Current arrangements for training dentists in Australia on primary care dentistry.

There is an expectation in Australia that dental students engage in primary care as they learn to recognise and respond to aspects of a person's general health and wellbeing. These skills, knowledge and behaviours are outlined by the Australian Dental Council, the accrediting body of dental training programs. Education in primary care dentistry can be seen integrated across the length and breadth of dental curricula yet is not commonly referred to as primary care. Interprofessional education provides opportunities for dental students to develop their professional identities as primary healthcare practitioners and be seen as such by other health professions. We propose that the primary care dentistry could be elevated by naming and noticing these activities in the curriculum.

L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy.

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Using chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) to measure the tumor extracellular pH (pHe), we confirmed that L-DOS47 raises the tumor pHe from 4 h to 96 h post injection in acidic tumors (average increase of 0.13 units). Additional studies showed that combining L-DOS47 with anti-PD1 significantly increases the efficacy of the anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

Creativity as a framework for innovation in dental education.

Dental education is rich with examples of innovation as educators have responded to advances in knowledge, technology, the needs of the community, and most recently the challenges of the COVID-19 pandemic. Current challenges requiring innovative pedagogies include developing graduates who are interprofessional collaborative practice-ready, adapting to technological advances, embedding sustainability in the curriculum, and addressing equity and diversity in dental education. Creativity is the production of something that is novel and useful and is intimately linked to innovation which is the implementation of new and improved ways of doing things. To develop innovative pedagogies and address the current challenges facing dental education, educators and dental schools must reflect on the factors necessary for supporting creativity and innovation and seek to remove barriers to or biases against creativity. Here, we discuss the importance of creativity in supporting innovation in dental education, and call for leadership to actively support all elements of creativity for continued innovation to address the challenges we face in educating the future oral health workforce.

L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor.

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds CEACAM6, a cell surface protein highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Our results demonstrate that combining L DOS47 with anti-PD1 significantly increases the efficacy of anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

Breastmilk influences development and composition of the oral microbiome.

Background: Human microbiomes assemble in an ordered, reproducible manner yet there is limited information about early colonisation and development of bacterial communities that constitute the oral microbiome. Aim: The aim of this study was to determine the effect of exposure to breastmilk on assembly of the infant oral microbiome during the first 20 months of life. Methods: The oral microbiomes of 39 infants, 13 who were never breastfed and 26 who were breastfed for more than 10 months, from the longitudinal VicGeneration birth cohort study, were determined at four ages. In total, 519 bacterial taxa were identified and quantified in saliva by sequencing the V4 region of the bacterial 16S rRNA genes. Results: There were significant differences in the development of the oral microbiomes of never breastfed and breastfed infants. Bacterial diversity was significantly higher in never breastfed infants at 2 months, due largely to an increased abundance of Veillonella and species from the Bacteroidetes phylum compared with breastfed infants. Conclusion: These differences likely reflect breastmilk playing a prebiotic role in selection of early-colonising, health-associated oral bacteria, such as the Streptococcus mitis group. The microbiomes of both groups became more heterogenous following the introduction of solid foods.

Temporal development of the infant oral microbiome.

The human oral microbiome is becoming recognized as playing roles in health and disease well beyond the oral cavity over the lifetime of the individual. The oral microbiome is hypothesized to result from specific colonization events followed by a reproducible and ordered development of complex bacterial communities. Colonization events, proliferation, succession and subsequent community development are dependent on a range of host and environmental factors, most notably the neonate diet. It is now becoming apparent that early childhood and prenatal influences can have long term effects on the development of human oral microbiomes. In this review, the temporal development of the infant human oral microbiome is examined, with the effects of prenatal and postnatal influences and the roles of specific bacteria. Dietary and environmental factors, especially breastfeeding, have a significant influence on the development of the infant oral microbiome. The evidence available regarding the roles and functions of early colonizing bacteria is still limited, and gaps in knowledge where further research is needed to elucidate these specific roles in relation to health and disease still exist.

Targeting of Evolutionarily Acquired Cancer Cell Phenotype by Exploiting pHi-Metabolic Vulnerabilities.

Evolutionary dynamics can be used to control cancers when a cure is not clinically considered to be achievable. Understanding Darwinian intratumoral interactions of microenvironmental selection forces can be used to steer tumor progression towards a less invasive trajectory. Here, we approach intratumoral heterogeneity and evolution as a dynamic interaction among subpopulations through the application of small, but selective biological forces such as intracellular pH (pHi) and/or extracellular pH (pHe) vulnerabilities. Increased glycolysis is a prominent phenotype of cancer cells under hypoxia or normoxia (Warburg effect). Glycolysis leads to an important aspect of cancer metabolism: reduced pHe and higher pHi. We recently showed that decreasing pHi and targeting pHi sensitive enzymes can reverse the Warburg effect (WE) phenotype and inhibit tumor progression. Herein, we used diclofenac (DIC) repurposed to control MCT activity, and Koningic acid (KA) that is a GAPDH partial inhibitor, and observed that we can control the subpopulation of cancer cells with WE phenotype within a tumor in favor of a less aggressive phenotype without a WE to control progression and metastasis. In a 3D spheroid co-cultures, we showed that our strategy can control the growth of more aggressive MDA-MB-231 cells, while sparing the less aggressive MCF7 cells. In an animal model, we show that our approach can reduce tumor growth and metastasis. We thus propose that evolutionary dynamics can be used to control tumor cells' clonal or sub-clonal populations in favor of slower growth and less damage to patients. We propose that this can result in cancer control for tumors where cure is not an option.

Collagen production and niche engineering: A novel strategy for cancer cells to survive acidosis in DCIS and evolve.

Growing tumors are dynamic and nonlinear ecosystems, wherein cancer cells adapt to their local microenvironment, and these adaptations further modify the environment, inducing more changes. From nascent intraductal neoplasms to disseminated metastatic disease, several levels of evolutionary adaptations and selections occur. Here, we focus on one example of such an adaptation mechanism, namely, "niche construction" promoted by adaptation to acidosis, which is a metabolic adaptation to the early harsh environment in intraductal neoplasms. The avascular characteristics of ductal carcinoma in situ (DCIS) make the periluminal volume profoundly acidic, and cancer cells must adapt to this to survive. Based on discovery proteomics, we hypothesized that a component of acid adaptation involves production of collagen by pre-cancer cells that remodels the extracellular matrix (ECM) and stabilizes cells under acid stress. The proteomic data were surprising as collagen production and deposition are commonly believed to be the responsibility of mesenchymally derived fibroblasts, and not cells of epithelial origin. Subsequent experiments in 3D culture, spinning disk and second harmonic generation microscopy of DCIS lesions in patients' samples are concordant. Collagen production assay by acid-adapted cells in vitro demonstrated that the mechanism of induction involves the RAS and SMAD pathways. Secretome analyses show upregulation of ECM remodeling enzymes such as TGM2 and LOXL2 that are collagen crosslinkers. These data strongly indicate that acidosis in incipient cancers induces collagen production by cancer cells and support the hypothesis that this adaptation initiates a tumor-permissive microenvironment promoting survival and growth of nascent cancers.

The potential acidogenicity of liquid breakfasts.

OBJECTIVES: To determine the potential acidogenicy of liquid breakfasts. METHODS: In vitro acid production by Streptococcus mutans was measured in the beverages at a pH of 5.5, as was the fall in pH over 10min. The buffering capacity was determined, as well as the calcium, inorganic phosphate and fluoride concentrations (total and soluble) of the beverages. Bovine milk (UHT) was used for comparison. RESULTS: The rate of acid production by S. mutans, and pH fall over 10min was greater in liquid breakfasts compared to bovine milk. All beverages except one demonstrated a significantly lower buffering capacity than bovine milk. All beverages contained significantly greater concentrations of soluble calcium than bovine milk, and all except two contained significantly more soluble inorganic phosphate. CONCLUSIONS: S. mutans was able to generate significantly more acid in the liquid breakfasts than in bovine milk, indicating these drinks may contribute to a cariogenic diet. In general, the liquid breakfasts required significantly less acid than bovine milk to reduce their pH to the approximate critical pH for enamel demineralisation. However, the liquid breakfasts also tended to contain significantly more soluble calcium and inorganic phosphate than bovine milk. CLINICAL SIGNIFICANCE: The substantial amounts and various types of sugars found within liquid breakfast beverages may result in a significant pH drop in dental plaque following consumption of these products.

Protein substrates of a novel secretion system are numerous in the Bacteroidetes phylum and have in common a cleavable C-terminal secretion signal, extensive post-translational modification, and cell-surface attachment.

The secretion of certain proteins in Porphyromonas gingivalis is dependent on a C-terminal domain (CTD). After secretion, the CTD is cleaved prior to extensive modification of the mature protein, probably with lipopolysaccharide, therefore enabling attachment to the cell surface. In this study, bioinformatic analyses of the CTD demonstrated the presence of three conserved sequence motifs. These motifs were used to construct Hidden Markov Models (HMMs) that predicted 663 CTD-containing proteins in 21 fully sequenced species of the Bacteroidetes phylum, while no CTD-containing proteins were predicted in species outside this phylum. Further HMM searching of Cytophaga hutchinsonii led to a total of 171 predicted CTD proteins in that organism alone. Proteomic analyses of membrane fractions and culture fluid derived from P. gingivalis and four other species containing predicted CTDs (Parabacteroides distasonis, Prevotella intermedia, Tannerella forsythia, and C. hutchinsonii) demonstrated that membrane localization, extensive post-translational modification, and CTD-cleavage were conserved features of the secretion system. The CTD cleavage site of 10 different proteins from 3 different species was determined and found to be similar to the cleavage site previously determined in P. gingivalis, suggesting that homologues of the C-terminal signal peptidase (PG0026) are responsible for the cleavage in these species.