What has the National Cancer Database taught us about oral cavity squamous cell carcinoma?

The wealth of data in the National Cancer Database (NCDB) has allowed numerous studies investigating patient, disease, and treatment-related factors in oral cavity squamous cell carcinoma (OCSCC); however, to date, no summation of these studies has been performed. The aim of this study was to provide a concise review of the NCDB studies on OCSCC, with the hopes of providing a framework for future, novel studies aimed at enhancing our understanding of clinical parameters related to OCSCC. Two databases were searched, and 27 studies published between 2002 and 2020 were included. The average sample size was 13,776 patients (range 356-50,896 patients). Four areas of research focus were identified: demographic and socioeconomic status, diagnosis, prognosis, and treatment. This review highlights the impact of age, sex, ethnicity, and socioeconomic status on the prognosis and management of OCSCC, describes the prognostic factors, and details the modalities and indications for neck dissection and adjuvant therapy in OCSCC. In conclusion, the NCDB is a very valuable resource for clinicians and researchers involved in the management of OCSCC, offering an incomparable perspective on a large dataset of patients. Future developments regarding hospital information management, review of data accuracy and completeness, and wider accessibility will help clinicians to improve the care of patients affected by OCSCC.

Oral Rehabilitation of Patients Sustaining Orofacial Injuries: The UPenn Initiative.

Tissue injuries in the oral and maxillofacial structures secondary to trauma, warfare, ablative cancer, and benign tumor surgery result in significant losses of speech, masticatory and swallowing functions, aesthetic deformities, and overall psychological stressors and compromise. Optimal oral rehabilitation remains a formidable challenge and an unmet clinical need due to the influence of multiple factors related to the physiologic limitations of tissue repair, the lack of site and function-specific donor tissues and constructs, and an integrated team of multidisciplinary professionals. The advancements in stem cell biology, biomaterial science, and tissue engineering technologies, particularly the 3-dimensional bioprinting technology, together with digital imaging and computer-aided design and manufacturing technologies, have paved the path for personalized/precision regenerative medicine. At the University of Pennsylvania, we have launched the initiative to integrate multidisciplinary health professionals and translational/clinical scientists in medicine, dentistry, stem cell biology, tissue engineering, and regenerative medicine to develop a comprehensive, patient-centered approach for precision and personalized reconstruction, as well as oral rehabilitation of patients sustaining orofacial tissue injuries and defects, especially oral cancer patients.

Beta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons.

Immunocytochemical studies of postmortem human tissue have shown that the neurons at risk for degeneration in Alzheimer's are marked by the ectopic expression of several cell cycle components. The current work investigates the roles that beta-amyloid activated microglia might play in leading neurons to re-express cell cycle components. Stable cultures of E16.5 mouse cortical neurons were exposed to beta-amyloid alone, microglial cells alone, or microglial cells activated by beta-amyloid. Increased cell death was found in response to each of these treatments, however, only the amyloid activated microglial treatment increased the number of neurons that were positive for cell cycle markers such as PCNA or cyclin D and incorporation of BrdU. Double labeling with BrdU and TUNEL techniques verified that the 'dividing' neurons were dying, most likely through an apoptotic mechanism. The identity of the soluble factor(s) elaborated by the microglia remains unknown, but FGF2, a suspected neuronal mitogen, was ruled out. These results further support a model in which microglial activation by beta-amyloid is a key event in the progression in Alzheimer's disease.

Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists.

Alzheimer's disease (AD) is characterized by the extracellular deposition of beta-amyloid fibrils within the brain and the subsequent association and phenotypic activation of microglial cells associated with the amyloid plaque. The activated microglia mount a complex local proinflammatory response with the secretion of a diverse range of inflammatory products. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious in reducing the incidence and risk of AD and significantly delaying disease progression. A recently appreciated target of NSAIDs is the ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is a DNA-binding transcription factor whose transcriptional regulatory actions are activated after agonist binding. We report that NSAIDs, drugs of the thiazolidinedione class, and the natural ligand prostaglandin J2 act as agonists for PPARgamma and inhibit the beta-amyloid-stimulated secretion of proinflammatory products by microglia and monocytes responsible for neurotoxicity and astrocyte activation. The activation of PPARgamma also arrested the differentiation of monocytes into activated macrophages. PPARgamma agonists were shown to inhibit the beta-amyloid-stimulated expression of the cytokine genes interleukin-6 and tumor necrosis factor alpha. Furthermore, PPARgamma agonists inhibited the expression of cyclooxygenase-2. These data provide direct evidence that PPARgamma plays a critical role in regulating the inflammatory responses of microglia and monocytes to beta-amyloid. We argue that the efficacy of NSAIDs in the treatment of AD may be a consequence of their actions on PPARgamma rather than on their canonical targets the cyclooxygenases. Importantly, the efficacy of these agents in inhibiting a broad range of inflammatory responses suggests PPARgamma agonists may provide a novel therapeutic approach to AD.

Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins.

Microglial interaction with amyloid fibrils in the brains of Alzheimer's and prion disease patients results in the inflammatory activation of these cells. We observed that primary microglial cultures and the THP-1 monocytic cell line are stimulated by fibrillar beta-amyloid and prion peptides to activate identical tyrosine kinase-dependent inflammatory signal transduction cascades. The tyrosine kinases Lyn and Syk are activated by the fibrillar peptides and initiate a signaling cascade resulting in a transient release of intracellular calcium that results in the activation of classical PKC and the recently described calcium-sensitive tyrosine kinase PYK2. Activation of the MAP kinases ERK1 and ERK2 follows as a subsequent downstream signaling event. We demonstrate that PYK2 is positioned downstream of Lyn, Syk, and PKC. PKC is a necessary intermediate required for ERK activation. Importantly, the signaling response elicited by beta-amyloid and prion fibrils leads to the production of neurotoxic products. We have demonstrated in a tissue culture model that conditioned media from beta-amyloid- and prion-stimulated microglia or from THP-1 monocytes are neurotoxic to mouse cortical neurons. This toxicity can be ameliorated by treating THP-1 cells with specific enzyme inhibitors that target various components of the signal transduction pathway linked to the inflammatory responses.

Adenosine depresses transmitter release but is not the basis for 'tetanic fade' at the neuromuscular junction of the rat.

It has been suggested that during repetitive neural stimulation adenosine accumulates at the neuromuscular junction and the resulting negative feedback action of adenosine is the major basis for tetanic fade (decline in action of adenosine during repetitive stimulation) This hypothesis was examined at the rat neuromuscular junction by examining the effects of blocking adenosine A1-receptors. Intracellular recording techniques were used to monitor end-plate potentials and miniature end-plate potentials. The data suggest that while adenosine serves a role in depressing transmitter release, adenosine accumulation during brief periods of stimulation is minimal and adenosine is not the cause for tetanic fade.