13% on days with EP compared to days with no EP, and 10% higher on days with a reported extreme weather event compared to days without such incident. This study represents a novel approach to improving local understanding of the impacts of EWE on the HIV-population’s utilization of healthcare, particularly when the frequency and intensity of EWE is expected to increase and disproportionately affect vulnerable populations. More studies are needed to understand the impact of EWE on routine outpatient settings.

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DNA Methylation and Intra-Clonal Heterogeneity: The Chronic Myeloid Leukemia Model

Cancers ◽

10.3390/cancers13143587 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3587

Author(s):

Benjamin Lebecque ◽

Céline Bourgne ◽

Véronique Vidal ◽

Marc G. Berger

Keyword(s):

Dna Methylation ◽

Chronic Myeloid Leukemia ◽

Fusion Protein ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Single Gene ◽

Clonal Heterogeneity ◽

Sequencing Technologies ◽

Genome Wide ◽

The Impact

Chronic Myeloid Leukemia (CML) is a model to investigate the impact of tumor intra-clonal heterogeneity in personalized medicine. Indeed, tyrosine kinase inhibitors (TKIs) target the BCR-ABL fusion protein, which is considered the major CML driver. TKI use has highlighted the existence of intra-clonal heterogeneity, as indicated by the persistence of a minority subclone for several years despite the presence of the target fusion protein in all cells. Epigenetic modifications could partly explain this heterogeneity. This review summarizes the results of DNA methylation studies in CML. Next-generation sequencing technologies allowed for moving from single-gene to genome-wide analyses showing that methylation abnormalities are much more widespread in CML cells. These data showed that global hypomethylation is associated with hypermethylation of specific sites already at diagnosis in the early phase of CML. The BCR-ABL-independence of some methylation profile alterations and the recent demonstration of the initial intra-clonal DNA methylation heterogeneity suggests that some DNA methylation alterations may be biomarkers of TKI sensitivity/resistance and of disease progression risk. These results also open perspectives for understanding the epigenetic/genetic background of CML predisposition and for developing new therapeutic strategies.

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Photocrosslinking and photopatterning of magneto-optical nanocomposite sol–gel thin film under deep-UV irradiation

Scientific Reports ◽

10.1038/s41598-021-84376-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

C. Bidaud ◽

D. Berling ◽

D. Jamon ◽

E. Gamet ◽

S. Neveu ◽

...

Keyword(s):

Uv Irradiation ◽

Cobalt Ferrite ◽

Sol Gel ◽

Optical Devices ◽

High Concentration ◽

Nanocomposite Thin Films ◽

Deep Uv ◽

High Concentrations ◽

193 Nm ◽

The Impact

AbstractThis paper is aimed at investigating the process of photocrosslinking under Deep-UV irradiation of nanocomposite thin films doped with cobalt ferrite magnetic nanoparticles (MNPs). This material is composed of a hybrid sol–gel matrix in which MNP can be introduced with high concentrations up to 20 vol%. Deep-UV (193 nm) is not only interesting for high-resolution patterning but we also show an efficient photopolymerization pathway even in the presence of high concentration of MNPs. In this study, we demonstrate that the photocrosslinking is based on the free radical polymerization of the methacrylate functions of the hybrid precursor. This process is initiated by Titanium-oxo clusters. The impact of the nanoparticles on the photopolymerization kinetic and photopatterning is investigated. We finally show that the photosensitive nanocomposite is suitable to obtain micropatterns with sub-micron resolution, with a simple and versatile process, which opens many opportunities for fabrication of miniaturized magneto-optical devices for photonic applications.

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Inadequate management of natural ecosystem in the Brazilian Amazon region results in the emergence and reemergence of arboviruses

Cadernos de Saúde Pública ◽

10.1590/s0102-311x2001000700025 ◽

2001 ◽

Vol 17 (suppl) ◽

pp. S155-S164 ◽

Cited By ~ 81

Author(s):

Pedro F. C. Vasconcelos ◽

Amélia P. A. Travassos da Rosa ◽

Sueli G. Rodrigues ◽

Elizabeth S. Travassos da Rosa ◽

Nicolas Dégallier ◽

...

Keyword(s):

Environmental Changes ◽

Epidemiological Data ◽

Brazilian Amazon ◽

Host Population ◽

Amazon Region ◽

Laboratory Animals ◽

Natural Ecosystem ◽

Brazilian Amazon Region ◽

Mining Dam ◽

The Impact

A total of 187 different species of arboviruses and other viruses in vertebrates were identified at the Evandro Chagas Institute (IEC) from 1954 to 1998, among more than 10,000 arbovirus strains isolated from humans, hematophagous insects, and wild and sentinel vertebrates. Despite intensive studies in the Brazilian Amazon region, especially in Pará State, very little is known about most of these viruses, except for information on date, time, source, and method of isolation, as well as their capacity to infect laboratory animals. This paper reviews ecological and epidemiological data and analyzes the impact of vector and host population changes on various viruses as a result of profound changes in the natural environment. Deforestation, mining, dam and highway construction, human colonization, and urbanization were the main manmade environmental changes associated with the emergence and/or reemergence of relevant arboviruses, including some known pathogens for humans.

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Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

Gastroenterology Research and Practice ◽

10.1155/2016/9189483 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

R.-D. Hofheinz ◽

U. Ronellenfitsch ◽

S. Kubicka ◽

A. Falcone ◽

I. Burkholder ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Progression Free Survival ◽

Optimal Sequence ◽

Primary Endpoints ◽

Disease Stabilization ◽

Antiangiogenic Drugs ◽

The Impact

Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis.Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression.Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58).Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

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When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

International Journal of Cell Biology ◽

10.1155/2011/470597 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 16

Author(s):

Katrin Schlie ◽

Jaeline E. Spowart ◽

Luke R. K. Hughson ◽

Katelin N. Townsend ◽

Julian J. Lum

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Patient Treatment ◽

Low Oxygen ◽

Tumor Environment ◽

And Function ◽

The Impact

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system.

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