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However, studies conducted in , [22] , [23] and [24] summarize that alcohol-containing mouth rinses are not associated with oral cancer. In a March brief, the American Dental Association said "the available evidence does not support a connection between oral cancer and alcohol-containing mouthrinse". Infection with human papillomavirus HPV , particularly type 16 there are over types , is a known risk factor and independent causative factor for oral cancer.

This new and rapidly growing sub population between 30 and 50 years old, [29] is predominantly nonsmoking, white, and males slightly outnumber females. Recent research from multiple peer-reviewed journal articles indicates that HPV16 is the primary risk factor in this new population of oral cancer victims.

HPV16 along with HPV18 is the same virus responsible for the vast majority of all cervical cancers and is the most common sexually transmitted infection in the US. Oral cancer in this group tends to favor the tonsil and tonsillar pillars, base of the tongue, and the oropharynx. Recent data suggest that individuals that come to the disease from this particular cause have a significant survival advantage, [30] as the disease responds better to radiation treatments than tobacco caused disease.

Chewing betel , paan and Areca is known to be a strong risk factor for developing oral cancer even in the absence of tobacco. It increases the rate of oral cancer 2. People after hematopoietic stem cell transplantation HSCT are at a higher risk for oral squamous cell carcinoma. A premalignant or precancerous lesion is defined as "a benign, morphologically altered tissue that has a greater than normal risk of malignant transformation. Some oral cancers begin as white patches leukoplakia , red patches erythroplakia or mixed red and white patches erythroleukoplakia or "speckled leukoplakia".

Other common premalignant lesions include oral submucous fibrosis and actinic cheilitis. This condition is characterized by limited opening of mouth and burning sensation on eating of spicy food. This is a progressive lesion in which the opening of the mouth becomes progressively limited, and later on even normal eating becomes difficult. It occurs almost exclusively in India and Indian communities living abroad.

Nanotechnology: a promising method for oral cancer detection and diagnosis

Oral squamous cell carcinoma is the end product of an unregulated proliferation of mucous basal cells. A single precursor cell is transformed into a clone consisting of many daughter cells with an accumulation of altered genes called oncogenes. What characterizes a malignant tumor over a benign one is its ability to metastasize.

This ability is independent of the size or grade of the tumor often seemingly slow growing cancers like the adenoid cystic carcinoma can metastasis widely. It is not just rapid growth that characterizes a cancer , but their ability to secrete enzymes, angiogeneic factors, invasion factors, growth factors and many other factors that allow it to spread.


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Diagnosis of oral cancer is completed for 1 initial diagnosis, 2 staging , and 3 treatment planning. A complete history, and clinical examination is first completed, then a wedge of tissue is cut from the suspicious lesion for tissue diagnosis.

Age, gender, race, and ethnicity

This might be done with scalpel biopsy, punch biopsy , fine or core needle biopsy. In this procedure, the surgeon cuts all, or a piece of the tissue, to have it examined under a microscope by a pathologist. With the first biopsy, the pathologist will provide a tissue diagnosis e. They may add additional information that can be used in staging, and treatment planning, such as the mitotic rate , the depth of invasion , and the HPV status of the tissue.

Other, more invasive tests, may also be completed such as fine needle aspiration , biopsy of lymph nodes , and sentinel node biopsy. When the cancer has spread to lymph nodes, their exact location, size, and spread beyond the capsule of the lymph nodes needs to be determined, as each can have a significant impact on treatment and prognosis. Small differences in the pattern of lymph node spread, can have a significant impact on treatment and prognosis.

Panendoscopy may be recommended, because the tissues of the entire upper aerodigestive tract are generally affected by the same carcinogens , so other primary cancers are a common occurrence. From these collective findings, taken in consideration with the health and desires of the person, the cancer team develops a plan for treatment.

Since most oral cancers require surgical removal, a second set of histopathologic tests will be completed on any tumor removed to determine the prognosis, need for additional surgery, chemotherapy, radiation, immunotherapy, or other interventions. There are a variety of screening devices, however, there is no evidence that routine use of these devices in general dental practice is helpful.

Such harms include false positives, unnecessary surgical biopsies and a financial burden. Oral cancer is a subgroup of head and neck cancers which includes those of the oropharynx , larynx , nasal cavity and paranasal sinuses , salivary glands , and thyroid gland. Oral melanoma , while part of head and neck cancers is considered separately. Oral cancer staging is an assessment of the degree of spread of the cancer from its original source. The evaluation of squamous cell carcinoma of the mouth and pharynx staging uses the TNM classification tumor, node, metastasis.

This is based on the size of the primary tumor, lymph node involvement, and distant metastasis. TMN evaluation allows the person to be classified into a prognostic staging group; [40]. Oral cancer squamous cell carcinoma is usually treated with surgery alone, or in combination with adjunctive therapy, including radiation, with or without chemotherapy.

In most centres, removal of squamous cell carcinoma from the oral cavity and neck is achieved primarily through surgery. This also allows a detailed examination of the tissue for histopathologic characteristics, such as depth, and spread to lymph nodes that might require radiation or chemotherapy. For small lesions T , access to the oral cavity is through the mouth. When the lesion is larger, involves the bone of the maxilla or mandible , or access is limited due to mouth opening, the upper or lower lip is split, and the cheek pulled back to give greater access to the mouth.

Spread of cancer from the oral cavity to the lymph nodes of the neck has a significant effect on survival. Where the neck lymph nodes have no evidence of involvement clinically, but the oral cavity lesion is high risk for spread e. T2 or above lesions , then a neck dissection of the lymph nodes above the level of the omohyoid muscle may be completed. Chemotherapy and radiotherapy are most often used, as an adjunct to surgery, to control oral cancer that is greater than stage 1, or has spread to either regional lymph nodes or other parts of the body. Chemotherapy is useful in oral cancers when used in combination with other treatment modalities such as radiation therapy but it is not used alone as a monotherapy.

When a cure is unlikely, it can also be used to extend life and can be considered palliative but not curative care. Monoclonal antibody therapy with agents such as cetuximab have been shown to be effective in the treatment of squamous cell head and neck cancers, and are likely to have an increasing role in the future management of this condition when used in conjunction with other established treatment modalities, although it is not a replacement for chemotherapy in head and neck cancers. Adding epidermal growth factor receptor monoclonal antibody EGFR mAb to standard treatment may increase survival, keeping the cancer limited to that area of the body and may decrease reappearance of the cancer.

Following treatment, rehabilitation may be necessary to improve movement, chewing, swallowing, and speech. Speech and language pathologists may be involved at this stage. Treatment of oral cancer will usually be by a multidisciplinary team, with treatment professionals from the realms of radiation, surgery, chemotherapy, nutrition, dentistry, and even psychology all possibly involved with diagnosis, treatment, rehabilitation, and care. Due to the location of oral cancer, there may be a period where the person requires a tracheotomy and feeding tube.

Survival rates for oral cancer depend on the precise site and the stage of the cancer at diagnosis. Similar survival rates are reported from other countries such as Germany. Globally, it newly occurred in about , people and resulted in , deaths in In , oral cancer resulted in , deaths, up from 84, deaths in Europe places second-highest after Southeast Asia among all continents for age-standardised rate ASR specific to oral and oropharyngeal cancer. It is estimated that there were 61, cases of oral and lip cancer within Europe in Additionally, there is a regional variability within the UK, with Scotland and northern England having higher rates than southern England.

The same analysis applies to lifetime risk of developing oral cancer, as in Scotland it is 1. Oral cancer is the sixteenth most common cancer in the UK around 6, people were diagnosed with oral cancer in the UK in , and it is the nineteenth-most -common cause of cancer death around 2, people died from the disease in The highest incidence of oral and pharyngeal cancer was recorded in Denmark, with age-standardised rates per , of The highest rates for mortality in were reported in Lithuania 7.

Hungary The incidence rates of oral cancer in western Europe found France, Germany and Belgium to be highest. The ASRs per , were When filtered by gender category, the same countries rank top 3 for male, however, in different order of Belgium Incidence of oral and oropharyngeal cancers were recorded, finding Portugal, Croatia and Serbia to have highest rates ASR per , These values are In , close to 37, Americans are projected to be diagnosed with oral or pharyngeal cancer.

It will cause over 8, deaths. Of those newly diagnosed, only slightly more than half will be alive in five years. Similar survival estimates are reported from other countries. Oral cancers overall risk higher in black males opposed to white males, however specific oral cancers-such as of the lip, have a higher risk in white males opposed to black males. Overall, rates of oral cancer between gender groups male and female seem to be decreasing, according to data from 3 studies. New cases of oral cancer in US as of , approximated almost 66, with almost attributed from tongue cancer, and nearly from the mouth, and the remainder from the oral cavity and pharynx.

In the previous year, 1. In Brazil, however, lip and oral cavity cancer is the 7th most common cancer, with an estimated 6, new cases diagnosed in the year This number is rising and has an overall higher ASIR at 7. Rates are increasing across both males and females. As of , almost new cases of oropharyngeal cancers will be diagnosed, with incidence rates being more than twice as high in men than women.

Oral cancer is one of the most-common types of cancer in Asia due to its association with smoking tobacco, bidi , betel quid and alcohol consumption. However, in some areas, specifically South East Asia, similar rates were recorded for both genders. Oral cancer is the third-most-common form of cancer in India with over 77 new cases diagnosed in 2.

There is limited data for the prevalence of oral cancer in Africa. The following rates describe the number of new cases for incidence rates or deaths for mortality rates per individuals per year. The incidence rate of oral cancer is 2. The rate is higher in males at 3.

The mortality rate is lower than the incidence rate at 1. The rate is again higher for males at 2. The following rates describe the number of new cases or deaths per individuals per year.

Oral Cancer

The incidence rate of oral cancer is 6. The rate is higher in males at 1. The data suggests lip cancer has the highest incidence rate while gingival cancer has the lowest rate overall. In terms of mortality rates, oropharyngeal cancer has the highest rate in males and tongue cancer has the highest rate in females. Lip, palatal and gingival cancer have the lowest mortality rates overall. AS is an example of a DNA aptamer that has progressed to clinical trials testing.

The aptamer in this case specifically targets nucleolin protein and has been trialed with metastatic, clear-cell, renal cell carcinoma patients who have been refractory to prior tyrosine kinase inhibitors [48]. The culture supplement was purchased from Sigma Aldrich. All cell cultures were carried out using pre-warmed reagents. The organotypic invasion assay and the quantitation of results were performed as described in Nurmenniemi et al. The media were collected, centrifuged, and fresh media with inhibitors were changed at days 4, 7, 10 and Nine representative images were taken from each of the three repeats of every treatment.

Images were analyzed as described in Nurmenniemi et al. Differences in the invasion area and depth were evaluated using a Student's t-test and Mann-Whitney test and p-values less than 0. The absorbance recorded at nm on a FLUOstar Optima plate reader was used as a representation of the relative number of living cells in culture. Gels were stained using ethidium bromide and viewed under UV light.

Fluorimeter used was a Horiba Jobin Yvon Fluoromax-P equipped with a photon counter and Peltier system for temperature control and stirring facility, coupled to a PC utilizing Datamax software for spectral analysis. Initial measurements were taken to verify the presence or absence of fluorescent emission of both aptamers for excitation wavelength of nm selective for tryptophan residues and emission wavelengths between and nm. Both aptamers were titrated in water and 10 mM phosphate buffer solutions pH 7. The 1. Both aptamers presented fluorescence emission spectra in this range.

Earlier tests showed that aptamer concentrations ranging from 0. Emission spectra were registered from to nm wavelength, after a reaction time of 90 sec from each aptamer addition. Both emission and excitation bandwidth were set to 3 nm. Aptamer was added from a concentrated stock solution so that the volume increment was negligible.


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The invasion of HSC-3 cells was studied with a human myoma organotypic model [49] exposing the carcinoma cells to various aptamers Unrelated, 1. Aptamer 1.

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On the contrary, none of the other compounds had an effect on HSC-3 invasion Figure 1. Similarly, the media analyzed by RIA from day 4 did not show differences between any of the treatments not shown. On day 10 there was a significant inhibition by 1. However, 3 M, Pink, and Yellow aptamers, as well as BAFB showed no significant decrease in the amount of collagen degradation products, indicating that they were not successful inhibitors of invasion.

The statistics were done as two-sample t -test and Mann-Whitney test. Increasing absorbance means less collagen degradation product present. B: The graph shows previous EIA values adjusted for negative control at day 10 media change.

Oral Cancer: MedlinePlus

Increasing levels mean less collagen degradation product. D: RIA has confirmed the EIA assays showing significantly lower collagen degradation products than that for tissues without inhibitor added, indicating that they were successful inhibitors of invasion. The cytotoxicity of the selected aptamers on HSC-3 cells was studied, to verify that the inhibition of invasion observed in the organotypic model was a result of the inhibition of the heparanase, as previously verified [46] and not cell cytotoxicity.

The MTS assay was performed over 72 hrs, with a single addition of the aptamer in the beginning of the assay, and measurements over the period intervals of 24, 48 and 72 hrs. No change in cell viability and cell growth was observed between the cells where aptamer was added and the control see Figure 3. Only the aptamers that showed inhibition of invasion were tested for cytotoxicity, to investigate if the inhibitory effect observed was due to cytotoxicity or inhibition of heparanase.

Aptamers that do not inhibit cell invasion clearly have no effect on the cells and therefore there was no reason to be further studied for cytotoxicity. The presence of the aptamer at 1 mM concentration was found to have no effect on the cell growth in comparison with the control. Short and long aptamers 1. Both aptamers have intrinsic fluorescence with peaks at nm, which increases in fluorescence intensity upon a corresponding increase of the aptamer concentration; the short showing less fluorescence than the long aptamer Figure 4A and B.

Water was used as a diluent to show that the aptamer and not phosphate buffer solution was the cause of the fluorescence, although the fluorescence for the short aptamer increased upon using phosphate buffer solution as the diluent. However, this was likely due to a difference in pH as in fluorescence spectroscopy pH changes have a significant influence on results. Fluorescence increases upon increasing the concentration of aptamer in both phosphate and water, showing that although the fluorescence is higher in phosphate, the aptamer is in fact the cause and the pH difference in water and PBS is the most likely reason for the increase of fluorescence of the aptamer in PBS.

The results show that both aptamers are able to quench the fluorescence of HSA, although the long aptamer was more effective. HSA quenching indicates that the aptamers reach sub domain IIA, where its single tryptophan is located. This tryptophan residue is located at site in subdomain IIA, within which there is a large hydrophobic cavity with many arginine residues near the surface [53] , which have been shown in different studies to serve as anchor points for aptamers [54]. Excitation wavelength at mM in a solution of sodium phosphate.

The quenching effect is more considerable for long than short aptamer. The addition of both aptamers to phosphate buffer and HSA increased the overall absorbance, showing that the aptamer was responsible for this increase rather than HSA. The increase was more pronounced for the long aptamer over the short aptamer, and both produced a shift of the maximum absorbance to the left upon addition of increasing concentrations of aptamer.

The shift observed from the short aptamer Figure 6A moved 6 nm to the left, suggesting that only a slight conformational change in the protein was occurring [55] and therefore, HSA quenching by this aptamer is most likely due to dynamic quenching. However, in the case of the long aptamer Figure 6B , not only was there a substantial shift in the maximal absorption by 20 nm to the left, but a complete change in the shape of the peak was observed, incorporating the peak at nm of the aptamer, suggesting that one complex was formed and that the quenching was due to the static quenching phenomenon with long aptamers [55].

Thus, the UV titrations suggested that the short aptamer did not form a complex with HSA and that the interactions were due to dynamic quenching, whereas the long aptamer was suggested to form a ground state complex with HSA, in contrast with other aptamers previously studied, which also show specificity and complex formation only with their target protein [56].

This work has been expanded and interactions of the aptamers with serum proteins and the specific position of their interaction has been calculated and published separately, as it was not within the scope of this article [57]. To assess the aptamers' suitability as therapeutic agents, it was necessary to have an understanding of how stable the unmodified aptamers would be in the body, as, in the bloodstream alone, there are many nucleases capable of degrading the aptamers.

Thus, to verify the stability of the aptamers in human serum, we have characterized any degradation products by gel electrophoresis.


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Comparison of bands on the gels for 1. With mouse serum, however, there was a decrease in primary band intensity at five hours' incubation time, suggesting that nucleases have degraded the aptamer by that time. In this study we have explored the potential of previously selected aptamers against heparanase as promising diagnostic and therapeutic agents against oral cancer. The aptamers were previously shown to have high affinity against heparanase and were functional in a Matrigel assay.

On these initial studies, it was found that the longer aptamers had a higher affinity for heparanase and they had performed well in fluorescent microscopy and Matrigel invasion assays. However, when we examined these aptamers on the organotypic invasion assay and analysed their potential to block invasion, it was found that the short aptamer was far more capable of doing so, compared to its long counterparts. However, it appears that although the long one has a slightly higher affinity, probably due to increased interactions between the protein and the primer parts of the aptamer, these resulted in reducing the ability of these aptamers to inhibit tissue invasion.

The presence of various proteins in the actual tissue, as compared to the Matrigel experiment previously performed, may be the reason for this, as the long aptamer may form other interactions with such proteins, or the primer tails may have a steric hindrance effect on the tissue, which is not apparent in the simpler matrigel model. This, in fact, was confirmed by the study of the interactions between the two aptamers and serum proteins.

In these studies it was found that the long aptamer formed a complex with human serum albumin, whereas the short aptamer did not form a complex and showed only a limited dynamic quenching. In a further study [57] , we have modelled the interactions of the short and long aptamers with HSA and have identified that indeed the long aptamer forms a complex with serum albumins in a single binding site, close to Trp of HSA or of BSA, at the subdomain IIA of these proteins, in a positively charged cavity lined with lysine and arginine residues [57].

It has been demonstrated that the shorter aptamer species lacks the ability to form complexes with serum proteins and exhibits thus higher specificity for its target, which justifies our choice of using it in any further therapeutic or diagnostic development and is in agreement with the myoma data presented in this work. One further important feature of this study is the demonstration that post-SELEX modifications may be more beneficial for aptamer selection than initial counter-selection steps, where this is possible.

In a series of studies with various methodologies of detection, aptamer affinity for their target has been compared to that for albumin. The majority of the exemplars for new aptamer-based detection methodologies are based on the thrombin aptamers. Similarly, aptamers have been shown to distinguish thrombin from albumin in a QCM experiment [59].

Another G-quadruplex based thrombin aptamer in cationic polythiophene protein detection arrays was also able to detect thrombin over albumin in the attomole range in less than one hour without any tagging of the target [60]. The thrombin aptamer has also been used in an electrochemical detection assay, where it has been able to separate thrombin from BSA, HSA, Lysozyme and immunoglobulin G [61]. Apart from the thrombin aptamers, other aptamers in detection assays have also been compared with albumin, or have shown specific binding in the presence of high concentration of albumins.

In an electrochemical sensor, aptamers against lysozyme have been shown to detect lysozyme in a mixture of six proteins including albumin [62]. Immunoglobulin E has also been detected in serum over albumin [63] , whereas an anti- F. Depending on the aptamer species, some aptamers present cross-reactivity with serum albumins, whereas the majority of them are capable of distinguishing between the protein they have been selected for, and albumins.

Thus, for example, when we investigated a number of KLK6 aptamers with serum albumins, we identified that the majority of the selected aptamers against that target were specific, but one of them had significant affinity for albumin [65]. Thus, the heparanase aptamer of this study, when truncated for the binding site of the specific target protein, does not form a stable complex with serum proteins, whereas its longer counterpart that contains the flanking primers, not selected for specific binding, can do. This candidate would have been lost if a counter-selection against albumins had been performed at the beginning, as it also presents affinity for these proteins prior to truncation.

However, with a simple truncation of the flanking primers, the aptamer gained the necessary specificity to be further developed for therapeutic and diagnostic applications. Furthermore, the effect seen in the inhibition of the invasion assay could have been a result of a cytotoxic effect on the part of aptamers. This possibility was eliminated in a cytotoxicity assay, which clearly demonstrated that the aptamers did not show any cytotoxic effect on these cells after 72 hours of incubation, thus verifying that the inhibition of invasion was in fact due to inhibition of heparanase.

Finally, aptamers were found to be stable in human serum even without any modification, making them potentially interesting therapeutic reagents on their own accord. This is important as such stability would reduce production costs of such an aptamer, if it were selected for subsequent therapeutic or diagnostic applications.

Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Heparanase is an endoglycosidase enzyme present in activated leucocytes, mast cells, placental tissue, neutrophils and macrophages, and is involved in tumour metastasis and tissue invasion. Organotypic invasion assay and analyses of the inhibitors on invasion The organotypic invasion assay and the quantitation of results were performed as described in Nurmenniemi et al. Download: PPT. Results The anti-heparanase aptamers inhibit carcinoma cell invasion The invasion of HSC-3 cells was studied with a human myoma organotypic model [49] exposing the carcinoma cells to various aptamers Unrelated, 1.

The short anti-heparanase aptamer does not exhibit any cytotoxicity The cytotoxicity of the selected aptamers on HSC-3 cells was studied, to verify that the inhibition of invasion observed in the organotypic model was a result of the inhibition of the heparanase, as previously verified [46] and not cell cytotoxicity. Figure 3. The MTS absorbance at nm is shown over 24, 48 and 72 h in the presence and absence of the 1. The short anti-heparanase aptamer does not bind significantly to serum proteins Short and long aptamers 1. Figure 4. Figure 5. Figure 6. Aptamers are stable in human serum To assess the aptamers' suitability as therapeutic agents, it was necessary to have an understanding of how stable the unmodified aptamers would be in the body, as, in the bloodstream alone, there are many nucleases capable of degrading the aptamers.

Discussion In this study we have explored the potential of previously selected aptamers against heparanase as promising diagnostic and therapeutic agents against oral cancer. References 1. Semin Thromb Hemost — View Article Google Scholar 2.