Chemoprevention of Melanoma: An Unexplored Strategy

2003 ◽  
Vol 21 (1) ◽  
pp. 158-165 ◽  
Author(s):  
Marie-France Demierre ◽  
Larry Nathanson
Keyword(s):  
Molecular Mechanisms ◽  
High Risk Patient ◽  
The United States ◽  
Premalignant Lesions ◽  
Incidence And Mortality ◽  
Protection Strategies ◽  
Synthetic Agents ◽  
Associated Risk Factors

The incidence and mortality of melanoma has continued to increase steeply—faster than most other preventable cancers in the United States. Current sun protection strategies have yet to reduce this increased incidence and mortality. Chemoprevention, defined as the use of natural or synthetic agents to delay, reverse, suppress, or prevent premalignant molecular or histologic lesions from progressing to invasive cancer, has become an important area in cancer research. Melanoma, with its associated risk factors and its known precursors or premalignant lesions, should lend itself well to chemoprevention. Prerequisites for this research should include determination of the molecular mechanisms of ultraviolet (UV) melanomagenesis; use of animal models to test candidate prevention agents; use of molecular and histologic markers as surrogate end point markers; collection of epidemiological, basic science, or in vitro data on potential chemoprevention candidate drugs; and selection of a high-risk patient population in which to carry out clinical chemoprevention trials. Preliminary data available in all these areas are reviewed. Possible mechanisms and molecular targets for the chemoprevention of UV-induced melanoma are discussed. This recent information should stimulate research in the chemoprevention of melanoma.

Abstract 866: Secreted Frizzled Related Protein 2 Modulates Post Myocardial Infarct Remodeling by Inhibiting Collagen Maturation through the Inhibition of Bone Morphogenetic Protein 1 Activity

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Wei He ◽  
Lunan Zhang ◽  
Richard E Pratt ◽  
Victor J Dzau
Keyword(s):  
Myocardial Infarction ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Myocardial Infarct ◽  
Primary Cultures ◽  
The United States ◽  
Coronary Artery Ligation ◽  
Related Protein ◽  
Artery Ligation

Myocardial infarction and post-infarction remodeling with heart failure are the major cause of mortality and morbidity in the United States. We recently reported that intracardiac implantation of genetically engineered mesenchymal stem cell (MSC) overexpressing the Akt gene dramatically reduced the infarct size and restored cardiac functions in rodent hearts after coronary artery ligation. Further, we identified Secreted Frizzled Related Protein 2 (sfrp2) as a key factor released by Akt-MSC mediating myocardial survival and repair. However, the underlying mechanism remains elusive. Bone Morphogenetic Protein1 (BMP1)/Tolloid (TLD)-like metalloproteinases belong to a subgroup of astacin family and play key roles in the regulation of extracelluar matrix (ECM) formation and cardiac fibrosis. These proteases have procollagen C-proteinase (PCP) activities which are responsible for the cleavage of C-propeptides from procollagen precursors to produce mature collagen fibrils. In this report, we showed that three days following myocardial infarction in rats, both BMP1 protein expression and activity were upregulated in the infarcted left ventricle. Interestingly, we found recombinant sfrp2 could inhibit BMP1 activity in MI tissue samples as measured by an in vitro PCP activity assay. Furthermore, using purified recombinant proteins, we demonstrated that sfrp2, but not sfrp1 or sfrp3, inhibited BMP-1 activity in vitro. Moreover, purified sfrp2 could physically interact with BMP1 protein as shown by the co-immunoprecipitation assay. To provide further evidence that sfrp2 can interfere with collagen processing, we demonstrated that exogenously added sfrp2 interfered with procollagen processing in primary cultures of cardiac fibroblast culture medium. Similar results were obtained when these cells were transiently transfected with sfrp2 expressing plasmids. In summary, our data suggest that one of the molecular mechanisms underlying the cardioprotective and repair effects of sfrp2 protein on myocardial infarction is through the inhibition of BMP-1 activity. Therefore, sfrp2 has the potential clinical application as a novel anti-fibrotic reagent for the modulation of cardiac remodeling after acute myocardial infarction.

scholarly journals Influence of Woodsmoke Exposure on Molecular Mechanisms Underlying Alzheimer’s Disease: Existing Literature and Gaps in Our Understanding

2020 ◽  
Vol 13 ◽  
pp. 251686572095487
Author(s):  
Adam Schuller ◽  
Luke Montrose
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Air Pollution ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Ambient Air ◽  
The United States ◽  
Ambient Air Pollution ◽  
Current Status

Woodsmoke poses a significant health risk as a growing component of ambient air pollution in the United States. While there is a long history of association between woodsmoke exposure and diseases of the respiratory, circulatory, and cardiovascular systems, recent evidence has linked woodsmoke exposure to cognitive dysfunction, including Alzheimer’s disease dementia. Alzheimer’s disease is a progressive neurodegenerative disorder with largely idiopathic origins and no known cure. Here, we explore the growing body of literature which relates woodsmoke-generated and ambient air pollution particulate matter exposure to Alzheimer’s disease (AD) onset or exacerbation, in the context of an inflammation-centric view of AD. Epigenetic modifications, specifically changes in DNA methylation patterns, are well documented following woodsmoke exposure and have been shown to influence disease-favoring inflammatory cascades, induce oxidative stress, and modulate the immune response in vitro, in vivo, and in humans following exposure to air pollution. Though the current status of the literature does not allow us to draw definitive conclusions linking these events, this review highlights the need for additional work to fill gaps in our understanding of the directionality, causality, and susceptibility throughout the life course.

scholarly journals Racial and Ethnic Disparities in COVID-19 Outcomes: Social Determination of Health

2020 ◽  
Vol 17 (21) ◽  
pp. 8115 ◽  
Author(s):  
Samuel Raine ◽  
Amy Liu ◽  
Joel Mintz ◽  
Waseem Wahood ◽  
Kyle Huntley ◽  
...  
Keyword(s):  
Black People ◽  
National Level ◽  
Ethnic Disparities ◽  
State Level ◽  
The United States ◽  
Racial And Ethnic Disparities ◽  
Incidence And Mortality ◽  
The Social ◽  
Social Determination Of Health

As of 18 October 2020, over 39.5 million cases of coronavirus disease 2019 (COVID-19) and 1.1 million associated deaths have been reported worldwide. It is crucial to understand the effect of social determination of health on novel COVID-19 outcomes in order to establish health justice. There is an imperative need, for policy makers at all levels, to consider socioeconomic and racial and ethnic disparities in pandemic planning. Cross-sectional analysis from COVID Boston University’s Center for Antiracist Research COVID Racial Data Tracker was performed to evaluate the racial and ethnic distribution of COVID-19 outcomes relative to representation in the United States. Representation quotients (RQs) were calculated to assess for disparity using state-level data from the American Community Survey (ACS). We found that on a national level, Hispanic/Latinx, American Indian/Alaskan Native, Native Hawaiian/Pacific Islanders, and Black people had RQs > 1, indicating that these groups are over-represented in COVID-19 incidence. Dramatic racial and ethnic variances in state-level incidence and mortality RQs were also observed. This study investigates pandemic disparities and examines some factors which inform the social determination of health. These findings are key for developing effective public policy and allocating resources to effectively decrease health disparities. Protective standards, stay-at-home orders, and essential worker guidelines must be tailored to address the social determination of health in order to mitigate health injustices, as identified by COVID-19 incidence and mortality RQs.

scholarly journals Global Dissemination ofblaKPCinto Bacterial Species beyond Klebsiella pneumoniae andIn VitroSusceptibility to Ceftazidime-Avibactam and Aztreonam-Avibactam

2016 ◽  
Vol 60 (8) ◽  
pp. 4490-4500 ◽  
Author(s):  
Krystyna M. Kazmierczak ◽  
Douglas J. Biedenbach ◽  
Meredith Hackel ◽  
Sharon Rabine ◽  
Boudewijn L. M. de Jonge ◽  
...  
Keyword(s):  
United States ◽  
Klebsiella Pneumoniae ◽  
Molecular Mechanisms ◽  
Bacterial Species ◽  
The United States ◽  
Asia Pacific ◽  
Gram Negative ◽  
Content Type ◽  
Global Problem

ABSTRACTTheKlebsiella pneumoniaecarbapenemase (KPC), first described in the United States in 1996, is now a widespread global problem in several Gram-negative species. A worldwide surveillance study collected Gram-negative pathogens from 202 global sites in 40 countries during 2012 to 2014 and determined susceptibility to β-lactams and other class agents by broth microdilution testing. Molecular mechanisms of β-lactam resistance among carbapenem-nonsusceptibleEnterobacteriaceaeandPseudomonas aeruginosawere determined using PCR and sequencing. Genes encoding KPC enzymes were found in 586 isolates from 22 countries (76 medical centers), including countries in the Asia-Pacific region (32 isolates), Europe (264 isolates), Latin America (210 isolates), and the Middle East (19 isolates, Israel only) and the United States (61 isolates). The majority of isolates wereK. pneumoniae(83.4%); however, KPC was detected in 13 additional species. KPC-2 (69.6%) was more common than KPC-3 (29.5%), with regional variation observed. A novel KPC variant, KPC-18 (KPC-3[V8I]), was identified during the study. Few antimicrobial agents tested remained effectivein vitroagainst KPC-producing isolates, with ceftazidime-avibactam (MIC90, 4 μg/ml), aztreonam-avibactam (MIC90, 0.5 μg/ml), and tigecycline (MIC90, 2 μg/ml) retaining the greatest activity againstEnterobacteriaceaecocarrying KPC and other β-lactamases, whereas colistin (MIC90, 2 μg/ml) demonstrated the greatestin vitroactivity against KPC-positiveP. aeruginosa. This analysis of surveillance data demonstrated that KPC is widely disseminated. KPC was found in multiple species ofEnterobacteriaceaeandP. aeruginosaand has now become a global problem.

scholarly journals Nephrotoxicity Biomarkers: Role and Significance in the Diagnosis of Drug-Induced Kidney Injury

2021 ◽  
Vol 9 (4) ◽  
pp. 173-184
Author(s):  
O. V. Muslimova ◽  
V. A. Evteev ◽  
I. A. Mazerkina ◽  
E. A. Sokova ◽  
A. B. Prokofiev ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Experimental Models ◽  
Injury Incidence ◽  
Drug Induced ◽  
Blood Concentrations ◽  
Incidence And Mortality ◽  
Hospital Patients

Drug-induced kidney injury (DIKI) accounts for 8 to 60% of episodes of acute kidney injury (AKI) among hospital patients. Early DIKI detection and timely adjustment of therapy will help reduce the kidney injury incidence and mortality. The aim of the study was to analyse scientific literature on the biomarkers used in DIKI diagnosis. The study revealed that the use of such kidney damage markers as serum creatinine, urinary output, urea nitrogen, sodium excretion, urinary sediment microscopy is limited because they do not give a full picture of the kidney injury degree and progression and do not allow for early AKI diagnosis. It was demonstrated that some of the most promising biomarkers are KIM-1, L-FABP, NAG, NGAL, cystatin C, clusterin, β2-microglobulin, МСР-1, IGFBP7, and TIMP-2. However, recommendations for determination of these biomarkers’ urine or blood concentrations for AKI diagnosis are somewhat preliminary, because there have been insufficient clinical and preclinical studies to establish validity of such tests. No precise algorithms based on determination of the biomarkers levels in urea and/or blood serum have been developed for AKI risk assessment, diagnosis, monitoring, and treatment. Thus, further research is necessary to investigate different AKI biomarkers and improve experimental models (both in vivo and in vitro), which will support assessment of potential nephrotoxic properties of existing and new medicinal products.

scholarly journals Candida Isolates From Blood and Other Normally Sterile Foci From ICU Patients: Determination of Epidemiology, Antifungal Susceptibility Profile and Evaluation of Associated Risk Factors

2021 ◽  
Vol 9 ◽  
Author(s):  
Bo Wang ◽  
Xinlong He ◽  
Feng Lu ◽  
Yajuan Li ◽  
Yuerong Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Molecular Mechanisms ◽  
Antifungal Susceptibility ◽  
Resistance Mechanism ◽  
Lavage Fluid ◽  
Icu Patients ◽  
Multiple Risk Factors ◽  
Microdilution Method ◽  
Associated Risk Factors

Background: The clinical diagnosis and therapy for ICU patients with invasive candidiasis are challenged by the changes of Candida community composition and antimicrobial resistance. The epidemiology and drug sensitivity of candidiasis in ICU as well as its risk factors and drug resistance mechanism were investigated.Methods: In the present study, 115 patients in ICU were recruited from June 2019 through July 2020. Among them, 83 Candida isolates were identified with MALDI-TOF mass spectrometry. The susceptibility to antifungals was measured by microdilution method. The molecular mechanisms of azole-resistant Candida tropicalis were explored by sequencing, and their outcomes were explicitly documented.Results:Candida glabrata and C. tropicalis were the predominant non-C. albicans Candida. The specimen sources were mainly urine, bronchoalveolar lavage fluid and blood. The age, length of hospitalization, tracheotomy, diabetes and concomitant bacterial infection were the main risk factors for candidiasis. The majority of Candida species exhibited susceptibility to antifungals. However, certain C. tropicalis were frequently resistant to azoles. The polymorphism of the ERG11 in C. tropicalis was likely associated with azole resistance.Conclusion: The multiple risk factors for candidiasis in ICU patients need to be considered. Certain C. tropicalis exhibit resistance to azoles likely due to the ERG11 gene polymorphism.

scholarly journals Unconventional Yeasts Are Tolerant to Common Antifungals, and Aureobasidium pullulans Has Low Baseline Sensitivity to Captan, Cyprodinil, and Difenoconazole

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 602
Author(s):  
Electine Magoye ◽  
Maja Hilber-Bodmer ◽  
Melanie Pfister ◽  
Florian M. Freimoser
Keyword(s):  
Environmental Samples ◽  
Aureobasidium Pullulans ◽  
Molecular Mechanisms ◽  
Plant Protection ◽  
Its Region ◽  
Pathogenic Fungi ◽  
Baseline Sensitivity ◽  
Naturally Occurring ◽  
Protection Strategies

Many yeasts have demonstrated intrinsic insensitivity to certain antifungal agents. Unlike the fungicide resistance of medically relevant yeasts, which is highly undesirable, intrinsic insensitivity to fungicides in antagonistic yeasts intended for use as biocontrol agents may be of great value. Understanding how frequently tolerance exists in naturally occurring yeasts and their underlying molecular mechanisms is important for exploring the potential of biocontrol yeasts and fungicide combinations for plant protection. Here, yeasts were isolated from various environmental samples in the presence of different fungicides (or without fungicide as a control) and identified by sequencing the internal transcribed spacer (ITS) region or through matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Among 376 isolates, 47 taxa were identified, and Aureobasidium pullulans was the most frequently isolated yeast. The baseline sensitivity of this yeast was established for 30 isolates from different environmental samples in vitro to captan, cyprodinil, and difenoconazole. For these isolates, the baseline minimum inhibitory concentration (MIC50) values for all the fungicides were higher than the concentrations used for the control of plant pathogenic fungi. For some isolates, there was no growth inhibition at concentrations as high as 300 µg/mL for captan and 128 µg/mL for cyprodinil. This information provides insight into the presence of resistance among naturally occurring yeasts and allows the choice of strains for further mechanistic analyses and the assessment of A. pullulans for novel applications in combination with chemical agents and as part of integrated plant-protection strategies.

scholarly journals Stem cell factor affects fate determination of human gonocytes in vitro

Reproduction ◽  
2007 ◽  
Vol 134 (6) ◽  
pp. 757-765 ◽  
Author(s):  
Jiongjiong Tu ◽  
Liqing Fan ◽  
Ke Tao ◽  
Wenbing Zhu ◽  
Jianjun Li ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Factor ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Tyrosine Kinase Receptor ◽  
Dependent Manner ◽  
Fate Determination

The stem cell factor (SCF), binding its tyrosine kinase receptor c-Kit, has been shown to play essential roles in the proliferation, differentiation, and survival of germline cells. However, few reports are available about the effect of SCF on the development of human gonocytes within the fetal testis. The objective of this study was to investigate whether SCF affects the biological behaviors of human gonocytes before or after they enter the mitotic arrest stage. Employing an organ culture system, we observed that addition of exogenous SCF could influence the morphology of human gonocytesin vitro. Moreover, SCF was able to trigger the colony formation of round gonocytes, which were characterized positive for alkaline phosphatase activity, Oct-4, SSEA-4, and c-Kit as well. We found that SCF exerted actions in a dose- and age-dependent manner, although the stimulatory effect lasted no more than 14 days. We also showed that SCF played a role in suppressing the apoptosis of human gonocytes. Blocking of SCF signaling with either phosphatidylinositol 3-kinase or mitogen-activated protein kinase inhibitor resulted in similar apoptotic features as well as the SCF-withdrawal cultures. Taken together, we report that SCF acts as a potent regulator in the fate determination of human gonocytes. Our studies should form the basis forin vitrostudies and facilitate investigation of the molecular mechanisms underlying this unique stage.

scholarly journals The Effects of Resveratrol on Prostate Cancer through Targeting the Tumor Microenvironment

2021 ◽  
Vol 11 (1) ◽  
pp. 16-32
Author(s):  
Natalie Silk ◽  
Jeremy Reich ◽  
Rahul Sinha ◽  
Shivansh Chawla ◽  
Kyla Geary ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Cancer Prevention ◽  
Molecular Mechanisms ◽  
The United States ◽  
In Vivo Experiments ◽  
Cancer Initiation ◽  
Proliferation And Metastasis

Prostate cancer is one of the most common cancers diagnosed in men in the United States and the second leading cause of cancer-related deaths worldwide. Since over 60% of prostate cancer cases occur in men over 65 years of age, and this population will increase steadily in the coming years, prostate cancer will be a major cancer-related burden in the foreseeable future. Accumulating data from more recent research suggest that the tumor microenvironment (TME) plays a previously unrecognized role in every stage of cancer development, including initiation, proliferation, and metastasis. Prostate cancer is not only diagnosed in the late stages of life, but also progresses relatively slowly. This makes prostate cancer an ideal model system for exploring the potential of natural products as cancer prevention and/or treatment reagents because they usually act relatively slowly compared to most synthetic drugs. Resveratrol (RSV) is a naturally occurring stilbenoid and possesses strong anti-cancer properties with few adverse effects. Accumulating data from both in vitro and in vivo experiments indicate that RSV can interfere with prostate cancer initiation and progression by targeting the TME. Therefore, this review is aimed to summarize the recent advancement in RSV-inhibited prostate cancer initiation, proliferation, and metastasis as well as the underlying molecular mechanisms, with particular emphasis on the effect of RSV on TME. This will not only better our understanding of prostate cancer TMEs, but also pave the way for the development of RSV as a potential reagent for prostate cancer prevention and/or therapy.

scholarly journals Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jiucui Li ◽  
Kongmiao Lu ◽  
Fenglan Sun ◽  
Shanjuan Tan ◽  
Xiao Zhang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Molecular Mechanisms ◽  
Pulmonary Inflammation ◽  
Epithelial Cell Line ◽  
High Morbidity ◽  
Regulated Necrosis ◽  
The Impact

Abstract Background Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) induces uncontrolled and self-amplified pulmonary inflammation, and has high morbidity and mortality rates in critically ill patients. In recent years, many bioactive ingredients extracted from herbs have been reported to effectively ameliorate ALI/ARDS via different mechanisms. Ferroptosis, categorized as regulated necrosis, is more immunogenic than apoptosis and contributes to the progression of ALI. In this study, we examined the impact of panaxydol (PX), isolated from the roots of Panax ginseng, on lipopolysaccharide (LPS)-induced ALI in mice. Methods In vivo, the role of PX on LPS-induced ALI in mice was tested by determination of LPS-induced pulmonary inflammation, pulmonary edema and ferroptosis. In vitro, BEAS-2B cells were used to investigate the molecular mechanisms by which PX functions via determination of inflammation, ferroptosis and their relationship. Results Administration of PX protected mice against LPS-induced ALI, including significantly ameliorated lung pathological changes, and decreased the extent of lung edema, inflammation, and ferroptosis. In vitro, PX inhibited LPS-induced ferroptosis and inflammation in bronchial epithelial cell line BEAS-2B cells. The relationship between ferroptosis and inflammation was investigated. The results showed that ferroptosis mediated inflammation in LPS-treated BEAS-2B cells, and PX might ameliorate LPS-induced inflammation via inhibiting ferroptosis. Meanwhile, PX could upregulate Keap1-Nrf2/HO-1 pathway, and selective inhibition of Keap1-Nrf2/HO-1 pathway significantly abolished the anti-ferroptotic and anti-inflammatory functions of PX in LPS-treated cells. Conclusion PX attenuates ferroptosis against LPS-induced ALI via Keap1-Nrf2/HO-1 pathway, and is a promising novel therapeutic candidate for ALI.

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