Saliva has been described as the mirror of the body. In a world of soaring healthcare costs and an environment where rapid diagnosis may be critical to a positive patient outcome, saliva is emerging as a viable alternative to blood sampling. In this review, we discuss the composition and various physiological roles of saliva in the oral cavity, including soft tissue protection, antimicrobial activities, and oral tissue repair. We then explore saliva as a diagnostic marker of local oral disease and focus particularly on oral cancers. The cancer theme continues when we focus on systemic disease diagnosis from salivary biomarkers. Communicable disease is the focus of the next section where we review the literature relating to the direct and indirect detection of pathogenic infections from human saliva. Finally, we discuss hormones involved in appetite regulation and whether saliva is a viable alternative to blood in order to monitor hormones that are involved in satiety.

SUMMAR Y Blind people report disturbances in alertness, mood and performance. In laboratory studies, these waking functions can only be maintained when the wake-dependent deterioration is opposed by appropriately-timed endogenous circadian rhythms. We aimed to quantify whether variations in waking function experienced by blind people living in society were dependent on the phase relationship between the sleep-wake cycle and the circadian pacemaker. The time course of alertness, mood and performance was assessed in 52 blind subjects with and without circadian rhythm disorders every 2 h for 2 days per week for 4 weeks. Sleep-wake timing and circadian phase were assessed from diaries and weekly measurements of urinary 6-sulphatoxymelatonin rhythms, respectively. In those subjects who woke at either a normal circadian phase (n = 26) or abnormally early (n = 5), alertness, mood and performance deteriorated significantly with increased time awake (P < 0.05). In 17 non-entrained (Ôfree-runningÕ) subjects, waking function varied significantly with circadian phase such that subjects rated themselves most sleepy (P = 0.03) and most miserable (P = 0.02) when they were awake during the time of peak melatonin production. The internal phase relationship between sleep-wake behaviour and the circadian melatonin rhythm in entrained subjects contributed to predictable differences in the daily profile of alertness, mood and performance. Disruption of this phase relationship in non-entrained blind individuals with circadian rhythm sleep disorders resulted in impaired waking function during the day equivalent to that usually only experienced when awake during the night. Treatment for circadian rhythm disorders should be targeted in normalizing these phase relationships.k e y w o r d s alertness,

MicroRNAs (miRs) are small, non-protein coding transcripts involved in many cellular functions. Many miRs have emerged as important cancer biomarkers. In the present study, we investigated whether miR levels in breast tumors are predictive of breast cancer local recurrence (LR). Sixty-eight women who were diagnosed with breast cancer at the Lombardi Comprehensive Cancer Center were included in this study. Breast cancer patients with LR and those without LR were matched on year of surgery, age at diagnosis, and type of surgery. Candidate miRs were identified by screening the expression levels of 754 human miRs using miR arrays in 16 breast tumor samples from 8 cases with LR and 8 cases without LR. Eight candidate miRs that showed significant differences between tumors with and without LR were further verified in 52 tumor samples using real-time PCR. Higher expression of miR-9 was significantly associated with breast cancer LR in all cases as well as the subset of estrogen receptor (ER) positive cases (p = 0.02). The AUCs (Area Under Curve) of receiver operating characteristic (ROC) curves of miR-9 for all tumors and ER positive tumors are 0.68 (p = 0.02) and 0.69 (p = 0.02), respectively. In ER positive cases, Kaplan-Meier analysis showed that patients with lower miR-9 levels had significantly better 10-year LR-free survival (67.9% vs 30.8%, p = 0.02). Expression levels of miR-9 and another miR candidate, miR-375, were also strongly associated with ER status (p<0.001 for both). The potential of miR-9 as a biomarker for LR warrants further investigation with larger sample size.

MAN1 is an integral protein of the inner nuclear membrane of the nuclear envelope (NE). MAN1 interacts with SMAD transcription factors, which in turn are regulated by the Transforming growth factor beta (TGF␤) superfamily of signaling molecules. To determine the role of MAN1 in mouse development, we used a gene-trap embryonic stem cell clone to derive mice with a functional mutation in MAN1 (Man1 GT/GT). Expression of Man1 during early development is initially low but increases at embryonic day 9.5 (E9.5). Coincident with this increase, homozygous gene-trapped Man1 (Man1 GT/GT) embryos die by E10.5. Examination of mutant embryos and tetraploid rescue experiments reveals that abnormal yolk-sac vascularization is the probable cause of lethality. We also established embryonic stem cell lines and their differentiated derivatives that are homozygous for the Man1 GT allele. Using these lines, we show that the Man1 GT allele results in increased phosphorylation, nuclear localization and elevated levels of SMAD transcriptional activity, predominantly of SMAD2/3, which are regulated by the ALK5 signaling pathway. Our studies identify a previously uncharacterized role for an integral nuclear envelope protein in the regulation of yolk-sac angiogenesis by TGF␤ signaling and reveal that the NE has an essential role in regulating transcription factor activity during mouse development.

We evaluated the chemopreventive effect of nonsteroidal anti-inflammatory drug (NSAID) use in head and neck squamous cell carcinomas (HNSCC) by conducting a case-control study based on the administration of a standardized questionnaire to 71 incident HNSCC cases and same number of healthy controls. NSAID use was associated with a 75% reduction in risk of developing HNSCC. A significant risk reduction was noted in association with frequency of NSAID use. Restricting the analysis to aspirin users revealed a significant 90% reduction in risk of developing HNSCC. This study provides evidence for a significant reduction in the risk of developing HNSCC in users of NSAIDs, and specifically aspirin users.