Lupine Publishers | Haematological Studies on Multiple Squamous Cell Carcinoma Patients in Nigeria

 Lupine Publishers | Journal of Oncology and Medicine

Abstract

Multiple squamous cell carcinomas (MSCCs) in albinos occur mainly due to light melanin and constant exposure to ultraviolet rays of sun light. A study to evaluate changes in haematological parameters was done in albinos with multiple squamous cell carcinomas in a tertiary health institution in Enugu, Nigeria. A total of 40 subjects were recruited for the study comprising 20 subjects each for MSCC and control. About 2ml of venous blood was collected by venepuncture into EDTA anticoagulated containers and Mindray BC-5300 used to measure the haematological parameters. The data were analysed using SPSS version 21 with t-test and significance level set at P<0.05. The results showed increase in ESR (19.80±3.40mm/hr, 6.80±2.33mm/hr, 0.000), WBC (5.91±0.45X109/L,4.65±0.59X109/L,P=0.000), Eosinophils (4.06±1.03%,0.54±0.50%, P=0.000) and Monocytes (5.53±1.18%, 1.53±0.51%, P=0.000), decrease in platelets (182.13±41.31 X109/L, 226.26±25.13 X109/L,P= 0.001) and no significant difference (P>0.05) in RBC (4.60±0. 30 X1012/L, 4.79±0.38 X1012/L, P=0.133), Haemoglobin (13.80±0.89g/dl, 14.40±1.16g/dl, P=0.121) , PCV (41.40±2.66%,43.20±3.50%, P=0.125) and lymphocytes (48.53±6.46%,45.12±5.09%, P=0.120) of MSCC subjects compared to control respectively. The RBC, Haemoglobin and packed cell volume were not affected with this cancer but platelets, WBC, monocytes, eosinophils, neutrophils showed changes that were statistically significant. The clinicians and all the health practitioners involved with the management of albinos with MSCC should monitors these changes and also be careful to avert cardiovascular disease due to shift in neutrophils to lymphocytes ratio.

Keywords: Haematological studies; Multiple squamous cell carcinoma patients; Nigeria

Introduction

Multiple squamous cell carcinomas (MSCCs) involve a lot of varied types of cancer that originate from squamous cells [1]. These cells make up the outer parts of skin and lining of some organs, respiratory and digestive tracts [1]. It has been reported that cancer may be regarded as a very large and exceptionally heterogeneous family of malignant diseases with squamous cell carcinomas comprising one of the largest subsets [2-4].

Cancer has been a public global health challenge with increased morbidity and mortality rates across the world. Cancer demands much attention as many a times are not diagnosed early and managed at the stage it can be controlled. Cancer presents with a lot of challenges including bleeding, pains, loss of weight, fever and so many other features that are excruciating and debilitating. Haematological parameters are good indicators of health and disease status [5,6]. It is important to consider studies in haematological parameters to ascertain the levels of alterations in these aspects of Laboratory Medicine that are crucial in wellbeing of the patients. There is strong evidence between diet and exposure of the skin to sunlight especially ultraviolet rays and MSCC [7,8]. The increased intake of high fat dairy foods increases MSCC tumor risk especially with person with history of skin cancer. Smoking, high beer and liquor consumption increase the risk of MSCC [9]. The study was done to determine haematological parameters of multiple squamous cell carcinoma patients in Nigeria

Materials and methods

Study area

The study was done in National Orthopedic Hospital, Enugu, Nigeria.

Subjects

A total of 40 subjects were recruited for the study comprising 20 subjects each for Multiple squamous cell carcinoma (MSCC) and apparently healthy subjects (Control) blood group who were apparently healthy individuals drawn from the Health institution.

Sample collection

About 2mls of venous blood was collected from the subjects into anticoagulated containers for haematological parameters determination.

Laboratory investigations

The hematological parameters were determined using Mindray BC-5300. The haematological parameters investigated include WBC, Neutrophils, Lymphocytes, Monocytes, Red Blood Cells, Hemoglobin, Packed Cell Volume, Platelets and Erythrocyte Sedimentation Rate (ESR).

Ethical Consideration

The details of the research were explained to the subjects and written consents obtained from them and were assured of joining the study willingly and confidentiality also assured. The subjects who gave their consents were allowed to participate in the study.

Statistical Analysis

The results were expressed as mean± standard deviation. The data were analysed with the statistical package for social science (SPSS) version 20 using t-test, ANOVA and the level of significance was set at P<0.05.

Table 1: Mean± sd values of haematological parameters of MSCC and control subjects.

Significant level - *P < 0.05,
ns - Not significant (P > 0.05)

The results showed increase in ESR (19.80±3.40mm/hr, 6.80±2.33mm/hr, 0.000) , WBC (5.91±0.45 X10⁹/L, 4.65±0.59 X10⁹/L, P=0.000) , Eosinophils (4.06±1.03%,0.54±0.50%, P=0.000) and Monocytes (5.53±1.18%, 1.53±0.51%, P=0.000), decrease in platelets (182.13±41.31 X10⁹/L, 226.26±25.13 X10⁹/L,P= 0.001) and no significant difference (P>0.05) in RBC (4.60±0. 30 X10¹²/L, 4.79±0.38 X10¹²/L, P=0.133), Haemoglobin (13.80±0.89g/ dl, 14.40±1.16g/dl, P=0.121) , PCV (41.40±2.66%,43.20±3.50%, P=0.125) and lymphocytes (48.53±6.46%,45.12±5.09%, P=0.120 of MSCC subjects compared to control respectively (Table 1).

Discussion

Multiple squamous cell carcinoma (MSCC) of the skin is an extensively rare entity but may be more in albinos because of their melanin level of their skin. It is associated with ultraviolet radiation, immunodeficiency states, local intramuscular metastasis and cell carcinoma [10]. The study of haematological parameters of albino patients with multiple squamous cell carcinomas showed increase in erythrocyte sedimentation rate (ESR). Although, ESR has been reported as nonspecific diagnostic tool but may aid in the diagnosis of MSCC as the increase was statistically significant compared to the levels in apparently healthy age and sex matched subjects. Patients with multiple squamous cell carcinomas have a significantly increased risk of developing a recurrence or spread to their lymph nodes, warranting frequent follow up visits to their dermatologists. Cutaneous squamous cell carcinoma when diagnosed and treated early is highly curable [11]. Albino subjects are easily affected by much exposure to sunlight and MSCC is seen on their skin not always covered against ultraviolet rays of the sun. It shows that MSCC elevates the levels of ESR in the patients which may affect the viscosity of their blood and osmotic fragility of the blood. The study also showed increase in WBC of MSCC patients relative to the control. This could be linked to increased oxidative stress among the patients. There could be increased generation of free radical and reactive oxygen species in the MSCC patients due to increased metabolism and stress and a lot of acute infections that resulted in the increase in the WBC. The study showed increase in eosinophils showing that there could be hypersensitivity reactions. That shows that MSCC is associated to allergens. The eosinophils increased significantly. The study also showed increase in monocytes. This shows that MSCC may have intracellular association with some infections and release of cytokine linked to this increased levels of monocytes. There was a shift in neutrophils to lymphocytes ratio which could point to risk of vadiovascular diseases in patients with MSCC. This shows that the body may utilize more of antibody mediated immunity than cell mediated immunity.

Haematological parameters have been reported as good indicators for health and disease status of patients [5,6]. The study revealed no significant difference in RBC, haemoglobin and packed cell volume together with lymphocytes. This shows that patients with MSCC may not suffer from anemia. The carcinoma may not suppress bone marrow activity. Those involved with the management of MSCC should be mindful of these changes especially in the WBC, eosinophils, neutrophils, erythrocyte sedimentation rate (ESR) and platelets. There may not be bleeding as seen in other cancers as the platelets were not low but decreased when compared to the control.

Conclusion

Cancer is a major global public health issue challenging the whole world with increased morbidity and mortality. Multiple squamous cell carcinomas could be neglected cancer diseases that are more common to albinos due to their melanin levels in the skin and constant exposure to ultraviolet radiation from sun light in the parts of their body not always covered with dress. The RBC, Haemoglobin and packed cell volume were not affected with this cancer but platelets, WBC, monocytes, eosinophils, neutrophils showed changes that were statistically significant. The clinicians and all the health practitioners involved with the management of albinos with MSCC should monitors these changes and also be careful to avert cardiovascular disease due to shift in neutrophils to lymphocytes ratio.

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Lupine Publishers | Myocardial Perfusion Imaging Reveals Breast Cancer

 Lupine Publishers | Journal of Oncology

Abstract

Diagnostic evaluation of chest pain using myocardial perfusion imaging (MPI) is a common method employed to look for coronary artery disease (CAD). The isotopes used in MPI are also useful for imaging cancer, including breast cancer. We present a case where breast cancer was diagnosed using a quantitative method which simultaneously looks for cancer and CAD.

Introduction

Diagnostic evaluation of patients with chest pain may include myocardial perfusion imaging. During the initial stress imaging evaluation, differences in regional blood flow and metabolism differentiates normal coronary blood flow from abnormal – viz. ischemia. Breast cancers are also associated with increased regional blood flow and metabolism and can be seen during the initial imaging as was done in this woman. Awareness of these similarities resulted in identification and successful treatment of her breast cancer prior to further spread of the cancer.

Case Report

A 39-year old woman presented with atypical chest pain. She was referred for myocardial perfusion imaging. Following pharmacologic stress, her initial images - shown here - were acquired 5-minutes after isotope injection. A mass was identified in her right breast and was surgically removed revealing a Stage IIA breast cancer without LN involvement. Additional workup revealed no evidence of metastatic disease. The patient elected to undergo no further treatment.

Discussion

Quantitative measurement following enhancement of regional blood flow differences, which reflect both changes in metabolism and regional blood flow, can be measured to unmask ischemia and cancers [1]. These changes can reflect CAD, which is itself caused by inflammation [2], as well as pre-cancerous changes, which can also be associated with inflammation.

Conclusion

By understanding the fundamental differences in tissue resulting from changes in metabolism and regional blood flow differences, nuclear imaging can quantitatively unmask CAD and hidden cancer (Figure 1).

Figure 1: Figure of FMTVDM.

Acknowledgment

FMTVDM issued to first author. Figures reproduces by expressed consent of first author.

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Lupine Publishers | Epigenetically Reprogrammed Methylation as a Gifted Potential Cancer Biomarker

 Lupine Publishers | Journal of Oncology

Introduction

Ontrary to genetic changes of DNA molecule which change exactly the sequence of DNA and are not reversible, the DNA methylation involves in addition of a methyl group to cytosine nucleotide to control genes expression which is reversible [1,2]. Methylation is unique change that consequence in different gene expression pattern and finally may trigger the onset of diseases like cancer [3]. Epigenetic reprogramming in cancer cells represents a unique methylation landscape concerning the net loss of global DNA methylation simultaneously with an increase in the levels of in CpGs islands. So, cancer epigenetically reprogrammed methylation landscape (i.e., Methylscape) can be a common feature exhibited by most cancer types and therefore can be a universal cancer biomarker. The DNA methylation in molecular level change the gene expression pattern of the cell but methylation can change the physicochemical properties of DNA polymer in solution including DNA structure and its affinity as well.

It is shown by Abu Ali Ibn Sina and his colleagues examined the consequence of levels and genomic distribution of methylcytosines on the physicochemical properties of DNA to sense the Methylscape biomarker [4]. They found that DNA polymeric behavior is powerfully affected by differential patterning of methylcytosine resulting in fundamental differences in DNA solvation and DNA-gold affinity as the discriminative biomarker between cancerous and normal genomes. They use the Methylscape differences to develop simple, greatly sensitive and selective electrochemical or colorimetric one-step assays for the detection of cancer.

In mammalian genomes, DNA methyltransferases (DNMTs) duty is transferring the methyl group from S-adenosylmethionine to cytosine at CpG dinucleotides (CpG islands) [5]. The majority of the methylation happens through DNA duplication in the S-phase of the cell cycle, and is the supreme rich form of post-replicative DNA alteration of eukaryotic organisms [6,7]. DNA methylation cause the 180° flip out of the DNA backbone into an active-site pocket of the enzyme where methylation of cytosine takes place [8]. In fact, well methylated DNA (hypermethylated) is classically coupled with inactive genes, whereas methylation depletion (hypomethylation) can be observed in active genes.

Actually it is confirmed that DNA segments containing methylated Cytosine like something which is happening in cancer cells, are very stiff and hard to bend, and present an inferior tendency to circularize or form nucleosomes by wrapping around histones and can be used as the discriminative universal cancer biomarker [4]. There is a big hope that in the near future by using some physical properties of methylated DNA in comparison to nonmethylated DNA the diagnostic kits will be approved with no advanced complicated molecular technologies.

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Lupine Publishers | Cancer: Our Body’s Global Warming Warning

 Lupine Publishers | Journal of Oncology and Medicine

Opinion

Monday 4 February 2019 was yet another World Cancer Day. We celebrated our efforts to find and eradicate cancer without admitting to ourselves that cancer isn’t a single disease, but rather a group of diseases all caused by our bodies responding to the toxic environment we are exposing ourselves to, just as our planet is responding to the toxic wastes we are dumping into it. The question is WHY do our bodies run amok. The answer lies in the same answer to why Global Warming exists. It is the untold unimaginable continued damage and destruction we cause to the world and to ourselves that accounts for the destruction of the planet and the development of cancer within us. While some individuals may have a genetic predisposition [1] for certain types of cancers, it is nonetheless this constant bombarding of ourselves with toxins, which our bodies try to react to and when overwhelmed the climate change of our bodies occur and call for the eradication of first the damaged cells and then eventually ourselves. Just as the continued bombardment of our Earth with environmental toxins is resulting in violent changes on the planet in an attempt to respond to and eradicate the cause of the toxins to the plant, so too are our bodies reacting to try to eradicate these toxins and their effect within our bodies. This process on a biological basis is reflected in how the cells of our body respond to the cellular environment as shown in Figure1. The process of developing cancer or not developing cancer is not a sudden change but rather a transitional series of events resulting from the interaction between the specific responses and expression of the genome of the cell involved and the specific environment in which the cell is immersed. This environment includes both carcinogenic and non-carcinogenic factors. As the insults occur, the cellular mechanisms to respond to those insults include a variety of responses, including cellular repair and immunologic reactions. The outcome is determined by the interaction between these two opposing sets of factors. Progression or regression is determined by these responses. Clearly no one wants to have cancer or for the planet to be destroyed. Confusion comes from not knowing what is helpful and what is hurting us. Until recently [2], we have been limited by testing (qualitative imaging, biomarkers, etc.), which at best can only provide a yes/no answer to the question of whether a person has cancer or not. Many of these tests do not even provide a yes/no answer, but rather infer there could be a problem. These qualitative approaches are unable to provide us with information warning us that these transitional changes are happening [3]; changes which we could act upon if we only knew they were occurring. Changes which when measured could be used to determine if a given treatment is working [4], harming us or having no effect. Measurable changes which can show us cancer in its early stages [5]. These transitional changes can now be measured using FMTVDM [2]. The only question is whether we use this tool to help find these transitional changes and guide our treatment regimens or whether we will continue to pretend that what we are doing is working?

Figure 1: Quantification of the “Health-Spectrum” for Cancer.

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Lupine Publishers | The Nuclear Imaging Uncertainty Principle. Do our Nuclear Cameras Really Work?

 Lupine Publishers | Journal of Oncology and Medicine

Mini Review

In 1927, Werner Heisenberg [1], published his “Uncertainty principle” which in brief states that it is impossible to simultaneously know both the position and momentum of an electron or any other particle with any degree of accuracy or “certainty.” To define the location of an electron required interaction with it. This interaction would result in movement of the electron and as a result, would move the electron. The best one could achieve is knowledge of where the electron was at the time of interaction. The first utilization of nuclear isotopes for medical imaging and evaluation of heart disease was conducted by Blumgart [2] in February of 1925 when he injected himself with Radium C, which emits alpha and beta particles and gamma rays. As such, the Geiger counter chamber developed by Blumgart and Yens, could detect the passage of blood carrying the radium. The studies would first be published in 1927 and become known as “circulation time” and would dynamically define myocardial contractility by comparing changes in count activity over time.

In 1957, Hal Anger [3] demonstrated the first gamma camera designed to detect the emission of radioactive decay emanating from the patient. In essence, a modern Geiger counter which could be held some distance from the chest to measure isotope decay while present in cardiac tissue. The decay (scintillation) is detected by the camera after being absorbed by the camera crystal (usually sodium iodide) with the subsequent release of an electron from the sodium iodide, which is subsequently detected by a photomultiplier (PMT) tube as shown in Figure 1, PMTs are composed of glass tube with a vacuum inside. Photons leaving the patient would approach the PMT from left to right, striking the photocathode material first. This results in electrons being produced as a consequence of the photoelectric effect. The focusing electrode subsequently directs these toward the electron multiplier composed of a series of electrodes (dynodes), each with a more positive voltage than the next. The electrons are accelerated toward the first dynode, arriving with a greater energy. This results in low energy electrons being generated by the first dynode, which are in turn accelerated toward the second dynode and so on.

Figure 1: Photomultiplier Tube.

The process is known as secondary emission and results in an amplification of the original scintillation. The electrons finally reach the anode (far right part of PMT) where the accumulated charge results in a sharp current pulse indicating the arrival of the photon at the photocathode. These scintillations are tallied by the computer. These anger cameras have been used to image various regions of the body using radioactive isotopes which are known to localize to the tissues in question. For cardiac disease this has primarily included thallium-201 and technetium-99m. The utilization of these cameras have been assumed to be able to detect changes in isotope availability by “counting” the amount of radioactivity as described and translating this information into a black and white or color format image for human viewing and interpretation of disease. However, to the best our knowledge, no such experimentation has been carried out to determine if today’s gamma cameras can in fact accurately count radioactive decay required for image comparison. This quantification is necessary to compare redistribution of isotopes and to avoid errors in interpretation. This requires more than simply the ability to produce pictures of different brightness; it requires actual ability to measure differences in isotope decay (scintillation), as did Blumgarts Geiger counter. This is the basis of devices used to determine human radiation exposure and is a requirement in diagnostic imaging. To investigate this, we conducted a series of experiments with known quantities of Tc99m and utilized two different matrixes commonly employed in clinical cardiology to determine if the cameras can accurately measure radioactive decay. The acquisition of technetium-99m isotopes for diagnostic purposes results from the radioactive decay of the parent compound (Molybdenum) to the daughter compound (technetium-99m) is shown in Figure 2.

Figure 2: Decay of Technetium-99m.

The production of technetium by bombardment of a molybdenum atom with deuterons was first documented by Carol Perrier and Emilio Segre in 1937. Technetium- 99m (meta stable) decays to Technetium 99 through the release of a gamma (photons) rays of 140.5 keV (98.6%) and 142.6 keV (1.4%) as shown. The result is Technetium-99 (Tc-99) with a half-life of 210,000 years. The halflife for technetium-99m is 6.01 hours as shown in Figure 3.

Figure 3: Radioactive decay curve of Technetium-99m.

The radioactive decay of technetium-99m is shown. The physical half-life for Tc-99m is 6.01 hours. Given this information, one can calculate that over the course of 55 minutes there is a 10% decay of the isotope. In clinical studies looking at sestamibi redistribution to determine ischemia [4,5] the initial stress imaging is made at 5 minutes with the second imaging at 60 minutes. Each sample of technetium-99m contained 10.1 mCi (37.37 mBq) of radioactive compound. Each sample was sealed in a syringe preventing any leakage of material. If the cameras are able to accurately measure isotope decay, the camera should reveal a 10% reduction in count activity from the first image and the second image taken 55 minutes later. Utilizing a Philips Forte Dual head single photon emission computed tomography (SPECT) camera with general all-purpose collimators, the camera was set to (1) a 64 x 64 matrix and (2) 128 x 128 matrix settings. As shown in Figures 4a- 4c.

Figure 4(a): The greater the number of pixels, the “sharper” the image.

Figure 4(b): Fewer pixels reduce “sharpness” while increasing scintillation detection.

Figure 4(c): More pixels increase image “sharpness” but at the expense of scintillation detection.

An effort to improve image “sharpness” is derived by increasing the number of pixels in a given field. Cameras set up with a 64 x 64 matrix (pixel) resolution, will result in a more blurred image, while a matrix of 128 x 128 (pixels) will increase image “sharpness.” As seen in Figures 4b & 4c, the cost of increasing “sharpness” occurs at the cost of more septa separating each pixel, which reduces the area available for information acquisition. Each septum itself is excluded from acquiring information on radioactive decay, exchanging information for sharpness, the greater the matrix (pixel) settings per image, the greater the localization of isotope emission within the field of view and the sharper the image. However, for each pixel, there are surrounding septa of lost information forming the border of the pixel. The question is whether the increase in image “sharpness” comes at the expense of “accuracy” of radioactive isotope count activity, which is the basis for image comparisons.

As shown in Figure 5a, the initial radioactive count obtained over 5 minutes from a syringe of 37.37 mBq of radioactive tc-99m using a 64 by 64-pixel matrix was 1,405,721. Using the same matrix and imaging 55 minutes later, Figure 5b shows the counts collected over 5 minutes were 1,251,359. The decay curve for tc-99m means that there should have been a 10% reduction in count activity. In this instance, there was a 10.98% reduction in measured isotope activity.

Figure 5(a): 64 x 64 matrix, initial acquisition.

Figure 5(b): 64 x 64 matrix, acquisition made 55 minutes after initial acquisition.

A 37.37 MBq syringe of technetium-99m-sestamibi is placed under the camera and counts acquired over 5 minutes. The same syringe is reimaged 55 minutes later for an equal amount of time. When the 64 x 64 matrix was used, the original count (5a) was 1,405,721, the second image (5b) count was 1,251,359, representing 89% of the original count activity. When the resolution was increased to 128 x 128 matrix, there was an additional 50% loss in data, with a 5-minute image (different syringe sample) count of (5c) 3,473,001. The second image count 55 minutes later (5d) was 2,966,394, representing a count decrease of 14.6%, 4.6 % more lost data than should have been shown. This reduction is due to increased pixels resulting in Fourier transform and modulation transfer factor data loss. Subsequently, total information is lost at the gain of localization information. Since we are looking for total cell uptake and release (redistribution) of the tracer, one must use the 64 x 64 matrix as a better index of isotope activity in exchange of resolution for accuracy [6,7].

As efforts to improve image “sharpness” were made by changing the matrix to 128 x128, Figure 5c shows the initial count activity measured over 5 minutes was 3,473,001. When the syringe was reimaged 55 minutes later using the 128 x 128 matrix, the counts collected over a 5-minute period, as shown in Figure 5d, were 2,966,394. While there was an increase in actual radioactive count activity compared with the 64 x 64 matrix, this came at a cost of accuracy with a 14.59% reduction in radioactive count activity. This is 4.68 times the data lost as was seen with the 64 x 64 matrix. While the visual appearance desired by most clinicians to make diagnostic decisions is important, images can be manipulated to confirm what the diagnostician is looking for. These adjustments may lead to incorrect conclusions and visual interpretations alone may lead to incorrect conclusions. Visual illusions such as this shown here can result in incorrect diagnostic decision when depended upon by the clinician. This particular illusion demonstrates visual problems resulting from pixel information. When these illusions are the result of instrumentality, diagnosticians cannot reliably use them to make clinical decisions and the utilization of attenuation algorithms cannot reliably reduce these errors, making it even more important that we know what our nuclear cameras are truly capable of measuring and how to most accurately use them, When done to determine if someone has ischemic heart disease, such illusions can result in misdiagnosis. For that reason, multiple researchers have been trying to develop algorithms, which will reduce this human error. It is impossible to reduce this human error, if part of the error is the result of instrumentation. These findings have demonstrated that independent of the visual image seen by the clinician, this information is dependent upon the accuracy of the computer’s ability to detect the radioactive decay of isotope needed to make image comparisons. Like, Heisenberg’s uncertainty principle, this uncertainty principle comes at a cost. The ability to detect the location of the emission of the gamma ray is influenced by the matrix surrounding the acquired image of the heart. This precision of location comes at the cost of lost accuracy as to the number of gamma rays being emitted. Given this spatial limitation (sharpness) versus accuracy, like Heisenberg we are left with a dilemma. Do we sacrifice accuracy for “sharpness” or should we be more concerned with the necessary accuracy required to compare (Figures 4-6), thereby reducing errors made in evaluation of the extent of ischemic heart disease?.

Figure 5(c): 64 x 64 matrix, initial acquisition.

Figure 5(d): 128 x 128 acquisition made 55 minutes after initial acquisition.

Figure 6: The importance of recognizing visual illusions.

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Lupine Publishers | Carbon Nanotubes: Exploring Intrinsic Medicinal Activities and Biomedical Applications

 Lupine Publishers | Journal of Oncology

Introduction

Carbon Nano materials the king of nonmaterial’s have fascinating nanofamily including buckyballs or buckminsterfullerenes [1], multiwalled carbon nanotubes [2], the single-walled carbon naotubes(SWCNTs) [3], Carbon Nanohorns(CNHs), Carbon nanocones, Carbon nanofibers (CNFs), carbon nanothread, Buckypaper, carbon dots, nanodimons, nanoonions, nanorods, nanoribbons. Also called as powerful particles, CNTs (carbon nanotubes) has thus bloomed over the past decade [4,5]. Increasing evidence has shown that certain CNT properties such as nano-sized dimension, high surface energy, and large reactive surface area are directly correlated to their biological activities [6,7]. Great property of loading various biomolecules, diagnostic and therapeutic moieties resulting in diversified biomedical applications of CNTs (Figure 1).

Figure 1: Intrinsic Biomedical Applications of Carbon Nanotubes (CNT).

I. Diagonsis and Imaging: CNT act as biosensor or Nanorobots, which helps in diagnosis of disease, their progression level and their pathological condition in quick and better way. CNT biosensor are made up by conjugating different biochemicals with CNTs, like in glucuometer biosensor, glucose peroxidase is conjugated with CNTs that is use for the detection of blood sugar level in diabetic patients. Another example is SWCNTs-DNA biosensor that is use of detection of antigen –antibody comlex, which further helps in molecular diagnosis in pathology [7,8]. Complex of fluorescent agents and CNTs act as radio-opique agent that is use for the detection of cell and biological system in In-vivo organs [9].

II. Cancer Therapy: Carbon nantubes are effective against Pancreatic Cancer, Brain Cancer, Blood Cancer, Breast Cancer, Colon Cancer, Liver Cancer, Lymph Node, Metastasis, Prostate Cancer by using different anticancer drugs like Paclitaxel, Daunorubicin, Amphotericin B, Carboplatin, siRNA, Doxorubicin, Metal halides, Methotrexate etc. Apart from drug delivery route there are another two methods for cancer therapy using CNTs are immunotherapy and anti-tumor hyperthermia therapy [10].

III. Gene Therapy: CNTs and CNHs are used as vector in genetic engineering due to their cylindrical nature, which wrap the desired DNA and deliver it to target site to cure the genetic disorders by correcting misread or missense gene sequence [7].

IV. Infection/HIV Therapy: CNTs itself have antimicrobial activity by oxidising intracellular glutathione and resulted increase the oxidative stress on microbial cell that cause natural death of pathogen. CNTs also used in number of vaccinations to active immune response by triggering MHC-II, which further promote natural antibody production to stop the infection [11]. HIV( human immunodeficiency virus) that attack the immune response and decline the natural immunity, till date we cannot stop it completely but we can suppress or stop virus multiplication and control the disease .In this case conjugation of CNTs with siRNA that further deliver to T-Cell to stop virus proliferation [12].

V. Ocular Delivery: In case of ocular delivery there are number of challenges to deliver the drug to get adequate response with minimizing risk of infection. So therefore, SWCNTs-NH₃+ used as carrier to deliver antigen synthetic vaccination, safely and effectively by avoiding risk of necrosis and tissue degeneration [13].

VI. As Antioxidant: CNTs and CNHs are natural anti-oxidants. They are used in preserving drug molecules in formulation by inhibiting their oxidation. Furthermore, due to this property they are also used in anti-aging cosmetics products that oxidized the skin and stay it healthy and young [7].

VII. Neurodegenerative (ND)/Alzheimer Disease: Graphene sheets, and by extension CNTs, are excellent conductors of electricity, and thus are highly useful in the regeneration of neurons. Neurons can grow successfully on CNT beds, and modifying the surface with 4-hydroxyonoenal, known to be involved with neuron growth, can improve the neuron length and degree of branching over CNTs [11]. CNTs have many small additional sites that provide high surface area for external modification that’s why it is use as carrier to deliver the acetylcholine through blood brain barrier (BBB) and to treat Alzheimer Disease [14-16].

VIII. Tissue/Bone Regenreation: CNTs for the purpose of bone regeneration are being developed, which use negatively charged functional groups with calcium bonded to them. This can provide a scaffold to which hydroxyapatite, the most common inorganic component of bone, can attach. CNTs are very strong, stiff, and flexible which makes them an excellent alternative to the titanium or ceramic bone scaffolds [17,18].

IX. Carbon based nonmaterial by virtue of its therapeutic and diagnostic dual functions have emerged as theranostic nanomedicine. Carbon nanotubes intrinsic medicinal activities along with drug candidates may enhance the effectiveness of drug delivery. Unprecedented growth of patents and publication in last decade has forecasted the future of carbon based drug materials. A precise control for synthesis, purification and tools to increase solubility and further bio-functionality may lead to the development of carbon naotube based formulations. There is a need of clinical investigations for exploring the intrinsic medicinal activities of carbon nanotubes.

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Lupine Publishers | Carbon Nanotubes: Exploring Intrinsic Medicinal Activities and Biomedical Applications

 Lupine Publishers | Journal of Oncology

Introduction

Carbon Nano materials the king of nonmaterial’s have fascinating nanofamily including buckyballs or buckminsterfullerenes [1], multiwalled carbon nanotubes [2], the single-walled carbon naotubes(SWCNTs) [3], Carbon Nanohorns(CNHs), Carbon nanocones, Carbon nanofibers (CNFs), carbon nanothread, Buckypaper, carbon dots, nanodimons, nanoonions, nanorods, nanoribbons. Also called as powerful particles, CNTs (carbon nanotubes) has thus bloomed over the past decade [4,5]. Increasing evidence has shown that certain CNT properties such as nano-sized dimension, high surface energy, and large reactive surface area are directly correlated to their biological activities [6,7]. Great property of loading various biomolecules, diagnostic and therapeutic moieties resulting in diversified biomedical applications of CNTs (Figure 1).

Figure 1: Intrinsic Biomedical Applications of Carbon Nanotubes (CNT).

I. Diagonsis and Imaging: CNT act as biosensor or Nanorobots, which helps in diagnosis of disease, their progression level and their pathological condition in quick and better way. CNT biosensor are made up by conjugating different biochemicals with CNTs, like in glucuometer biosensor, glucose peroxidase is conjugated with CNTs that is use for the detection of blood sugar level in diabetic patients. Another example is SWCNTs-DNA biosensor that is use of detection of antigen –antibody comlex, which further helps in molecular diagnosis in pathology [7,8]. Complex of fluorescent agents and CNTs act as radio-opique agent that is use for the detection of cell and biological system in In-vivo organs [9].

II. Cancer Therapy: Carbon nantubes are effective against Pancreatic Cancer, Brain Cancer, Blood Cancer, Breast Cancer, Colon Cancer, Liver Cancer, Lymph Node, Metastasis, Prostate Cancer by using different anticancer drugs like Paclitaxel, Daunorubicin, Amphotericin B, Carboplatin, siRNA, Doxorubicin, Metal halides, Methotrexate etc. Apart from drug delivery route there are another two methods for cancer therapy using CNTs are immunotherapy and anti-tumor hyperthermia therapy [10].

III. Gene Therapy: CNTs and CNHs are used as vector in genetic engineering due to their cylindrical nature, which wrap the desired DNA and deliver it to target site to cure the genetic disorders by correcting misread or missense gene sequence [7].

IV. Infection/HIV Therapy: CNTs itself have antimicrobial activity by oxidising intracellular glutathione and resulted increase the oxidative stress on microbial cell that cause natural death of pathogen. CNTs also used in number of vaccinations to active immune response by triggering MHC-II, which further promote natural antibody production to stop the infection [11]. HIV( human immunodeficiency virus) that attack the immune response and decline the natural immunity, till date we cannot stop it completely but we can suppress or stop virus multiplication and control the disease .In this case conjugation of CNTs with siRNA that further deliver to T-Cell to stop virus proliferation [12].

V. Ocular Delivery: In case of ocular delivery there are number of challenges to deliver the drug to get adequate response with minimizing risk of infection. So therefore, SWCNTs-NH₃+ used as carrier to deliver antigen synthetic vaccination, safely and effectively by avoiding risk of necrosis and tissue degeneration [13].

VI. As Antioxidant: CNTs and CNHs are natural anti-oxidants. They are used in preserving drug molecules in formulation by inhibiting their oxidation. Furthermore, due to this property they are also used in anti-aging cosmetics products that oxidized the skin and stay it healthy and young [7].

VII. Neurodegenerative (ND)/Alzheimer Disease: Graphene sheets, and by extension CNTs, are excellent conductors of electricity, and thus are highly useful in the regeneration of neurons. Neurons can grow successfully on CNT beds, and modifying the surface with 4-hydroxyonoenal, known to be involved with neuron growth, can improve the neuron length and degree of branching over CNTs [11]. CNTs have many small additional sites that provide high surface area for external modification that’s why it is use as carrier to deliver the acetylcholine through blood brain barrier (BBB) and to treat Alzheimer Disease [14-16].

VIII. Tissue/Bone Regenreation: CNTs for the purpose of bone regeneration are being developed, which use negatively charged functional groups with calcium bonded to them. This can provide a scaffold to which hydroxyapatite, the most common inorganic component of bone, can attach. CNTs are very strong, stiff, and flexible which makes them an excellent alternative to the titanium or ceramic bone scaffolds [17,18].

IX. Carbon based nonmaterial by virtue of its therapeutic and diagnostic dual functions have emerged as theranostic nanomedicine. Carbon nanotubes intrinsic medicinal activities along with drug candidates may enhance the effectiveness of drug delivery. Unprecedented growth of patents and publication in last decade has forecasted the future of carbon based drug materials. A precise control for synthesis, purification and tools to increase solubility and further bio-functionality may lead to the development of carbon naotube based formulations. There is a need of clinical investigations for exploring the intrinsic medicinal activities of carbon nanotubes.

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Lupine Publishers | Calcium Supplementation: A Review of Oral Calcium Intake on Human Health

 Lupine Publishers | Journal of Oncology

Abstract

Adequate calcium intake is essential for the maintenance of bone health and the preservation of bone mineral density. The lay person believes that calcium is always good for health. Successful marketing and various clinical practice guidelines have made prescribing calcium supplements a billion dollar market in recent years. The aim of this study was to scan the literature and find out whether calcium supplements should be prescribed to all patients with fractures so as to improve their bone healing or should it be restricted to elderly post- menopausal females who have osteoporotic bones. The inference drawn was that dietary calcium is easier to absorb and may have beneficial effects as compared to calcium supplements and it should be limited to the total daily intake to 1000–1200 mg optimally from dietary sources. Calcium supplementation does not significantly reduce fracture risk in postmenopausal women but it reduces the risk of osteoporosis. It increases the risk of urolithiasis. A favourable role of calcium has been seen in postmenopausal women, elderly population, children and adolescents. Calcium is a double-edged sword, which may be both potentially crucial and perilous and hence should be prescribed with caution.

Keywords: calcium; Osteoporosis; Dementia; Kidney stones; Constipation

Introduction

A frequently asked question by a healthy, young lady presenting with a limb fracture being managed conservatively with immobilisation in a plaster is “Should I take Calcium supplementation so that my fracture heals well?.” Adequate calcium intake is essential for the maintenance of bone health during growing phases [1] and the preservation of bone mineral density in elderly individuals [2]. Calcium supplementation is a widespread practice in different age-groups and has been promoted widely to improve bone density [3]. The lay person believes that calcium is always good for health due to successful marketing and various clinical practice guidelines and prescribing calcium supplements has become a billion dollar market in recent years and has been taken by millions of both men and women, children, adults, and the elderly wishing to improve their skeletal health.

Aim

The aim of this review article was to find out whether calcium supplements should be prescribed to all patients with fractures so as to improve their bone healing or should it be restricted to elderly post- menopausal females who have osteoporotic bones.

Discussion

A. Introduction: Osteoporosis is one of the leading causes of disability in the elderly. Because calcium deficiency contributes to osteoporosis, daily dietary calcium intake of 1,000–1,200 mg is recommended [4]. Such a large calcium intake through diet alone can be difficult; therefore, calcium supplements are widely used [4]. Epidemiological studies have demonstrated that a significant number of population throughout the globe fail to achieve the recommended daily calcium intake [5]. In addition to its pivotal role in bone metabolism, the potential role of calcium in non-skeletal tissues has also been investigated, particularly in elderly people [6].

B. Role of Calcium: Calcium is an important and integrative component of human body with 99% of the body’s calcium being contained within the skeleton [7]. Calcium homeostasis plays a major role in maintaining human life activities, such as maintenance of the skeleton, regulation of hormonal secretion, transmission of nerve impulses, and vascular activities [8]. The homeostasis of calcium is mainly maintained by both parathyroid hormone (PTH) and calcitonin [9].

Benefits of Calcium Supplementation

A. Osteoporosis: Osteoporosis is a skeletal disorder associated with aging and characterized by compromised bone strength due to reduced bone mass and reduced bone quality leading to increased bone fragility thereby predisposing a person to increased risk of fracture, notably at the vertebrae, hip, and forearm. It is suggested that Vitamin D and calcium supplementation, either in the form of calcium supplements or dietary calcium, plays a positive role in prevention od osteoporosis in people of different ages and genders. Calcium supplementation plays a protective role for bone health, improving bone mass density (BMD) and decreasing morbidity of osteoporosis and osteoporotic fractures in different genders and age-groups [10].

B. Postmenopausal women: Bone remodelling is accelerated in the peri-menopausal and postmenopausal periods and is characterized by a decrease in estrogen production and an increase in resorption of calcium from bone resulting in a marked decrease in bone density. Calcium supplementation may be recommended in postmenopausal women with a history of osteoporotic fractures, a diagnosis of osteoporosis, vitamin D deficiency, or a high risk for osteoporosis (eg, primary ovarian insufficiency) [11] but are not of any proven benefit in primary prevention of fractures in community dwelling asymptomatic premenopausal women [12].

C. Pregnant and lactating women: Calcium supplementation in pregnant or lactating women for the skeletal health of foetus and mother is of doubtful benefit. In a study in pregnant women in Gambia, West Africa, with low calcium intakes, calcium supplement resulted in significantly lower bone mineral content, bone area, and BMD at the hip throughout 12-month lactation. The women also had greater decreases in bone mineral during lactation at the lumbar spine and distal radius and had biochemical changes consistent with greater bone mineral mobilization [13]. In pregnant and lactating women with low calcium intakes, calcium supplementation is recommended [14].

D. Children: For growing children, bone modeling (i.e., formation over resorption) is the predominant skeletal process which requires mineralization; hence, calcium requirements are increased, particularly during neonatal and pubertal growth spurts. For healthy children, there has been no recommendation for routine calcium supplementation, however children with a high risk of osteoporosis (eg, celiac disease, inflammatory bowel disease, or congenital bone disorder) or low calcium intake may benefit from calcium supplementation. In a study conducted in rural Gambian children accustomed to a low-calcium diet, calcium supplementation resulted in higher bone mineral content and BMD [15].

E. Cardiovascular System: A study conducted among an elderly Chinese population indicated that dietary calcium intake could reduce the risk of death from all causes and cardiovascular diseases [16]. Another study conducted among postmenopausal women revealed that high intake of dietary and supplemental calcium were associated with a decrease in the mortality of ischemic heart disease [17].

F. Gastrointestinal tract: A randomized, double-blind trial performed on people with a history of colorectal adenomas, receiving either 1,200 mg/d elemental calcium or placebo has revealed a significant reduction in the risk of recurrent colorectal adenomas with calcium supplementation6. Calcium carbonate is more often associated with gastrointestinal side effects, including constipation, flatulence, and bloating [18]. The explanation behind those findings is the ability of calcium to combine with bile acids in the intestines, reducing the rectal epithelial proliferation rate [19].

Adverse effects of Calcium Supplementation

A. Cardiovascular System: It is estimated by a metaanalysis (including eleven randomized controlled trials) that calcium supplements have up to 30% increase risk for myocardial infarction [20]. The explanation behind these findings is that calcium supplements potentially contribute to elevated serum calcium levels and possibly accelerated cardiovascular calcification [21].

B. Gastrointestinal Diseases: Calcium supplements may increase the incidence of constipation, severe diarrhoea, and abdominal pain [22].

C. Renal Stones: A major concern regarding the safety of calcium has been the occurrence of kidney stones. An abnormality of urinary super-saturation is one of the main factors for the formation of kidney stones23. Individuals who consumed any amount of supplemental calcium had an increased risk for kidney stones compared with individuals who did not consume supplemental calcium [24].

D. Age Related Macular Degeneration: A recent crosssectional study found that >800 mg/d of calcium consumption in people aged >67 years may increase the risk of age related macular degeneration compared with those who do not take calcium [25].

E. Dementia and Alzheimer’s Disease: Some trials have reported an association between calcium supplementation and increased risk for vascular events [26]. Vascular risk factors are related to vascular dementia and Alzheimer disease [27]. Calcium supplementation might have direct toxic effects on vulnerable neurons, because the increased calcium levels may amplify ischemic cell death and worsen the outcome after cerebrovascular events [19]. calcium influx and intracellular calcium overload have a crucial role in apoptosis and necrosis [28]. The mechanism of calcium supplements in the pathogenesis of dementia could be the steep increase in serum calcium levels caused by the supplements [20]. Calcium plays a central role in the mechanisms of cell death. In necrosis, the transmembrane influx of calcium ions activates proteases that are responsible for degrading critical proteins and disrupting membrane function [29].

F. Dietary Calcium: Dairy products in the form of milk, yogurt, and cheese are rich sources of calcium. About 72 percent of calcium comes from milk, cheese and yogurt and from foods to which dairy products have been added as in pizza, lasagna, dairy desserts. The remaining calcium comes from vegetables (7 percent); grains (5 percent); legumes (4 percent); fruit (3 percent); meat, poultry, and fish (3 percent); eggs (2 percent); and miscellaneous foods (3 percent) [30].

G. Difference between Dietary Calcium and Supplementary Calcium: The difference between dietary calcium and calcium intake by supplements could be explained by variations in corresponding changes in serum calcium concentration. Dietary intake does not increase the serum calcium levels to the same extent as supplements20. In addition, dietary calcium intake involves simultaneous intake of all other components of calciumcontaining foods and much lower dosages of calcium than calcium supplements.

Conclusion

Dietary calcium is easier to absorb and may have beneficial effects as compared to calcium supplements. Calcium from food sources has not been linked to morbidity, so limiting dietary consumption would not be advised. The recommendation should be to limit the total daily intake to 1000–1200 mg, optimally from dietary sources. Different dosages of calcium may induce different results. A favourable role of calcium has been seen in postmenopausal women, elderly population, children and adolescents. Calcium prevents osteoporosis but at the same time, increases the occurrence of cardiovascular diseases and risk of urolithiasis. Calcium supplementation does not significantly reduce fracture risk in postmenopausal women but it reduces the risk of osteoporosis. Calcium is a double-edged sword, which may be both potentially crucial and perilous and hence should be prescribed with caution. The issue of safety in people receiving calcium has long been a matter of debate. There is an abundance of data for beneficial effects and side effects in the literature on the role of calcium. All taken together, it is important to balance the advantages and disadvantages of calcium supplementation on human health [31].

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Lupine Publishers | What is beyond the Nivolumab Monotherapy approval for advanced Hepatocellular Carcinoma?

 Lupine Publishers | Journal of Oncology and Medicine

Keywords: Hepatocellular carcinoma; Immune checkpoint inhibitors; Nivolumab; FDA

Editorial

With an estimated 500,000 new cases per year, hepatocellular carcinoma (HCC) represents the third leading cause of cancer death worldwide. The incidence is rising in the west, largely due to an increasing incidence of hepatitis C virus infection [1]. The majority of HCC patients are diagnosed with disease too advanced for curative treatment. Only liver resection and liver transplantation are considered curative, with poor efficiency of other modalities such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE), although this may provide a modest prolongation in survival; however, the relapse in the majority of these patients is inevitable [2]. An array of translational research and pilot clinical trials have revealed that adoptive immunotherapy's are safe by patients with HCC, but they lack efficacy [3]. Now, we are in the new era of immunotherapy's such as immune checkpoint inhibitors and CAR-T strategies, which would bring benefit to the HCC patients.

On September 22, 2017, the Food and Drug Administration granted accelerated approval to nivolumab (OPDIVO, Bristol- Myers Squibb Co.) for the treatment of HCC in patients who have been previously treated with sorafenib. The approval was based on a 154-patient subgroup of CHECKMATE-040 (NCT 01658878), a multicenter, open-label trial conducted in patients with HCC and Child-Pugh. A cirrhosis who progressed on or were intolerant to sorafenib. Patients received nivolumab 3 mg/kg by intravenous infusion every two weeks. The confirmed overall response rate, as assessed by blinded independent central review using RECIST 1.1, was 14.3% (95% CI: 9.2, 20.8), with three complete responses and 19 partial responses. The response duration ranged from 3.2 to 38.2+ months; 91% of responders had responses lasting six months or longer and 55% had responses lasting 12 months or longer. Adverse reactions occurring in patients with HCC in CHECKMATE-040 were similar to those previously reported in product labelling, with the exception of a higher incidence of elevations in transaminases and bilirubin levels [4].

There are other immune checkpoint inhibitors that are being tested as monotherapy for efficacy and safety in HCC. Nivolumab was the first approved, but others will follow, as it has occurred in other malignancies. There is a bunch of possibilities for the treatment strategy using immune checkpoint inhibitors. Future directions point to various stages of HCC treatment, such as neo adjuvants and adjuvants after resection and ablation, combination therapy with transcatheter arterial chemoembolization, first-and second-line treatments, and all sorts of combinations with other immunotherapies, targeted molecules and novel therapies.

In the table annexed to this editorial you will find a list of ongoing clinical trials combining the immune checkpoint inhibitors with other therapies. At the top of the Table 1 are listed the trials with simultaneous blockage with anti-PD-1/PD-L1 and anti- CTLA-4 antibodies, which are expected to be promising regimens in HCC immunotherapy. The high efficacy of the combination therapy was demonstrated in malignant melanoma [5]. Simultaneous inhibition of the B7-CTLA-4 pathway by an anti-CTLA-4 antibody may increase the number of activated CD8+ T cells in lymph nodes, followed by an increase in the number of activated CD8+ T cells infiltrating the tumour tissues, thereby enhancing the antitumor effects. Their combination with molecular targeted agents (e.g., sorafenib or axitinb) also appears promising.

Table 1: Summary of ongoing trials with immune checkpoint inhibitors in HCC.

In particular, the approach combining an immune checkpoint inhibitor with an existing loco regional therapy for HCC is currently under evaluation. TACE or RFA is expected to enhance the effects of immunotherapy by inducing local inflammation, releasing gneoantigens that activate antigen presentation and immune system activation. The results of the combination therapy with anti- CTLA-4 antibody and loco regional therapy in advanced HCC have recently been published [6]. The NCT01853618 study evaluated the efficacy of adjuvant therapy with tremelimumab (anti-CTLA-4 antibody) after RFA or TACE in several, but not all, HCC nodules, with favourable outcomes, including a partial response rate of 26%, time to tumor progression of 7.4 months, and overall survival of 12.3 months.

The results of trials of the immune checkpoint inhibitor- combined strategies are awaited with high expectations by the medical community.

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Lupine Publishers | Cancer and Advantages of Immunosuppression

 Lupine Publishers | Journal of Oncology

Abbrevations: NK: Natural Killer; GVHD: Graft-vs-Host Disease; CRS: Cytokine Release Syndrome

Editorial

As oncologists learn to target the immune response to “self and non-self,” a delicate therapy balance will eventually be achieved with predictable outcomes, benefits, and toxicity in the fightThe study of how the immune system recognizes friend and foe, or as the immunologist Sir Macfarlane Burnet phrased it, “distinguishes between self and non-self,” has driven important discoveries that are transforming our ability to treat cancer.

Over the last few clinicians have unraveled the interactions (both innate and adaptive immunity) that lead to the eradication of viruses, bacteria, parasites, and now, cancer. Notable cellular players include T cells, B cells, natural killer (NK) cells, neutrophils, eosinophils, basophils, dendritic cells, and macrophages, along with a host of secreted mediators - antibodies, complement, cytokines, and chemokines - each of which fulfills particular immunologic functions. Processes, autoimmune disease can be a consequence. These diseases also occur if shared. When the immune system fails to regulate these antigens are recognized by the immune system in cells; one example is Lambert-Eaton syndrome. Monoclonal antibodies that target tumour reactive T cells (eg, nivolumab and pembrolizumab) can also cause autoimmune disease; other examples include graft-vs-host disease (GVHD) in allogeneic bone marrow transplant recipients and cytokine release syndrome (CRS), which is associated with adoptive T cell therap.

ute Myeloid Leukemia (AML). Blood 128: 763.

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Lupine Publishers | Targeting the Immune Checkpoint in Cancer: Is This a Viable Treatment Option for AML?

 Lupine Publishers | Journal of Oncology 

Abbrevations: AML: Acute Myeloidleukaemia; CBF: Core Binding Factor; mAb: Monoclonal Antibody; MDS: Myelodysplastic Syndrome

Editorial

The immune suppressive mechanisms displayed by malignant cells are considered a central process in the pathogenesis of cancer. Research in this area has gained significant momentu mover the past 20 years, with several immune checkpoints identified, including; CTLA-4, CD200/CD200R, Tim-3/Galectin-9 and PD-L1/PD-1 (Figure 1). Whilst characterising the molecular basis of leukaemia for risk stratification remains at the forefront of AML research; this must now extend to understating how the seimmune checkpoint path ways fit into the equation. A good example of why this is important is to consider CD200expression level in AML, which is a negative prognostic indicator [1]. CD200 is an immunosuppressive lig and, that when engaged with its receptor CD200R, has the capacity to attenuate T-cell and NK-cell anti-tumour activity in AML. Interestingly, most cases of CBF AML express high levels of CD200, yet CBF AML performs relatively well clinically. This paradox suggests there is a complex interplay between AML molecular heterogeneity and immune surveillance. Given the recent development and FDA approval of several immune checkpoint therapies, a full understanding of these processes and integration with standard molecular risk stratification is warranted.

Figure 1: Illustrated are immune checkpoint legends expressed on AML blast cells (left) with the cognate T-cell receptors (right), including; CD200/CD200R, PD-L1/PD-1, CTLA-4, CD47 and Galectin-9/Tim-3. Currently clinical trials are exploring the therapeutic potential CD200, PD-1 and CTLA-4 with the mAb’s Samalizumab, Pembrolizumab/Nivolumab and Ipilimumab respectively. CD47 mAb therapy is at a preclinical stage.

The immune checkpoint story is becoming complex for AML, since several studies report that that these immune surveillance pathways function in tandem. For example, the Galectin-9/Tim-3 immune checkpoint has been shown to cooperate with the PDL1/ PD-1 pathway in AML, which is central in driving CD8+ T-cell exhaustion. Thus targeting both Tim-3/Galectin-9 and PD-L1/PD-1 was required to achieve significant cyto reduction and improved survival in pre-clinical models [2]. Another study illustrated that the CD200/CD200R and PD-L1/PD-1 immune checkpoints are also linked in AML. In this instance, activation of CD200R was sufficient to drive the up regulation of PD-1 on memory CD8 T-cells. Further analysis relaveled that targeting both CD200/CD200R and PD-L1/ PD-1 immune checkpoints were required to significantly restore memory CD8 T-cell function [3].

This finding indicates that these immune checkpoints may be important in driving AML relapse. Indeed, this notion is realised in a current phase-II trial (NCT02708641), which is assessing the effects of the PD-L1/PD-1 checkpoint inhibitor ‘Pembrolizumab’ as a post-remission treatment in AML. The potential use of targeting the immune checkpoint in post-remission is also recognised in findings published from a recent phase-IB/II study involving the PD-L1/PD-1 checkpoint inhibitor ‘Nivolumab’. The report shows that when used in combination with azacytidine for relapsed AML, Nivolumab showed an improvement in prognosis and increased numbers of effectors CD8+ T-cells [4]. Given that the PD-L1/ PD-1 checkpoint functions in combination with other immune checkpoints, the question now is to understand whether targeting a combination of these pathways in AML performs well clinically.

To this end, results from a current phase-II trial (NCT02530463) targeting PD-L11/PD-1 with Nivolumab in combination with the CTLA-4 inhibitor ‘Ipilimumab’ in MDS are eagerly awaited. As are the next generation of therapeutic mAb’s such as ‘Samalizumab’ (Alexion Pharmaceuticals), which is designed to target the CD200/ CD200R checkpoint. The potential for immune checkpoint therapy in AML is clearly evident, however the interplay between these pathways needs full appreciation and placed into context with molecular stratification and standard therapy (Figure 1).

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Lupine Publishers | Acute Erythroblastic Leukemia Revealed by Dermatological Manifestations

 Lupine Publishers | Journal of Oncology

Abstract

Acute erythroblastic leukemia is characterized by the proliferation of a predominant erythrocyte population on other lineages. Cutaneous manifestations remain rare and misleading, making the diagnosis of difficult to suspect as first-line. Here, we report an unusual and rare case of acute leukemia in a 24 year old male with gingival hypertrophy and dermatological manifestations. This case emphasizes that dentist and dermatologist should be well acquainted with these manifestations of systemic diseases.

Case Report

We report the case of 24 years old patient, with no significant pathological history, who had a rash for 10 days in a context of fever and very bad general condition. At admission the patient was febrile, tachycardic and dyspneic. Physical examination revealed erythemato-purplished papulo-nodules on the face, trunk, limbs and a gingival hyperplasia. The oral state was deplorable. Bilateral cervical lymphadenopathy was also found without the patosplenomegaly (Figures 1-3). The biological assessment showed a CRP of 150 and a pancytopenia with a Hbat 7.5g / dl, normal VGM and CCMH, a deep thrombocytopeniaat 85000 / l, leukocytesat 1500 / l. The blood smear showed 35% of circulating blasts and 22% of erythroblasts (Figure 4).

Figure 1: Clinical Manifestations of AML.

Figure 2: Clinical Manifestations of AML.

Figure 3: Clinical Manifestations of AML.

Figure 4: Blood smear showing 35% of circulating blasts.

The medullo gram showed a hyper-cellular marrow with a rate of myeloblasts greater than 45% compared to all non-erythroblastic elements and erythroblastic hyperplasia estimated at more than 65%; with signs of dyserythropoiesis suggestive of the diagnosis of erythroleukemia (Figure 5). Blood immune phenol typing was positive for CD13, CD33, MPO and Glycophotin A. The evolution was unfavourable; the patient died due to massive alveolarhemorrhage.

Figure 5: Hyper cellular marrow infiltrated by a blastic contingent estimated at 45%.

Discussion

Acute erythroblastic leukemia is characterized by the proliferation of a pre dominantery throcyte population on other lineages. There are two types: Erythroleukemia: defined by the presence in the bone marrow of more than 50% of the erythroid precursors of all the medullary cells, and more than 20% of myeloblasts of the whole non-erythrocytemedullary cells - Pure erythroid leukemia: it presents a neoplastic proliferation made of more than 80% of erythrocyte cells without obvious presence of the myeloblastic contingent [1]. It is usually manifested by signs of bone marrow failure and cytopenia [2,3], skin involvement remains rare, varied and disorienting the diagnosis; they are found mainly in Acute myelovlastic leukemia [4,5]. Cutaneous manifestations during leukemia are infrequent and varied. They designate all the cutaneouslesions related to the haematological malignancy directly or indirectly following their treatment; we essentially distinguish.

The specific dermatological lesions which can reveal hematological diseases [4], are mainly represented by leukaemides (leukaemia cutis), which are red brown to purple dermal papules, plaques or nodules. Granulocyticsarcom as an extra-medullary tumour masses, ulcerated plaques and gingival hypertrophy [5]. The infectious dermatoses secondary to the biological disturbances accompanying the malignan themopathy and their treatments. The occurrence of specific cutaneouslesions in leukemia is synonymous with a major aggravation of the prognosis (with for example a survival twice as short if there is a specific cutaneous involvement); this seriousness make some authors propose different treatments with a medium-long stay hospitalization[6-8].

In our case, acute myelonlastic leukemia 6 (AML 6 ) was revealed by diffuse leukemias resulting from the infiltration and proliferation of malignantha ematological cells (blasts) in the skin and by gingival hyperplasia secondary to mucosal infiltration [5]. The clinical presentation of acute leukemia including AML6 in the form of ulcer ativenecroticgingivitis in the foreground, is a rare form to be remembered, mentioned in all courses of medicine and dentistry, stipulating that Gingival involvement is a classic feature of leukemia [6] The frequent association of skin cancers with haematological malignancies is also highlighted in several publications [5].

Conclusion

The cutaneous localizations are among the rarest extreme dullary lesions of acute myeloid leukaemia’s (AML) not exceeding 1%. They are generally considered as factors of worse prognosis. Their cytogenetic or mutational specificities remain un established to date.

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Lupine Publishers | Promising Role of Fractional Calculus in Biomedicine and Biophysics

 Lupine Publishers | Journal of Oncology

Introduction

The study of complex systems and investigation of their structural and dynamical properties have attracted considerable interests among scientists in general and physicists, biologists and medical researchers in particular. Complex systems can be found almost everywhere however the highest level of complexities is related to living and biological organisms and systems. Due to the lack of a reliable and effective tool to investigate such systems, we have not reached to the complete understanding and comprehensive pictures of the phenomena and processes which occur in these systems. Of course a comprehensive knowledge of biological and biomedical complex phenomena will be achieved when we employ simultaneously different field of science and engineering including: biology, chemistry, physics, mathematics, mechanical engineering and so on.

Fortunately in recent year's powerful tool of fractional calculus has been proposed for study of complex and nonlinear phenomena. It is in fact very useful tool for describing the behavior of nonlinear systems which are characterized by: special kind of non-locality, long-term memory and fractal properties. There exist many biological objects and systems with memory, nonlocal effects and nonlinear behaviors and such these non-localities and memory effects in biological objects and systems mean that the next state of the organism or system relies not only on its present state but also upon all of its previous states. As a result, the concept of fractional dynamics and in fact adopting fractional calculus can play an important role in the study of dynamical biological systems. Up to now few number of important issues such as: protein folding phenomena and mechanics of cancer cells (for more details see the references which have investigated physics of protein and physics of cancer in detail) have been investigated using the framework of fractional dynamics [1].

However many other important issues still remain as open issues, such as: modeling of interactions between light (laser) and biological tissue and modeling of intracellular (and intercellular) interactions in the framework of fractional dynamics. As a physicist or biologists and even medical researchers, we always are able to model natural phenomena for instance modeling of tumor growth using systems of differential equations and nowadays it is well know that the fractional-order ones are more comprehensive and also incorporate memory effect and the concept of non-locality in the model.

Mathematically the idea is in fact, to rewrite the ordinary governing differential equations in the fractional form by replacing the standard derivative with a fractional derivative of arbitrary order which is defined in the Caputo sense as follows:

where Γ denotes the Gamma function and , . And its Laplace transform can be given by:

Where, F(s) is the Laplace transform of f (t). Solutions of fractional differential equations generally will be expressed using a generalized special function named as Mittag-Leffler function. This function can be considered as a generalized exponential function and has several different forms. For instance the one-parameter Mittag-Leffler function is defined by the series expansion as:

Where C is the set of complex numbers? It is worth mentioning that the exponential function is just a special case of α = l Mittag-Leffler function, for example for the special case of , the Mittag-Leffler function Eq. (3) reduces to the exponential function E₁(z) = e^z . This point is very important because of that the natural exponential function has been considered as a fundamental function of natural science and in particular biology up to now, so that many phenomena could be described using it and now scientist are able to think that with such this new framework (i.e. fractional differential equations and their solutions in terms of Mittag-Leffler functions) they can find many new results and information about biological and biomedical phenomena [2,3].

Finally, based on all above mentioned reasons, as a conclusion we should say that we believe that the powerful tool of fractional calculus and in fact the frame work of fractional dynamics can give.com new insights in understanding and modeling of nonlinear complex phenomena in various living cellular structures and their interactions and we invite all biologist and medical researchers to consider this new powerful approach for their future studies.

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