The Role of Tobacco-Derived Carcinogens in Pancreas Cancer

The extremely poor outcome from pancreas cancer is well known. However, its aetiology less well appreciated, and the molecular mechanisms underlying this are poorly understood. Tobacco usage is one of the strongest risk factors for this disease, and this is a completely avoidable hazard. In addition, there are well described hereditary diseases which predispose, and familial pancreas cancer. We have sought here to summarise the role of tobacco-derived carcinogens and the mode of their tumorigenic action on the pancreas. There is compelling evidence from animal and human studies (laboratory including cell line studies and epidemiologic) that tobacco derived carcinogens cause pancreas cancer. However, the manner in which they do so is not entirely apparent. There is also compelling evidence that synergism with genetic and other life-style factors—like diet obesity—results in a multifactorial causation of the disease. Ascertaining the role of tobacco carcinogens in the development of this cancer and their interaction with other risk factors will enable novel therapeutic and preventative strategies to improve outcome from this appalling malignancy.

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Cancer epidemiology and public health

10.1093/med/9780198816805.003.0060 ◽

2021 ◽

pp. 17-42

Author(s):

Paolo Boffetta ◽

Zuo-Feng Zhang ◽

Carlo La Vecchia

Keyword(s):

Public Health ◽

Risk Factors ◽

Molecular Mechanisms ◽

Cancer Epidemiology ◽

Attributable Risk ◽

World Population ◽

The World ◽

Near Future ◽

Epidemiology And Public Health

Neoplasms continue to dominate globally as one of the major sources of human disease and death. There are multiple modifiable causes of cancer and understanding their attributable risk factors for each cancer is of importance. This chapter covers the role of cellular and molecular mechanisms as well as the experimental and epidemiological approaches as determinants of the main cancers. Even if major discoveries in the clinical management of cancer patients will be accomplished in the near future, the changes will mainly affect the affluent part of the world population. Promising approaches focused on prevention of the known causes, reducing its consequences, notably in resource-constrained settings are highlighted.

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Role of Inherited Thrombophilia Risk Factors in Patients with CKD-5 Receiving Haemodialysis

Acta Haematologica ◽

10.1159/000509413 ◽

2020 ◽

pp. 1-12

Author(s):

Dimitra Liapi ◽

Aikaterini Sfiridaki ◽

Aikaterini Livadiotaki ◽

Athanasios Alegakis ◽

Kostas Stylianou ◽

...

Keyword(s):

Risk Factors ◽

Molecular Mechanisms ◽

Methylenetetrahydrofolate Reductase ◽

Mthfr C677t ◽

Control Group ◽

Factor V ◽

Unknown Aetiology ◽

Vascular Events ◽

Thrombophilic Mutations

Background: The inherited thrombophilic mutations of the factor V gene (FVG1691A Leiden-FVL), prothrombin gene (PTG20210A), and the methylenetetrahydrofolate reductase gene C677T (MTHFR C677T) are risk factors for thromboembolic events and are related to the pathogenesis of vascular diseases. Objectives: The main objective of this study was to explore the role of these factors in the pathogenesis of chronic kidney disease (CKD) and survival of patients with CKD-5 receiving haemodialysis. Methods: A cohort of 395 patients with CKD-5 on haemodialysis, from 6 dialysis units in Crete, Greece were recruited based on their medical records and were followed for 5 years. We collected data on CKD-5 aetiology, thrombophilic gene expression, vascular access thrombosis, time of death, and causes of death. Results: The mutated genes just as prevalent in patients with CKD-5 as they were in a control group with no renal disease (p > 0.05). FVL heterozygosity was significantly more prevalent (11.4 vs. 5.7%; p = 0.036) in patients presented with CKD of unknown aetiology, compared to CKD secondary to known aetiologies. The survival of patients with CKD-5 receiving haemodialysis was not affected by the presence of any thrombophilic mutation. This held true for the whole cohort and for the cohort that included only lethal vascular events. Most patients with MTHFR C677T heterozygosity, and all patients with MTHFR C677T homozygosity, died from vascular events during the follow-up period. Conclusion: The FVL mutation may act as a risk factor for CKD. This study increases our understanding of molecular mechanisms in the pathogenesis of CKD of unknown aetiology. Τhe presence of thrombophilic mutations did not affect the overall survival of patients with CKD-5. This finding probably reflects the effect of medical care on patient outcomes.

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Overexpressing PLA2G6 mutations cause symptoms of young–onset dystonia–parkinsonism type 14 and reduction in DHA levels in zebrafish model

10.21203/rs.3.rs-25963/v1 ◽

2020 ◽

Author(s):

Tu-Hsueh Yeh ◽

Han-Fang Liu ◽

Mei-Ling Cheng ◽

Yin-Cheng Huang ◽

Ying-Zu Huang ◽

...

Keyword(s):

Risk Factors ◽

Dopaminergic Neurons ◽

Molecular Mechanisms ◽

Motor Disorder ◽

Loss Of Function ◽

Phospholipase Activity ◽

Young Onset ◽

Factors Associated ◽

Metabolomics Analysis

Abstract Background: Parkinson’s disease (PD) is the most common neurodegenerative motor disorder, which is currently incurable. Mutations in many genes have been demonstrated to be the primary risk factors associated with the familial or idiopathic PD; however, the mechanisms underlying these genetic mutations resulting in parkinsonism remains unclear. Phospholipase A2 group VI (PLA2G6) has been shown to regulate lipid metabolism and homeostasis in the nervous system. Previous studies have shown that point mutations in PLA2G6 might be the risk factors associated with the young–onset of dystonia–parkinsonism type 14 (PARK14). However, limited information is available regarding its pathogenic role and the mechanism underlying its function. Methods: To study the role of PLA2G6 mutations in zebrafish PARK14 models, we injected different mutation constructs of human PLA2G6 genes and zebrafish pla2g6 deletion constructs in the zebrafish larvae. We analyzed the locomotion behavior, performed immunohistochemistry to examine the formation of dopaminergic neurons, and identified the defective metabolites affected by PLA2G6 mutations through metabolomics analysis. Results: Injection of human PLA2G6 mutations and zebrafish pla2g6 deletion constructs induced symptoms such as motility defects and reduced number of dopaminergic neurons, and these symptoms resembled those observed in PARK14. These phenotypes could be rescued by treatment with L-dopa. Furthermore, the injection of two PLA2G6 mutation constructs, D331Y and T572I, led to a decrease in the phospholipase activity of PLA2G6 and its lipid metabolites, indicating that these two mutations are the loss-of-function mutations. We further performed metabolomics analysis to identify which lipids are majorly affected by the overexpression of PLA2G6 and PLA2G6 mutants. We found that injecting D331Y or T572I mutation constructs led to higher phospholipid and lower DHA levels. Conclusions: D331Y and T572I injections in zebrafish were sufficient to create a PD phenotypes. In addition, D331Y and T572I are loss of function mutations and cause defective phospholipase activity and reduced the level of DHA. These results have helped us elucidate the role of PLA2G6 mutations in PARK14 and further led to a deeper understanding of the molecular mechanisms underlying PD. The results of this study may also facilitate the development of therapeutic strategies for PD.

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Targeting Platelet in Atherosclerosis Plaque Formation: Current Knowledge and Future Perspectives

International Journal of Molecular Sciences ◽

10.3390/ijms21249760 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9760

Author(s):

Lei Wang ◽

Chaojun Tang

Keyword(s):

Risk Factors ◽

Molecular Mechanisms ◽

Vascular System ◽

Current Knowledge ◽

Vascular Inflammation ◽

Plaque Formation ◽

Inflammatory Factors ◽

Future Perspectives ◽

Atherosclerotic Plaque Formation

Besides their role in hemostasis and thrombosis, it has become increasingly clear that platelets are also involved in many other pathological processes of the vascular system, such as atherosclerotic plaque formation. Atherosclerosis is a chronic vascular inflammatory disease, which preferentially develops at sites under disturbed blood flow with low speeds and chaotic directions. Hyperglycemia, hyperlipidemia, and hypertension are all risk factors for atherosclerosis. When the vascular microenvironment changes, platelets can respond quickly to interact with endothelial cells and leukocytes, participating in atherosclerosis. This review discusses the important roles of platelets in the plaque formation under pro-atherogenic factors. Specifically, we discussed the platelet behaviors under disturbed flow, hyperglycemia, and hyperlipidemia conditions. We also summarized the molecular mechanisms involved in vascular inflammation during atherogenesis based on platelet receptors and secretion of inflammatory factors. Finally, we highlighted the studies of platelet migration in atherogenesis. In general, we elaborated an atherogenic role of platelets and the aspects that should be further studied in the future.

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Oxidative Imbalance and Kidney Damage: New Study Perspectives from Animal Models to Hospitalized Patients

Antioxidants ◽

10.3390/antiox8120594 ◽

2019 ◽

Vol 8 (12) ◽

pp. 594 ◽

Cited By ~ 7

Author(s):

Daniela Pellegrino ◽

Daniele La Russa ◽

Alessandro Marrone

Keyword(s):

Risk Factors ◽

Animal Models ◽

Molecular Mechanisms ◽

Public Health Problem ◽

Kidney Damage ◽

Major Public Health Problem ◽

Altered Expression ◽

Oxidative Balance ◽

Increased Risk

Chronic kidney disease (CKD) is a major public health problem worldwide and affects both elderly and young subjects. Its main consequences include the loss of renal function, leading to end-stage renal disease, an increased risk of cardiovascular disease, a significant increase in morbidity and mortality, and a decrease in health-related quality of life. This review arose in significant part from work in the authors’ laboratory, complemented by literature data, and was based on a translational approach: we studied the role of many CKD risk factors, such as hypertension, obesity, and oxidative stress/inflammation. The aim was to identify new molecular mechanisms of kidney damage to prevent it through successful behavior modifications. For this purpose, in our studies, both human and animal models were used. In the animal models, we analyzed the mechanisms of renal damage induced by hypertension (spontaneously hypertensive rats) and obesity (cafeteria diet-fed rats), showing that redox disequilibrium in plasma and tissue is extremely important in renal alteration in terms of both oxidative damage (lipid peroxidation, altered expression antioxidant enzymes) and apoptotic pathway (intrinsic/extrinsic) activation. In hemodialysis patients, we explored the correlation between the global oxidative balance and both inflammatory markers and cardiovascular risk, showing a strong correlation between the oxidative index and the blood levels of C-reactive protein and previous cardiovascular events. This multilevel approach allowed us to individually and synergistically analyze some aspects of the complex pathogenic mechanisms of CKD in order to clarify the role of the new amplified risk factors for CKD and to prepare an effective personalized prevention plan by acting on both modifiable and nonmodifiable risk factors.

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Role of the chosen general practitioner in educating women on the importance of regular gynecological examinations

Medicinski pregled ◽

10.2298/mpns1110486m ◽

2011 ◽

Vol 64 (9-10) ◽

pp. 486-489 ◽

Cited By ~ 1

Author(s):

Zlatka Markov ◽

Dragana Bosic-Zivanovic

Keyword(s):

Risk Factors ◽

Cervical Cancer ◽

General Practitioner ◽

Health Centre ◽

Malignant Diseases ◽

Abnormal Finding ◽

Regular Screening ◽

Novi Sad ◽

Do So

Introduction. Since regular screening is the best way of preventing the development of cervical cancer, the objective has been set to assess the motivation of women to have regular gynecological examinations and to estimate the role of the chosen general practitioner. Material and Methods. The survey was performed on the basis of the prospective study done at the Health Centre ?Novi Sad? in 2009 during the systematic regular examinations carried out by general practitioners. Results. It was found that 60.8% of the examined women had regular checkups; 21.5% visited their doctor once in the period of two to five years and 4.9% had undergone the examination in a period > 10 years, whereas 1.9 women had never had an examination. Other examinees had occasional check-ups with various time laps between them. Discussion. The reasons for not visiting a gynecologist were fear of the examination, absence of discomforts and lack of time. However, 87.2% of the examinees visited a gynecologist after they had been advised to do so by their general practitioner. Gynecological finding was good in 87.6% of the women, 3.4% were found to have carcinoma and 8.9% had some other abnormal finding. Conclusion. According to the obtained results, it has been concluded that the chosen general practitioner has a very important role in motivating women to have regular gynecological examinations and in educating them on the risk factors for developing malignant diseases and on the possible prevention.

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Differential expression of Exaiptasia pallida GIMAP genes upon induction of apoptosis and autophagy suggests a potential role in cnidarian symbiosis and disease

Journal of Experimental Biology ◽

10.1242/jeb.229906 ◽

2020 ◽

Vol 223 (21) ◽

pp. jeb229906

Author(s):

Grace F. Bailey ◽

Jenny C. Coelho ◽

Angela Z. Poole

Keyword(s):

Molecular Mechanisms ◽

Potential Role ◽

Chemical Induction ◽

Basal Metazoan ◽

Associated Proteins ◽

Induction Of Apoptosis ◽

Exaiptasia Pallida ◽

Lps Treatment ◽

Do So

ABSTRACTCoral reefs, one of the world's most productive and diverse ecosystems, are currently threatened by a variety of stressors that result in increased prevalence of both bleaching and disease. Therefore, understanding the molecular mechanisms involved in these responses is critical to mitigate future damage to the reefs. One group of genes that is potentially involved in cnidarian immunity and symbiosis is GTPases of immunity associated proteins (GIMAP). In vertebrates, this family of proteins is involved in regulating the fate of developing lymphocytes and interacts with proteins involved in apoptosis and autophagy. As apoptosis, autophagy and immunity have previously been shown to be involved in cnidarian symbiosis and disease, the goal of this research was to determine the role of cnidarian GIMAPs in these processes using the anemone Exaiptasia pallida. To do so, GIMAP genes were characterized in the E. pallida genome and changes in gene expression were measured using qPCR in response to chemical induction of apoptosis, autophagy and treatment with the immune stimulant lipopolysaccharide (LPS) in both aposymbiotic and symbiotic anemones. The results revealed four GIMAP-like genes in E. pallida, referred to as Ep_GIMAPs. Induction of apoptosis and autophagy resulted in a general downregulation of Ep_GIMAPs, but no significant changes were observed in response to LPS treatment. This indicates that Ep_GIMAPs may be involved in the regulation of apoptosis and autophagy, and therefore could play a role in cnidarian–dinoflagellate symbiosis. Overall, these results increase our knowledge on the function of GIMAPs in a basal metazoan.

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How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

Biochemical Society Transactions ◽

10.1042/bst20190944 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1019-1034 ◽

Cited By ~ 1

Author(s):

Rachel M. Woodhouse ◽

Alyson Ashe

Keyword(s):

Histone Modifications ◽

Molecular Mechanisms ◽

Epigenetic Inheritance ◽

Nematode Caenorhabditis Elegans ◽

Histone Methyltransferases ◽

Transgenerational Epigenetic Inheritance ◽

C Elegans ◽

Recent Developments ◽

Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

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Mesophyll conductance: the leaf corridors for photosynthesis

Biochemical Society Transactions ◽

10.1042/bst20190312 ◽

2020 ◽

Vol 48 (2) ◽

pp. 429-439 ◽

Cited By ~ 3

Author(s):

Jorge Gago ◽

Danilo M. Daloso ◽

Marc Carriquí ◽

Miquel Nadal ◽

Melanie Morales ◽

...

Keyword(s):

Molecular Mechanisms ◽

Current Knowledge ◽

Main Role ◽

Mesophyll Conductance ◽

Future Studies ◽

Cell Structures ◽

Leaf Tissues ◽

Change Framework ◽

Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

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