Lupine Publishers | Subjection between Breast Cancer and Body Mass Index, the Role of L-Carnitine in Prediction and Outcomes of the Disease

Lupine Publishers | Open Access Journal of Oncology and Medicine

 

Abstract

Increasing the effectiveness of antitumor therapy in breast cancer patients who take L-carnitine during preoperative systemic antitumor therapy compared with patients receiving standard neoadjuvant systemic antitumor therapy served as a prerequisite for studying possible antitumor mechanisms of L-carnitine. The positive effect of L-carnitine is due to the transfer of palm-n-LC through the inner membrane into the mitochondrial matrix, which promotes the formation of a significant number of ATP molecules. It has also been shown that L-carnitine can have a double protective effect, enhancing the energy dynamics of the cell and inhibiting the hyperexcitability of the cell membrane, that making it an ideal nutrient for the prevention and treatment of cancer. This article summarizes the results of epidemiological and clinical studies of the use of L-carnitine in the treatment of breast cancer
Keywords: Body mass index (BMI); Breast cancer (BC); Obesity; Overall survival; L carnitine

Introduction

The incidence of breast cancer in the world in general and in Ukraine in particular is growing. In 2017, in Ukraine the incidence reached 16 percent of female population, for which, the breast cancer ranked first in structure of oncological incidence among women. In analyzing the data of the National Cancer Registry of Ukraine, it should be noted, that in comparison with 2014 year, the prevalence rate of breast cancer in 2016has increased by 5,1%, that indicates importance of improvement diagnostic procedures and methods of treatment it [1]. Studying the scientific literature on this subject, we noticed that there is a strong biological relationship between obesity and a poor outcome of breast cancer. And having analysed the date of Ministry of Health in Ukraine it can be concluded, that about 26% of women in 2017 year had overweight or obesity.
Obesity has a chronic metabolic character, which is the result of the interaction of the endogenous factors, environmental conditions and lifestyle. Endogenous factors could be considered a violation of the genetic and hormonal balance. The external conditions and type of lifestyle include irregular rhythm nutrition, use of substandard products and sedentary lifestyle. Obesity is the first risk factor for metabolic syndrome, diabetes type II, cardiovascular disease and some forms of cancer, including breast cancer. Since overweight is a risk factor for breast cancer, there is reason to believe that among patients with breast cancer the percentage of obese women is higher than in the population. The risk of breast cancer in postmenopausal women by 30%, it is more than in premenopausal, women with obesity-50%. Furthermore it was proven that obesity is associated with poor prognosis in patients with breast cancer, regardless of menopausal status, and effectiveness of systemic medication breast cancer in patients that have over weight is lower than in patients with normal BMI.
Although obesity is associated with a poor outcome in women with breast cancer, it is unclear how weight loss after diagnosis will change its course and results. Recently, complementary and alternative medicine (CAM) is widely accepted among patients with breast cancer, which may provide several beneficial effects including reduction of therapy-associated toxicity, improvement of cancer-related symptoms, fostering of the immune system, and even direct anticancer effects [2]. L-carnitine is a metabolite of C₄ oil LC, which is involved in the transfer of palm-n-LC through the inner membrane into the mitochondrial matrix and is a substrate for the formation of ATP molecules. Carnitine is a trim ethylated amino acid naturally synthesized in the liver, brain and kidneys from protein lysine and methionine. Several factors, such as sex hormones and glucagon, can influence the distribution and level of carnitine in tissues [3,4].
In the absence of L-carnitine, the inner membrane of the mitochondria becomes impermeable to fatty acids, which entails a chain of various metabolic disorders in the human body. Carnitine has a modulating effect on the function of acetylcholine excitatory neurotransmitter, glutamate excitatory amino acid, insulin growth factor-1 (IGF-1) and nitric oxide (NO)[3]. Also proved, that L-carnitine may have a dual protective effect by enhancing the energy dynamics of the cell and inhibiting cell membrane hyper excitability, which make it an ideal nutrient for cancer prevention and treatment [5]. In view of the foregoing, the study of the influence of the body mass index on the effectiveness of systemic treatment of breast cancer is an urgent scientific problem and a promising field of research. This article presents the information of epidemiological and clinical studies of the influence of the body mass index on the effectiveness of breast cancer treatment by individualizing therapeutic measures taking into account the characteristics of patient's metabolism.
Studies on the Effects of BMI on The Course and Outcome of Breast Cancer and the Role of L-Carnitine in the Treatment of Cancer: The effectiveness of the prescribing of L-carnitine for breast cancers' treatment, as well as the effect of BMI on the outcome of the disease is proven in epidemiological and clinical studies.

Epidemiological and Clinical Studies

DSM Chan and co-authors [6] reported that women who have BMI> 30 course and outcomes of breast cancer are significantly worse than women with BMI <30. They proved, that women with BMI> 30 have the overall relative risk of total mortality 1.41, women with BMI of 25> 30 - 1.07. At the same time, for every 5 kg / m² of the increase BMI, the risk of both total mortality and mortality from breast cancer increased, namely by 18% and 14%, respectively M. Protani and co-authors [7] have shown that women with breast cancer, who are suffering in obesity, have lower survival rate than women with breast cancer without obesity. Recently published data of randomized clinical researches by ML Neuhouser and coauthors [8] demonstrated, that for women> 50 years old, with 2 and 3 stages of obesity (BMI> 35) is typically the development of GR+ breast cancer.
Similarly, B. Pajares et al. [9] who found significantly worse results for patients with BMI >35 compared with patients with BMI <25, stated that the magnitude of the effect depended on the cancer subtype (estrogen receptor (ER) / progesterone (PR) positive and HER2 negative, HER2 positive, triple negative). An analysis of the pooled data of the three adjuvant studies of the Eastern Cooperative Cancer Group showed significantly worse results for patients with obesity (BMI > 30) than for patients with normal BMI with a hormonal receptor-positive disease. And it was noted absence of negative effect of obesity on survival in patients with other breast cancer subtypes. C Fontanella et al. [10] studied the effect of BMI on different molecular subtypes of breast cancer and concluded that in women with ER / PR-positive and HER2-negative breast cancer, as well as with TNBC, the risk of death is significantly higher than in other subtypes of cancer.
It is proved that even the highest BMI figures are not a risk factor for death for patients with luminal A-like subtype of breast cancer. The reason for this is that fatty tissue produces an excessive amount of estrogen, a high level of which is associated with an increased risk of developing breast, endometrial, ovarian and some other cancers. It has also been proven that the level of adipokine, that promotes cell proliferation, increases in the blood with increasing of level of fat in organism. And adiponectin, which people with obesity have less than people with normal BMI, can have anti proliferative effects. Such data can serve as evidence of the effect of BMI on the course and outcome of breast cancer. Yet another proof of influence developing metabolic syndrome on the course and outcome of breast cancer was proposed by R. Bhandari et al. [11]. They proved that that the presence of metabolic disorders (that is, the metabolic syndrome) is associated with an increased risk of breast cancer in adult women.
The above data led to the need to investigate medicines that contribute to fat burning, such as L-carnitine. Based on the data provided by Rania M. Khalil and co-authors [12], we can prove the positive effect of this medicine on the course and outcome of breast cancer. The study showed that patients who received Tamoxifen with L-carnitine had significant decrease of Her-2 / neu and IGF-1 level (P <0.05) in the serum compared with patients who received only Tamoxifen. Using of L-carnitine led to significant decrease Her- 2 / neu level in the serum (P <0.05) compared to each of the control patients, namely, 59.5%. The effect of tamoxifen on IGF-1 (P <0.05) -decrease its level by 5.4% [13].However, it has been proved that using of L-carnitine in the treatment of ER+ breast cancer does not significantly reduce the level of estradiol, but leads to decrease both tumor markers CEA and CA15.3 (P <0.05,% decrease by 80.9% and 67, 8%, respectively) [13].
Using of L-carnitine in patients with breast cancer and obesity improves the metabolism of fatty acids in mitochondria, restores normal mitochondrial function and, thus, improves the general condition and quality of patients’ life [14]. Carnitine may alsomimic some of the biological activities of glucocorticoids, particularly immunomodulation, via suppressing TNF-a and IL-12 release from monocytes (5). L-carnitine as adjuvant therapy in cisplatin-treated cancer patients proved a beneficial effect in reducing the cisplatin- induced organ toxicity [15]. It is possible that, the extremely lipophilic nature of carnitine may be responsible for the decrease in EGFbinding [16]. Carnitine may insert in the cell membrane and/or interact with one of the many cellular enzymes having lipid substrates or cofactors. In addition, carnitine may interact directly with the EGFR [17].
Experimental evidence is available showing that ROS may induce the light and independent phosphorylation of the EGFR activating Her-2/neu. Moreover, the expression of the receptor is induced in conditions of oxidative stress [18]. L-carnitine, via its free radical scavenging and antioxidant properties, may inhibit ROS-mediated EGFR phosphorylation. It has been found that palmitoyl-carnitine can inhibit the activity of heart and brain protein kinase C in a competitive manner and subsequent phosphorylation of the EGFR [19]. Although the tumor markers and IGF-1 showed no significant difference in TAM-treated patients before and after administration of L-CAR, there was a tendency to decline after L-CAR supplementation [13]. The results of the above studies became a prerequisite for conducting clinical studies aimed at establishing the role of L-carnitine in the treatment of breast cancer.
To date, the search in the online clinical research registration system ClinicalTrials.gov using key words L-carnitine + breast cancer has revealed several studies evaluating the efficacy and safety of L-carnitine in the treatment of breast cancer patients. Analyzing the obtained results, we can conclude that L-carnitine was the drug of choice for neuropathies, as a consequence of chemotherapy, in patients with breast cancer.

Conclusion

L-carnitine is widely used in clinical practice. However, recently this medicine causes growing interest among oncologists. In a number of studies, L-carnitine has proven itself as a medicine that capable, during the preoperative systemic antitumor therapy, to increase its effectiveness compared with standard neoadjuvant systemic antitumor therapy. And also, taking L-carnitine with neoadjuvant systemic antitumor therapy helps to increase the number of cases of complete morphological regression (V degree of therapeutic pathomorphosis). To date, there are several clinical studies that are researching using L-carnitine in various malignant tumors, the results of which are the basis for further in-depth study of the effect of the medicine in the treatment of malignant neoplasms.


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Lupine Publishers | Micro-Environmental Systems and Endothelial Cells in Cooperative Tumorigenesis Account for Potential Malignant Transformation in Neurofibromatosis Type 1 Patients

Lupine Publishers | Open Acess Journal Of Oncology and Medicine

Abstract

Overall tumorigenesis in neurofibromatosis type 1 patients constitutes a series of specific targeting events with a central role enacted by proliferation of fibroblasts and endothelial cells in overproduction of growth factors and cytokines such as transforming growth factor-beta and CXCL12 cytokine. The plexiform neurofibroma well-illustrates dimensions of such cooperative participation within operative fields of the initial Schwann cell proliferation leading in a significant number of patients to malignant transformation of the peripheral nerve sheath tumors. Inclusive directions in operative targeting of Schwann cells or astrocytes are staged performance in the transformation of hyperproliferative induction and constitute further evolutionarily defined incorporation of such systems as endothelial cells. Hyperproliferative cell subsets are initial and also consequential target formulation of potential malignant states as induced in malignant peripheral nerve sheath tumors.

 

Introduction

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder and involves both heterozygous and homozygous absence/reduction of neurofibromin that acts normally as a tumor suppressor. There is a need to assess predisposing genetic factors and loss of heterozygosity causing emergence of aggressive neoplasms in patients with NF1 [1]. The two hit hypothesis helps account for the emergence of Schwann cell-based proliferations and for neurofibromas and plexiform neurofibromas. Gherkin may act on tumorigenesis of cutaneous neurofibromas via growth hormone secretagogue receptor [2]. It is important to consider the neurofibroma that is based on micro-environmental potentiation of tumor generation in patients that develop malignant nerve sheath tumors and astrocytomas in patients with NF1 +/- genotype; this occurs in a manner that involves growth factor overactivity and mast cell and endothelial overactivity within a milieu that dysfunctionally stimulates tumorigenesis. Reactive oxygen species overproduction lead to epithelial-mesenchymal transit in patients with neurofibromin deficiency and plays a crucial role in NF1 tumor growth [3]. RAS activation alone is not sufficient for malignant transformation of peripheral nerve sheath tumors; signal transduction may potentially help identify therapies for this neoplasm type [4].

 

Neurofibromin

The dynamics of neurofibromin as a cytoplasmic protein involve the regulation of K-Ras, and the PI3K/Akt pathways; absence of neurofibromin leads to overactivation of these pathways in various ways in inducing tumorigenesis in such lesions as optic tract pilocytic astrocytomas, brain stem astrocytomas and also other CNS astrocytomas in terms of progression of these lesions. The cell of origin determines the temporal course of neurofibromatosis-1 low-grade glioma formation [5]. The micro-environment of plexiform neurofibromas of peripheral nerves and of nerve plexi include a 10% risk of malignant change with subsequent aggressive clinical behavior in the affected patients. Over expression of cellular retinoid acid binding protein 2 is reported in several cancer types, including malignant peripheral nerve sheath tumors (MPNSTs) [6].

Related Tumor Predispositions

The neurofibromin insufficiency status in Schwann cells and fibroblasts allows for enhanced participation of immune system component cells such as microglia as evidenced in optic pathway low-grade astrocytomas. Telomere erosion is described in many tumor types and may potentially drive genomic instability and clonal progression in NF1-associated MPNSTs [7]. Tumor dimensions include proliferation of astrocytic cells in optic pathways, and of various subtypes of stromal cells such as fibroblasts and mast cells in the peripheral nervous system. It is significant to consider particularly the micro-environmental active participation in the genesis of the most common tumor type in Neurofibromatosis type 1 patient, that is the neurofibroma, which invokes proliferation of fibroblasts and endothelial cells. The congenital plexiform neurofibroma is in fact a hypervascular lesion that transgresses tissue margins and induces a significant risk for malignant transformation. NF1 loss is the primary driver of tumorigenesis in neurofibromatosis type 1-related plexiform neurofibroma [8]. It is further to such considerations that important cooperative intervention in malignant transformation of plexiform neurofibromas invokes multi-type cells in inducing proliferation of an integral Schwann cell-fibroblastic twin population in enhancing potential malignant transformation of the peripheral nerve sheath. A therapeutic window for neuroprotective intervention exists as detected by optical coherence tomography in mice with optic glioma, and particularly as an accurate biomarker of retinal ganglion cell apoptosis [9]. The heterozygous absence of one neurofibromin allele in mice results in plexiform neurofibromas and low-grade optic pathway astrocytomas. Mast cells appear to play a causal role in neurofibroma formation and also in microglia in optic pathway glioma evolution [10]. Such implications of the micro-enviromental factors includes a distinctive cooperative participation that carries implications for significant enhancement of cell proliferation and of such cytokines such as transforming growth factor and CXCL12 in formulating malignant transformation in such tumors. The methylemetetrahydrofolate reductase 1298 and 677 gene polymorphisms are related to optic glioma and hamartoma risk in NF1 patients through effects on DNA synthesis and methylation [11].

Convergent Targeting

The related tuberous sclerosis complex is analogous to neurofibromatosis type 1 as a neurogenetic disorder associated with increased risk for astrocytomas in the form of subependymal giant cell astrocytomas. A convergent targeting of systems of cell proliferation include in particular cyclic AMP and Ras in a manner that includes dimensions of micro-environmental conditioning. Mutations of the NF 1 gene are frequent in many cancer types in patients without NF1 and this is suggestive of a more general role for the NF1 gene in oncogenesis. In melanoma NF1 mutations potentially drive tumorigensis and promote drug resistance [12]. Inclusive dynamics allow for permissive tumorigenesis in a manner that includes the incorporation of malignant transformation within confines of a Schwann cell-fibroblast-endothelial cell system in the case of malignant peripheral nerve sheath tumors. Astrocytes and microglia are analogous counterparts in the induction of CNS astrocytomas. Such considerations are inclusive phenomena of multi-component induction of potential malignancy that recharacterizes conditioning of the micro-environment of proliferative states preceding tumorigenesis. Interaction between neoplastic Schwann cells and their surrounding neural microenvironment has important implications for early cellular events promoting tumorigenesis in neurofibroma development [13].

Performance Dynamics

Performance dynamics of tumors in neurofibromatosis type 1 may potentially modify the biologic significance of a two-hit hypothesis in a manner that implicates micro-environmental conditioning of the resultant cell hyperplasias and proliferations in such lesions as peripheral nerve sheath tumors and astrocytomas. NF1 provides unique vantage points to examine co-contributions of molecular, cellular, and tissue processes in tumor biology [14]. Such proposed dimensions invoke in particular an over-activation in production and action of growth factors that provoke selective malignant transformation of hyper-proliferative lesions composed of Schwann cells and astrocytes in the peripheral and central nervous systems respectively. Plasma soluble levels of transforming growth factor-beta and interleukin-6 are increased in NF1 patients and a shift towards an anti0inflammatory profile has been reported in cells expressing cytokines [15].

Hyperproliferation

The hyperproliferative states affecting Schwann cells and astrocytes invoke also fibroblast and microglial cell proliferations in a manner transforming tumorigenesis. Such facilitation to tumorigenesis invokes dimensions of transformation as well seen in plexiform neurofibromas that may undergo malignant transformation in a significant number of affected individuals. Such considerations are selective targeting of specific cell subpopulations in a manner that allows permissive transformation. Insertional mutagenesis identifies a STAT3/Arid1b/beta-catenin pathway that drives neurofibroma initiation in the context of Nf1 loss [16]. Mast cells and fibroblasts may potentially incorporate endothelial cells that may participate as central dysregulatory dimensions in plexiform neurofibroma tumorigenesis. The provocations for malignant transformation further cooperate in systems of derivative consequence as hypervascular lesions that subsequently lead to potential malignant cells in individual patients. Cross species comparative oncogenomic may identify driver mutations in mouse cancer models and allow validation in human tumors [17].

Concluding Remarks

Propositional implications in tumorigenesis include the multi-component participation of Schwann cells on the one hand and of fibroblasts, mast cells, endothelial cells and also of microglia in an inductive process that includes specific pathways of malignant transformation. Endothelial cell proliferation is related to substantial participation in modes related to key-events of increased proliferation of Schwann cells and astrocytes in initial stages of lesion infliction. Inclusive phenomena have thus become systems of consequence in affecting such specific cell proliferative states. Such events occur within the added dimensions of directed targeting of multiple-agent micro environmental modeling of the initial proliferation of the Schwann cells or astrocytes. A pivotal series of roles played by fibroblasts, endothelial cells, mast cells and of microglia and astrocytes appears a dynamic milieu within added consequences of malignant transformation of both Schwann cells and astrocytes that progress as cooperative systems of tumorigenesis.

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LUPINE PUBLISHERS Open Access L Latest Trends in Textile and Fashion Designing Fashion Choices of Gen Y in Retrospective

 

Nithyaprakash Venkatasamy 

 

Bannari Amman Institute of Techn

 

Abstract

 

Gen Y’s lifestyle is analogous to America’s 20th century professional woman trying to live outside the traditional parameters of the society. The movements of Pre-Raphaelites, early 20th century Hollywood stars, Bohemianism in the early stages, Style preferences of BCBG: Bon Chic Bon Genre and current deconstructed silhouettes reveal the traits of free spiritedness, not just because it adds on personal flavour but rather free spiritedness evolution as a way of life and attitude.

 

https://www.researchgate.net/publication/323279685_LUPINE_PUBLISHERS_Open_Access_L_Latest_Trends_in_Textile_and_Fashion_Designing_Fashion_Choices_of_Gen_Y_in_Retrospective