Biological consequences of cancer radiotherapy in the context of oral squamous cell carcinoma.

Approximately 50% of subjects with cancer have been treated with ionizing radiation (IR) either as a curative, adjuvant, neoadjuvant or as a palliative agent, at some point during the clinical course of their disease. IR kills cancer cells directly by injuring their DNA, and indirectly by inducing immunogenic cell killing mediated by cytotoxic T cells; but it can also induce harmful biological responses to non-irradiated neighbouring cells (bystander effect) and to more distant cells (abscopal effect) outside the primary tumour field of irradiation.Although IR can upregulate anti-tumour immune reactions, it can also promote an immunosuppressive tumour microenvironment. Consequently, radiotherapy by itself is seldom sufficient to generate an effective long lasting immune response that is capable to control growth of metastasis, recurrence of primary tumours and development of second primary cancers. Therefore, combining radiotherapy with the use of immunoadjuvants such as immune checkpoint inhibitors, can potentiate IR-mediated anti-tumour immune reactions, bringing about a synergic immunogenic cell killing effect.The purpose of this narrative review is to discuss some aspects of IR-induced biological responses, including factors that contributes to tumour radiosensitivity/radioresistance, immunogenic cell killing, and the abscopal effect.

Vitamin D Deficiency as It Relates to Oral Immunity and Chronic Periodontitis.

The biologically active form of vitamin D, 1,25 dihydroxyvitamin D (1,25(OH)2D) and its receptor, the vitamin D receptor (VDR), play roles in maintaining oral immunity and the integrity of the periodontium. Results of observational cross-sectional clinical studies investigating the association between vitamin D serum level and the incidence and severity of chronic periodontitis indicate that, perhaps owing to the immunomodulatory, anti-inflammatory, and antibacterial properties of 1,25(OH)2 D/VDR signalling, a sufficient serum level of vitamin D is necessary for the maintenance of periodontal health. In cases of established chronic periodontitis, vitamin D supplementation is associated with reduction in the severity of periodontitis. As cross-sectional studies provide only weak evidence for any causal association and therefore are of questionable value, either longitudinal cohort studies, case controlled studies, or randomized control trials are needed to determine whether or not deficiency of vitamin D is a risk factor for chronic periodontitis, and whether or not vitamin D supplementation adjunctive to standard periodontal treatment is in any way beneficial. In this article, we discuss the relationship between vitamin D, oral immunity and periodontal disease and review the rationale for using vitamin D supplementation to help maintain periodontal health and as an adjunct to standard periodontal treatment.

Oral manifestations of thrombocytopaenia.

The appearance in the mouth of haemorrhagic petechiae, ecchymoses or blood blisters with spontaneous bleeding is suggestive of a haemorrhagic disorder that may be caused either by functional impairment of platelets or of blood vessel walls, by an abnormal decrease in the number of circulating platelets (thrombocytopaenia), or by defects in the blood clotting mechanism. Thrombocytopaenia from decreased production or increased destruction of platelets may be caused by multiple factors including immune mediated mechanisms, drugs or infections. A diagnosis of thrombocytopaenic purpura can be made when any other disease entity that might be causing the purpura is excluded on the basis of the medical history, the physical examination, a complete blood count and a peripheral blood smear. In this paper, we outline the clinical features of oral thrombocytopaenic purpura and briefly discuss some aspects of its aetiopathogenesis and treatment.

Adverse Immunologically Mediated Oral Mucosal Reactions to Systemic Medication: Lichenoid Tissue Reaction/Interface Dermatitis-Stomatitis, Autoimmune Vesiculobullous Disease, and IgE-Dependent and Immune Complex Reactions.

Drug-induced hypersensitivity immune reactions are exaggerated immunoinflammatory responses to allergenic components of the medications that occur in genetically susceptible subjects. The type of hypersensitivity immune response generated, whether antibody mediated or T cell mediated, or an immune complex reaction is determined by multiple factors, including the molecular characteristics of the allergen, the route of administration of the medication, the manner of presentation of the allergen by antigen-presenting cells to naïve T cells, the repertoire of the T cell receptors, and the cytokine profile within the microenvironment. This review deals with the clinical and histopathological aspects of adverse immunologically mediated oral mucosal reactions to systemic medication. We elaborate on diseases showing features of lichenoid tissue reaction/interface dermatitis-stomatitis, autoimmune vesiculobullous oral lesions, and immunoglobulin E- (IgE-) and immune complex-mediated oral reactions to drugs.

The Biological Activities of Vitamin D and Its Receptor in Relation to Calcium and Bone Homeostasis, Cancer, Immune and Cardiovascular Systems, Skin Biology, and Oral Health.

Vitamin D plays an important role in calcium homeostasis and bone metabolism, with the capacity to modulate innate and adaptive immune function, cardiovascular function, and proliferation and differentiation of both normal and malignant keratinocytes. 1,25(OH)2D, the biologically active form of vitamin D, exerts most of its functions through the almost universally distributed nuclear vitamin D receptor (VDR). Upon stimulation by 1,25(OH)2D, VDR forms a heterodimer with the retinoid X receptor (RXR). In turn, VDR/RXR binds to DNA sequences termed vitamin D response elements in target genes, regulating gene transcription. In order to exert its biological effects, VDR signalling interacts with other intracellular signalling pathways. In some cases 1,25(OH)2D exerts its biological effects without regulating either gene expression or protein synthesis. Although the regulatory role of vitamin D in many biological processes is well documented, there is not enough evidence to support the therapeutic use of vitamin D supplementation in the prevention or treatment of infectious, immunoinflammatory, or hyperproliferative disorders. In this review we highlight the effects of 1,25(OH)2D on bone and calcium homeostasis, on cancer, and refer to its effects on the cardiovascular and immune systems.

Burning Mouth Syndrome: Aetiopathogenesis and Principles of Management.

Burning mouth syndrome (BMS) is a chronic debilitating oral condition characterised by a burning sensation of the oral mucosa in an otherwise apparently normal person. Its aetiology and pathogenesis are obscure, but both psychogenic factors and peripheral and central neuropathies appear to be implicated. There is no cure for BMS, and treatment with either local or systemic medications focuses on the relief of symptoms and on improving quality of life. In recalcitrant cases, psychological/psychiatric intervention may be helpful. In order to improve treatment outcomes, a better understanding of the pathogenesis of this syndrome might provide a basis for the development of more effective management strategies. In this short review, we discuss current knowledge of the diagnosis, aetiopathogenesis, and management of BMS.

Biologic therapies for refractory juvenile dermatomyositis: five years of experience of the Childhood Arthritis and Rheumatology Research Alliance in North America.

BACKGROUND: The prognosis of children with juvenile dermatomyositis (JDM) has improved remarkably since the 1960's with the use of corticosteroid and immunosuppressive therapy. Yet there remain a minority of children who have refractory disease. Since 2003 the sporadic use of biologics (genetically-engineered proteins that usually are derived from human genes) for inflammatory myositis has been reported. In 2011-2016 we investigated our collective experience of biologics in JDM through the Childhood Arthritis and Rheumatology Research Alliance (CARRA). METHODS: The JDM biologic study group developed a survey on the CARRA member experience using biologics for Juvenile DM utilizing Delphi consensus methods in 2011-2012. The survey was completed online by the CARRA members interested in JDM in 2012. A second survey was similarly developed that provided more opportunity to describe their experiences with biologics in JDM in detail and was completed by CARRA members in Feb 2013. During three CARRA meetings in 2013-2015, nominal group techniques were used for achieving consensus on the current choices of biologic drugs. A final survey was performed at the 2016 CARRA meeting. RESULTS: One hundred and five of a potential 231 pediatric rheumatologists (42%) responded to the first survey in 2012. Thirty-five of 90 had never used a biologic for Juvenile DM at that time. Fifty-five of 91 (denominators vary) had used biologics for JDM in their practice with 32%, 5%, and 4% using rituximab, etanercept, and infliximab, respectively, and 17% having used more than one of the three drugs. Ten percent used a biologic as monotherapy, 19% a biologic in combination with methotrexate (mtx), 52% a biologic in combination with mtx and corticosteroids, 42% a combination of a biologic, mtx, corticosteroids (steroids), and an immunosuppressive drug, and 43% a combination of a biologic, IVIG and mtx. The results of the second survey supported these findings in considerably more detail with multiple combinations of drugs used with biologics and supported the use of rituximab, abatacept, anti-TNFα drugs, and tocilizumab in that order. One hundred percent recommended that CARRA continue studying biologics for JDM. The CARRA meeting survey in 2016 again supported the study and use of these four biologic drug groups. CONCLUSIONS: Our CARRA JDM biologic work group developed and performed three surveys demonstrating that pediatric rheumatologists in North America have been using multiple biologics for refractory JDM in numerous scenarios from 2011 to 2016. These survey results and our consensus meetings determined our choice of four biologic therapies (rituximab, abatacept, tocilizumab and anti-TNFα drugs) to consider for refractory JDM treatment when indicated and to evaluate for comparative effectiveness and safety in the future. Significance and Innovations This is the first report that provides a substantial clinical experience of a large group of pediatric rheumatologists with biologics for refractory JDM over five years. This experience with biologic therapies for refractory JDM may aid pediatric rheumatologists in the current treatment of these children and form a basis for further clinical research into the comparative effectiveness and safety of biologics for refractory JDM.

Postherpetic Neuralgia and Trigeminal Neuralgia.

Postherpetic neuralgia (PHN) is an unpredictable complication of varicella zoster virus- (VZV-) induced herpes zoster (HZ) which often occurs in elderly and immunocompromised persons and which can induce psychosocial dysfunction and can negatively impact on quality of life. Preventive options for PHN include vaccination of high-risk persons against HZ, early use of antiviral agents, and robust management of pain during the early stage of acute herpes zoster. If it does occur, PHN may persist for months or even years after resolution of the HZ mucocutaneous eruptions, and treatment is often only partially effective. Classical trigeminal neuralgia is a severe orofacial neuropathic pain condition characterized by unilateral, brief but recurrent, lancinating paroxysmal pain confined to the distribution of one or more of the branches of the trigeminal nerve. It may be idiopathic or causally associated with vascular compression of the trigeminal nerve root. The anticonvulsive agents, carbamazepine or oxcarbazepine, constitute the first-line treatment. Microvascular decompression or ablative procedures should be considered when pharmacotherapy is ineffective or intolerable. The aim of this short review is briefly to discuss the etiopathogenesis, clinical features, and treatment of PHN and classical trigeminal neuralgia.

HIV-Associated Oral Mucosal Melanin Hyperpigmentation: A Clinical Study in a South African Population Sample.

Objective. The aim of the study was to determine the prevalence of HIV-associated oral mucosal melanin hyperpigmentation (HIV-OMH) in a specific population of HIV-seropositive South Africans and to analyse the associations between HIV-OMH clinical features and the demographic and immunological characteristics of the study cohort. Material and Methods. This cross-sectional study included 200 HIV-seropositive Black subjects. The collected data comprised age, gender, CD4+ T cell count, viral load, systemic disease, medications, oral site affected by HIV-OMH, extent (localized or generalized), intensity of the pigmentation (dark or light), and smoking and snuff use. Results. Overall, 18.5% of the study cohort had HIV-OMH. Twenty-two and a half percent had OMH that could not with confidence be attributed to HIV infection, and 59% did not have any OMH. There was a significant but weak association between smoking and the presence of HIV-OMH. Conclusions. The prevalence of HIV-OMH in the study population was 18.5%, the gingiva being the most commonly affected site. It appears that the CD4+ T cell count does not play any role in the biopathology of HIV-OMH.

Basal cell carcinoma, squamous cell carcinoma and melanoma of the head and face.

Ultraviolet light (UV) is an important risk factor for cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma of the skin. These cancers most commonly affect persons with fair skin and blue eyes who sunburn rather than suntan. However, each of these cancers appears to be associated with a different pattern of UV exposure and to be mediated by different intracellular molecular pathways.Some melanocortin 1 receptor (MC1R) gene variants play a direct role in the pathogenesis of cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma apart from their role in determining a cancer-prone pigmentory phenotype (fair skin, red hair, blue eyes) through their interactions with other genes regulating immuno-inflammatory responses, DNA repair or apoptosis.In this short review we focus on the aetiological role of UV in cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma of the skin, and on some associated biopathological events.

Biological Events in Periodontal Ligament and Alveolar Bone Associated with Application of Orthodontic Forces.

Orthodontic force-induced stresses cause dynamic alterations within the extracellular matrix and within the cytoskeleton of cells in the periodontal ligament and alveolar bone, mediating bone remodelling, ultimately enabling orthodontic tooth movement. In the periodontal ligament and alveolar bone, the mechanically induced tensile strains upregulate the expression of osteogenic genes resulting in bone formation, while mechanically induced compressive strains mediate predominantly catabolic tissue changes and bone resorption. In this review article we summarize some of the currently known biological events occurring in the periodontal ligament and in the alveolar bone in response to application of orthodontic forces and how these facilitate tooth movement.

Oculocutaneous Albinism and Squamous Cell Carcinoma of the Skin of the Head and Neck in Sub-Saharan Africa.

Oculocutaneous albinism which is characterised by impaired melanin biosynthesis is the most common inherited pigmentary disorder of the skin and it is common among Blacks in sub-Saharan Africa. All albinos are at great risk of developing squamous cell carcinoma of sun-exposed skin, and Black albinos in sub-Saharan Africa are at about a 1000-fold higher risk of developing squamous cell carcinoma of the skin than the general population. In Black albinos, skin carcinoma tends to run an aggressive course and is likely to recur after treatment, very probably because the aetiology and predisposing factors have not changed. Prevention or reduction of occurrence of squamous cell carcinoma of the skin in Black albinos might be achieved through educating the population to increase awareness of the harmful effects of exposure to sunlight and at the same time making available effective screening programs for early detection of premalignant and malignant skin lesions in schools and communities and for early treatment.

Periodontal Biological Events Associated with Orthodontic Tooth Movement: The Biomechanics of the Cytoskeleton and the Extracellular Matrix.

The mechanical stimuli generated by orthodontic forces cause deformation of extracellular matrices and cells, vascular changes, inflammation, and the release of active biological agents generating a complex multifactorial sequence of biological events culminating in bone remodelling enabling orthodontic tooth movement. Orthodontic forces on the teeth generate stresses in periodontal tissues according to a number of variables including the type (continuous, interrupted, or intermittent), magnitude, direction, and frequency of the applied load. Whether the strain is compressive or tensile determines whether bone deposition or bone resorption will occur. The mechanically induced strains mediate structural changes in extracellular matrices and in cells, consequently affecting cellular gene expression and function. In the extracellular matrix, mechanosensing molecules integrated into the structure of various proteins can be activated upon load-induced protein unfolding. These specialized molecules have the capacity to sense and then to convert microenvironmental biomechanical stimuli into intracellular biochemical signals that interact to generate a coordinated tissue response. It is also possible that the applied force may directly cause nuclear deformation with configurational changes in chromatin, thus influencing gene expression. In this review article we summarize the current general concepts of mechanotransduction influencing the remodelling of periodontal tissues thus enabling tooth movement in response to applied orthodontic loads.

Oral mucosal melanoma: some pathobiological considerations and an illustrative report of a case.

Oral mucosal melanoma is a relatively rare malignancy with an aggressive clinico-pathological behaviour. The mean 5-year survival rate is about 15 %. It arises primarily from melanocytes found in the basal cell layer of the epithelium, but may sometimes arise from melanocytes residing in the lamina propria. The pathogenesis is complex, and few of the molecular mechanisms underlying the development of oral mucosal melanoma have been defined. The extraneous risk factors associated with oral mucosal melanoma, if any, are unknown. Oral mucosal melanomas account for about 25 % of all mucosal melanomas of the head and neck, and exhibit a profile of cytogenetic alterations, and a pathobiological behaviour and clinical course different from that of cutaneous melanomas. As they are usually painless and grow quickly, as a rule, they are diagnosed late in the course of the disease when the lesions are already large and have metastasized to regional lymph nodes. In this paper we discuss some aspects of the pathobiology of oral mucosal melanoma, and present an illustrative case report.

Osseointegration: biological events in relation to characteristics of the implant surface.

Osseointegration of titanium implants is a complex biological process involving interactions between immuno-inflammatory responses, angiogenesis and osteogenesis, all of which are influenced by the physical and chemical characteristics of the implant surface. An implant surface with moderately rough topography and high surface energy influences cellular activities, enhancing peri-implant bone wound healing. Primary mechanical stability of the implant is essential for osseointegration. In this article we review some of the more important biological events of peri-implant bone wound healing in the process of osseointegration, and discuss how the biophysical properties of implant surfaces influence cellular responses.

Oral sarcoidosis: a case report and review of the literature.

Sarcoidosis is a chronic multi-system immuno-inflammatory disorder characterized by non-caseating granulomatous infiltration of affected tissues that may result in fibrosis and organ dysfunction. It generally affects genetically predisposed young adults who develop a local dysregulated cell-mediated immune response towards an undefined 'sarcoidal antigen'. From recent data, it has become evident that Propionibacterium acnes and Mycobacterium tuberculosis are the probable antigenic agents which initiate sarcoidosis. Oral sarcoidosis is rare with only about 70 cases having been reported in the literature. The purpose of this report is to present a case of oral and cutaneous sarcoidosis in a black female that was probably triggered by mycobacteria.

Oral candidosis in relation to oral immunity.

Symptomatic oral infection with Candida albicans is characterized by invasion of the oral epithelium by virulent hyphae that cause tissue damage releasing the inflammatory mediators that initiate and sustain local inflammation. Candida albicans triggers pattern-recognition receptors of keratinocytes, macrophages, monocytes and dendritic cells, stimulating the production of IL-1ß, IL-6 and IL-23. These cytokines induce the differentiation of Th17 cells and the generation of IL-17- and/or IL-22-mediated antifungal protective immuno-inflammatory responses in infected mucosa. Some immune cells including NKT cells, γδ T cells and lymphoid cells that are innate to the oral mucosa have the capacity to produce large quantities of IL-17 in response to C. albicans, sufficient to mediate effective protective immunity against C. albicans. On the other hand, molecular structures of commensal C. albicans blastoconidia, although detected by pattern-recognition receptors, are avirulent, do not invade the oral epithelium, do not elicit inflammatory responses in a healthy host, but induce regulatory immune responses that maintain tissue tolerance to the commensal fungi. The type, specificity and sensitivity of the protective immune response towards C. albicans is determined by the outcome of the integrated interactions between the intracellular signalling pathways of specific combinations of activated pattern-recognition receptors (TLR2, TLR4, Dectin-1 and Dectin-2). IL-17-mediated protective immune response is essential for oral mucosal immunity to C. albicans infection.

Oral medicine case book 65: Necrotising stomatitis.

Necrotising stomatitis is a fulminating anaerobic polybacterial infection affecting predominantly the oral mucosa of debilitated malnourished children or immunosuppressed HIV-seropositive subjects. It starts as necrotising gingivitis which progresses to necrotising periodontitis and subsequently to necrotising stomatitis. In order to prevent the progression of necrotising stomatitis to noma (cancrum oris), affected patients should be vigorously treated and may require admission to hospital. Healthcare personnel should therefore be familiar with the signs and symptoms of necrotising gingivitis/necrotising periodontitis, of their potential sequelae and of the need for immediate therapeutic intervention.

Race/ethnicity in biomedical research and clinical practice.

There is ongoing debate as to whether persons of different racial/ethnic groups are biologically significantly different, and, if such differences exist, whether they are relevant in relation to disease susceptibility and to treatment outcomes. There is also debate about the benefits of using race/ethnicity as a factor in clinical decision making, and as a variable in biomedical or public health research, because of the emotional sensitivities attached to race/ethnic categorisation. Such categorisation may also divert attention from underlying issues such as socioeconomic status and lack of access to modern health care. In this short article we will discuss these controversies, and will emphasize the importance of responsible and sensitive use of race/ethnicity as a variable in biomedical research and in clinical practice.