Self-reported oral health is associated with systemic health outcomes and all-cause mortality.

BACKGROUND: Self-reported oral health questions (OHQs) are used commonly for epidemiologic surveillance of periodontal disease (PD). The authors' objective was to investigate how OHQs are associated with well-established systemic comorbidities of PD and their impact on all-cause mortality. The authors hypothesized that OHQs exhibit associations with systemic comorbidities similar to PD. METHODS: Two independent data sets were used to achieve these objectives: the Women's Health Study, a prospective cohort of women 45 years or older with self-reported information on PD, OHQs, cardiovascular disease, diabetes, and osteoporosis in various timeframes (continuous from 1992) and the National Health and Nutrition Examination Survey (NHANES), with data on OHQs and linked mortality (1999-2018). The authors applied multivariate logistic regression models and Cox proportional hazard regression survival analyses to test their hypotheses. RESULTS: The Women's Health Study participants who reported having PD until 2006 were more likely to later report deteriorating oral health, bone loss around their teeth, or periodontal treatment in 2018. Self-rated fair or poor oral health was independently associated with increased risk of cardiovascular disease (odds ratio, 1.39; 95% CI, 1.14 to 1.69; P < .001), diabetes (odds ratio, 1.21; 95% CI, 1.02 to 1.43; P = .028), and osteoporosis (odds ratio, 1.60; 95% CI, 1.38 to 1.84; P < .001). National Health and Nutrition Examination Survey participants who self-rated fair or poor oral health had higher risks of all-cause mortality (hazard ratio, 1.18; 95% CI, 1.02 to 1.37; P = .027). CONCLUSIONS: Self-reported oral health had a similar magnitude of associations with systemic comorbidities as established with PD previously. Moreover, self-rated fair or poor oral health, suboptimal dental visits, or infrequent flossing were associated with increased all-cause mortality. PRACTICAL IMPLICATIONS: These results support the use of OHQs in assessing systemic connections, especially when clinical dental access is limited. This clinical trial was registered at ClinicalTrials.gov. The registration number is NCT00000479.

Tooth Retention and Clinical and Radiographic Long-Term Results Among Patients Treated with the Full-Mouth Laser-Assisted New Attachment Procedure (LANAP): A Case Series.

There are limited long-term treatment results for patients who receive full-mouth laser-assisted new attachment procedure (LANAP). The present study examined cases of full-mouth LANAP therapy for tooth retention, including clinical and radiographic changes. Sixty-six generalized stage III/IV periodontitis patients aged 30 to 76 years were identified via consecutive retrospective chart reviews in a private practice limited to periodontics. Following treatment with the LANAP protocol, differences between baseline and the patient's most recent periodontal maintenance visit (mean: 6.7 years) were determined regarding interproximal probing depths (iPD) and interproximal bone loss (iBL) percentages. Factors affecting tooth loss were analyzed using Cox proportional hazard regression survival analysis. The average tooth loss for the study population was 0.11 teeth/patient/year. Premolars were more likely to be retained compared to the reference group of incisors (hazard ratio = 0.38; 95% CI = 0.16 to 0.90; P = .03), adjusting for canines, molars, and other potential confounding factors. Age at the time of LANAP treatment, gender, history of diabetes, and baseline iBL and iPD were all significantly associated with tooth loss after full-mouth LANAP treatment. Clinical changes in iPD were more significant among premolars and molars when followed up for a period of less than 7 years. Tooth retention after full-mouth LANAP treatment was favorable in this cohort of private practice patients. Int J Periodontics Restorative Dent 2023;43:181-191. doi: 10.11607/prd.6418.

Candidate loci shared among periodontal disease, diabetes and bone density.

Introduction: While periodontal disease (PD) has been associated with type 2 diabetes (T2D) and osteoporosis, the underlying genetic mechanisms for these associations remain largely unknown. The aim of this study is to apply cross-trait genetic analyses to investigate the potentially shared biology among PD, T2D, and bone mineral density (BMD) by assessing pairwise genetic correlations and searching for shared polymorphisms. Methods: We applied cross-trait genetic analyses leveraging genome-wide association study (GWAS) summary statistics for: Periodontitis/loose teeth from the UKBB/GLIDE consortium (PerioLT, N=506594), T2D from the DIAGRAM consortium (Neff=228825), and BMD from the GEFOS consortium (N=426824). Among all three, pair-wise genetic correlations were estimated with linkage disequilibrium (LD) score regression. Multi-trait meta-analysis of GWAS (MTAG) and colocalization analyses were performed to discover shared genome-wide significant variants (pMTAG <5x10-8). For replication, we conducted independent genetic analyses in the Women's Genome Health Study (WGHS), a prospective cohort study of middle-aged women of whom 14711 provided self-reported periodontal disease diagnosis, oral health measures, and periodontal risk factor data including incident T2D. Results: Significant genetic correlations were identified between PerioLT/T2D (Rg=0.23; SE=0.04; p=7.4e-09) and T2D/BMD (Rg=0.09; SE=0.02; p=9.8e-06). Twenty-one independent pleiotropic variants were identified via MTAG (pMTAG<5x10-8 across all traits). Of these variants, genetic signals for PerioLT and T2D colocalized at one candidate variant (rs17522122; ProbH4 = 0.58), a 3'UTR variant of AKAP6. Colocalization between T2D/BMD and the original PerioLT GWAS p-values suggested 14 additional loci. In the independent WGHS sample, which includes responses to a validated oral health questionnaire for PD surveillance, the primary shared candidate (rs17522122) was associated with less frequent dental flossing [OR(95%CI)= 0.92 (0.87-0.98), p=0.007], a response that is correlated with worse PD status. Moreover, 4 additional candidate variants were indirectly supported by associations with less frequent dental flossing [rs75933965, 1.17(1.04-1.31), p=0.008], less frequent dental visits [rs77464186, 0.82(0.75-0.91), p=0.0002], less frequent dental prophylaxis [rs67111375, 0.91(0.83-0.99), p=0.03; rs77464186, 0.80(0.72-0.89), p=3.8e-05], or having bone loss around teeth [rs8047395, 1.09(1.03-1.15), p=0.005]. Discussion: This integrative approach identified one colocalized locus and 14 additional candidate loci that are shared between T2D and PD/oral health by comparing effects across PD, T2D and BMD. Future research is needed to independently validate our findings.

Number of teeth is associated with all-cause and disease-specific mortality.

BACKGROUND: Tooth loss has been shown to correlate with multiple systemic comorbidities. However, the associations between the number of remaining natural teeth (NoT) and all-cause mortality have not been explored extensively. We aimed to investigate whether having fewer NoT imposes a higher risk in mortality. We tested such hypotheses using three groups of NoT (20-28,10-19, and 0-9), edentulism and without functional dentition (NoT < 19). METHODS: The National Health and Nutrition Examination Survey in the United States (NHANES) (1999-2014) conducted dental examinations and provided linkage of mortality data. NHANES participants aged 20 years and older, without missing information of dental examination, age, gender, race, education, income, body-mass-index, smoking, physical activities, and existing systemic conditions [hypertension, total cardiovascular disease, diabetes, and stroke (N = 33,071; death = 3978), or with femoral neck bone mineral density measurement (N = 13,131; death = 1091)] were analyzed. Cox proportional hazard survival analyses were used to investigate risks of all-cause, heart disease, diabetes and cancer mortality associated with NoT in 3 groups, edentulism, or without functional dentition. RESULTS: Participants having fewer number of teeth had higher all-cause and disease-specific mortality. In fully-adjusted models, participants with NoT0-9 had the highest hazard ratio (HR) for all-cause mortality [HR(95%CI) = 1.46(1.25-1.71); p < .001], mortality from heart diseases [HR(95%CI) = 1.92(1.33-2.77); p < .001], from diabetes [HR(95%CI) = 1.67(1.05-2.66); p = 0.03], or cancer-related mortality [HR(95%CI) = 1.80(1.34-2.43); p < .001]. Risks for all-cause mortality were also higher among the edentulous [HR(95%CI) = 1.35(1.17-1.57); p < .001] or those without functional dentition [HR(95%CI) = 1.34(1.17-1.55); p < .001]. CONCLUSIONS: Having fewer NoT were associated with higher risks for all-cause mortality. More research is needed to explore possible biological implications and validate our findings.

Two-Sample Mendelian Randomization Analysis of Associations Between Periodontal Disease and Risk of Cancer.

Background: Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks. Methods: Our primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided. Results: The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups. Conclusions: Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.

Number of teeth is associated with hip fracture and femoral neck bone mineral density in the NHANES.

PURPOSE/INTRODUCTION: Tooth loss has been found to be associated with fractures and osteoporosis. However, the associations between number of teeth with bone mineral density as well as with hip fractures have not been explored in the same study setting. METHODS: Data from the cross-sectional National Health and Nutrition Examination Survey (2005-2010, 2013-2014, and 2017-2018) with completed femoral neck bone mineral density (BMD) measurements, osteoporosis questionnaires, and dentition examinations were analyzed. A total of 15,198 participants, with a mean age of 53.9 and diverse ethnicity, males (52%), and females (48%), were analyzed. Multivariate logistic regression analyses for self-reported hip fractures, self-reported osteoporosis, and measured low femoral BMD accounting for traditional risk factors were tested for the total number of natural teeth (NoT) present, or by NoT in the anterior or posterior segments. RESULTS: Subjects with fewer natural teeth present were more likely to report a hip fracture, osteoporosis, or having lower levels of femoral neck BMD. With one additional tooth present in the mouth, there was a decreased association with self-reported hip fracture [OR(95%CI) = 0.98(0.96-0.99); P = 0.005] or with less likelihood of having low femoral neck BMD [OR(95%CI) = 0.99(0.97-1.00); P = 0.007]. CONCLUSIONS: With the limitation of the cross-sectional study design, results should be interpreted cautiously, yet our analyses point to an association between a decreased number of natural teeth present and self-reported hip fractures or low femoral neck BMD. The number of teeth present could be potentially utilized for assessing risks of hip fracture and osteoporosis. Future research is needed to validate our findings.

Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.

In vivo identification of Bmp2-correlation networks during fracture healing by means of a limb-specific conditional inactivation of Bmp2.

Bmp2 is known to play an essential role in the initiation of fracture healing via periosteal activation. Specifically, activation and subsequent differentiation of periosteal progenitor cells requires Bmp2 signaling for activation of the osteo-chondrogenic pathway. Here, we explored the interactive transcriptional gene-gene interplays between Bmp2 and 150 known candidate genes during fracture repair. We constructed the interactive Bmp2 signaling pathways in vivo, by comparing gene expression levels prior and 24 h post femur fracture, in presence (wild type) and in absence of Bmp2 (Bmp2c/c;Prx1::cre limb-specific conditional knockout). Twenty-six differentially expressed genes (pre- vs. post-fracture), which demonstrated high correlations within each experimental condition, were used to construct the co-expression networks. Topological dynamic shifts across different co-expression networks characterized the 26 differentially expressed genes as non-redundant focal linking hubs, redundant connecting hubs, periphery genes, or non-existent. Top-ranked up- or down-regulated genes were identified and discussed. Protein-protein interactions in public databases support our findings. Thus, the co-expression networks from this study can be used for future experimental hypotheses.

Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study.

Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with <17 teeth was 1.20 (1.04-1.39). With regard to tumor site, the HRs (95% CIs) for the same comparison were 1.23 (1.01-1.51) for proximal colon cancer, 1.03 (0.76-1.38) for distal colon cancer and 1.48 (1.07-2.05) for rectal cancer. In addition, compared to those without periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis.

Treatment of Moderate to Severe Buccal Gingival Recession Defects with Placental Allografts.

A multicenter prospective consecutive case series study was conducted to evaluate the effectiveness of placental allografts to correct moderate to severe buccogingival recession defects. Nineteen healthy patients, 13 women and 6 men, ranging in age from 29 to 63 years, with 43 maxillary and mandibular gingival recession defects of > 4 mm deep were included. Clinical examination at multiple postsurgery time points revealed healthy maturation of gingival tissues with normal color and texture matched to adjacent soft tissue areas. Complete root coverage was not achieved in all cases in this proof of principle evaluation. Severe buccal bone loss had occurred in most of the selected cases, which may have negatively influenced the results. Nonetheless, it was possible to achieve root coverage and demonstrate gain in clinical attachment level and height of keratinized tissue when placental allograft was used. Future randomized clinical trials are needed to further explore the potential of placental allografts for treatment of localized gingival recession defects.

Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium.

BACKGROUND: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI). METHODS: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49,066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17,672/31,394 with/without periodontitis); 68,761 participants with BMI and genotype data; and 57,871 participants (18,881/38,990 with/without periodontitis) with data on BMI and periodontitis. RESULTS: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data. CONCLUSIONS: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.

CD147 and Ki-67 overexpression confers poor prognosis in squamous cell carcinoma of oral tongue: a tissue microarray study.

OBJECTIVE: Squamous cell carcinoma of the oral tongue (SCCOT) exhibits high risk for recurrence and regional metastasis even after surgical resection. We assessed the clinicopathologic and prognostic significance of a group of functionally related biomarkers. STUDY DESIGN: We used a tissue microarray consisting of SCCOT from 32 patients for this study. These patients were treated at the University of Texas MD Anderson Cancer Center from 1995 to 2008. Biomarker expression levels were examined by immunohistochemistry and graded semiquantitatively to determine their prognostic significance. RESULTS: CD147 and Tp63 expressions were significantly associated with a higher T stage and Ki-67 labeling index, as well as a shorter overall survival (OS) rate. Expression of Tp63 associated positively with poorly differentiated histology. There was significant association of Tp63 with the expression levels of CD147 and Glut-1. Glut-1 overexpression was marginally associated with a higher T stage. There was no prognostic significance of CD44 v6 expression in SCCOT. CONCLUSION: SCCOT with CD147 overexpression in combination with high Ki-67 labeling index had poor OS. CD147 and Ki-67 overexpression is associated with aggressive disease with poor prognosis in SCCOT.

Cardiovascular risks associated with incident and prevalent periodontal disease.

AIM: While prevalent periodontal disease associates with cardiovascular risk, little is known about how incident periodontal disease influences future vascular risk. We compared effects of incident versus prevalent periodontal disease in developing major cardiovascular diseases (CVD), myocardial infarction (MI), ischaemic stroke and total CVD. MATERIAL AND METHODS: In a prospective cohort of 39,863 predominantly white women, age ≥45 years and free of cardiovascular disease at baseline were followed for an average of 15.7 years. Cox proportional hazard models with time-varying periodontal status [prevalent (18%), incident (7.3%) versus never (74.7%)] were used to assess future cardiovascular risks. RESULTS: Incidence rates of all CVD outcomes were higher in women with prevalent or incident periodontal disease. For women with incident periodontal disease, risk factor adjusted hazard ratios (HRs) were 1.42 (95% CI, 1.14-1.77) for major CVD, 1.72 (1.25-2.38) for MI, 1.41 (1.02-1.95) for ischaemic stroke and 1.27 (1.06-1.52) for total CVD. For women with prevalent periodontal disease, adjusted HRs were 1.14 (1.00-1.31) for major CVD, 1.27 (1.04-1.56) for MI, 1.12 (0.91-1.37) for ischaemic stroke and 1.15 (1.03-1.28) for total CVD. CONCLUSION: New cases of periodontal disease, not just those that are pre-existing, place women at significantly elevated risks for future cardiovascular events.

Network biology of tumor stem-like cells identified a regulatory role of CBX5 in lung cancer.

Mounting evidence links cancers possessing stem-like properties with worse prognosis. Network biology with signal processing mechanics was explored here using expression profiles of a panel of tumor stem-like cells (TSLCs). The profiles were compared to their parental tumor cells (PTCs) and the human embryonic stem cells (hESCs), for the identification of gene chromobox homolog 5, CBX5, as a potential target for lung cancer. CBX5 was found to regulate the stem-like properties of lung TSLCs and was predictive of lung cancer prognosis. The investigation was facilitated by finding target genes based on modeling epistatic signaling mechanics via a predictive and scalable network-based survival model. Topologically-weighted measurements of CBX5 were synchronized with those of BIRC5, DNMT1, E2F1, ESR1, MLH1, MSH2, RB1, SMAD1 and TAF5. We validated our findings in another Taiwanese lung cancer cohort, as well as in knockdown experiments using sh-CBX5 RNAi both in vitro and in vivo.

White blood cell count and psychomotor cognitive performance in the elderly.

BACKGROUND: White blood cell (WBC) count is associated with many inflammatory diseases such as cardiovascular disease, diabetes and hypertension. Research on the relationship of WBC count and cognition in the elderly is relatively sparse. This study examined the association between WBC count and cognitive performance in older adults. METHODS: Data from the National Health and Nutrition Examination Survey (1999-2002) containing 1670 older adults were analysed. Every subject completed a household interview, examination of digit symbol substitution test (DSST) scores, WBC count measurement and a questionnaire regarding personal health. WBC count was restricted to the normal range and divided into quartiles, using a multiple hierarchical regression model to estimate the relationship between WBC counts and DSST scores. Quartile-based analysis with an extended-model approach was used for further covariates adjustment. Trends test examining the associations across increasing quartiles of WBC counts and DSST scores were also conducted. RESULTS: In the multiple hierarchical regression model, the ß coefficient, representing the change of DSST scores for each 1000 cells uL(-1) increase in WBC count, was -0·097 (R(2) = 0·343, P < 0·001). After additional competent covariates adjustment, the negative correlation remained (all P < 0·001). In quartile-based multiple linear regression, the negative trends between DSST scores and WBC count quartiles in the stratified comparison with extended-model approach were all statistically significant (P for trends <0·001). CONCLUSIONS: Higher WBC counts, even within the normal range, were associated with poor psychomotor cognitive performance in the elderly.

Oral health status and self-reported functional dependence in community-dwelling older adults.

OBJECTIVES: To assess the strength of association between graded groups of oral health status and self-reported functional dependence in community-dwelling older adults. DESIGN: Population-based cross-sectional study. SETTING: National Health and Nutritional Examination Survey (NHANES) 1999 to 2004. PARTICIPANTS: Three thousand eight hundred fifty-six participants aged 60 and older (mean age 71.2) without missing values in the examined correlates. MEASUREMENTS: Oral health status was evaluated according to edentulism, severity of periodontal disease, and recommendation of periodontal care and compared with that of healthy controls. Self-reported functional dependence was assessed according to 19 questions in five domains: activities of daily living (ADLs), instrumental activities of daily living (IADLs), leisure and social activities (LSAs), lower extremity mobility (LEM), and general physical activities (GPAs). RESULTS: After controlling for demographic and dental variables, health-related behaviors, C-reactive protein, and comorbidities, edentulism was significantly associated with disability in IADLs (odds ratio (OR)=1.58), LSAs (OR=1.63), LEM (OR=1.31), and GPAs (OR=1.45) compared with healthy controls. Likewise, severe periodontitis was associated with disability in IADLs (OR=1.58), LSAs (OR=1.70), and LEM (OR=1.63). The trends toward disability in IADLs, LSAs, LEM, and GPAs were statistically significant across increasing severity of oral health problems. CONCLUSION: Poor oral health, specifically edentulism and severe periodontitis, is associated with multiple domains of late-life disability, but a causal relationship cannot be established based on current study design.

The epithelial-mesenchymal transition mediator S100A4 maintains cancer-initiating cells in head and neck cancers.

Cancer-initiating cells (CIC) comprise a rare subpopulation of cells in tumors that are proposed to be responsible for tumor growth. Starting from CICs identified in head and neck squamous cell carcinomas (HNSCC), termed head and neck cancer-initiating cells (HN-CIC), we determined as a candidate stemness-maintaining molecule for HN-CICs the proinflammatory mediator S100A4, which is also known to be an inducer of epithelial-mesenchymal transition. S100A4 knockdown in HN-CICs reduced their self-renewal capability and their stemness and tumorigenic properties, both in vitro and in vivo. Conversely, S100A4 overexpression in HNSCC cells enhanced their stem cell properties. Mechanistic investigations indicated that attenuation of endogenous S100A4 levels in HNSCC cells caused downregulation of Notch2 and PI3K (phosphoinositide 3-kinase)/pAKT along with upregulation of PTEN, consistent with biological findings. Immunohistochemical analysis of HNSCC clinical specimens showed that S100A4 expression was positively correlated with clinical grading, stemness markers, and poorer patient survival. Together, our findings reveal a crucial role for S100A4 signaling pathways in maintaining the stemness properties and tumorigenicity of HN-CICs. Furthermore, our findings suggest that targeting S100A4 signaling may offer a new targeted strategy for HNSCC treatment by eliminating HN-CICs.

Elimination of head and neck cancer initiating cells through targeting glucose regulated protein78 signaling.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer that contains cellular and functional heterogeneity. Previously, we enriched a subpopulation of highly tumorigenic head and neck cancer initiating cells (HN-CICs) from HNSCC. However, the molecular mechanisms by which to govern the characteristics of HN-CICs remain unclear. GRP78, a stress-inducible endoplasmic reticulum chaperone, has been reported to play a crucial role in the maintenance of embryonic stem cells, but the role of GRP78 in CICs has not been elucidated. RESULTS: Initially, we recognized GRP78 as a putative candidate on mediating the stemness and tumorigenic properties of HN-CICs by differential systemic analyses. Subsequently, cells with GRP78 anchored at the plasma membrane (memGRP78+) exerted cancer stemness properties of self-renewal, differentiation and radioresistance. Of note, xenotransplantation assay indicated merely 100 memGRP78+ HNSCCs resulted in tumor growth. Moreover, knockdown of GRP78 significantly reduced the self-renewal ability, side population cells and expression of stemness genes, but inversely promoted cell differentiation and apoptosis in HN-CICs. Targeting GRP78 also lessened tumorigenicity of HN-CICs both in vitro and in vivo. Clinically, co-expression of GRP78 and Nanog predicted the worse survival prognosis of HNSCC patients by immunohistochemical analyses. Finally, depletion of GRP78 in HN-CICs induced the expression of Bax, Caspase 3, and PTEN. CONCLUSIONS: In summary, memGRP78 should be a novel surface marker for isolation of HN-CICs, and targeting GRP78 signaling might be a potential therapeutic strategy for HNSCC through eliminating HN-CICs.

A family history of diabetes mellitus is associated with poor glycemic control and increased metabolic risks among people with diabetes: data from the National Health and Nutrition Examination Survey 1999-2004.

BACKGROUND: Several lines of evidence from studies involving both general and non-diabetic populations have shown that a family history of diabetes was associated with an increased risk for cardiovascular diseases and metabolic alterations. However, little is known about the relationship of a family history of diabetes to glycemic control and metabolic risks among people with diabetes. METHODS: We conducted a cross-section study of 946 diabetic adults from the National Health and Nutrition Examination Survey between 1999 and 2004. Familial risk of diabetes was classified as average, moderate, or high. Logistic regression analyses were conducted to determine the association between familial risk of diabetes and poor glycemic control, as defined by A1C > or = 8%. According to stratified levels of familial risk of diabetes, adjusted means of various metabolic risks, including A1C, BMI, lipid profiles, and C-reactive protein, were obtained by using multiple linear regression. RESULTS: Independent of basic demographics, health-related behaviors, use of anti-diabetic medications, diabetes duration, cardiovascular co-morbidities, and various metabolic risks, the odds ratio of poor glycemic control comparing participants with a high familial risk of diabetes to those with an average risk was 1.91 (95% confidence interval 1.02-3.58). In the multivariate analysis, the adjusted means of A1C in participants with high, moderate, and averaged familial risk of diabetes were 7.75%, 7.45%, and 7.25%, respectively (p for trend 0.036). Participants with a high familial risk of diabetes also had higher triglycerides and body mass index (p for trend 0.042 and 0.02, respectively). CONCLUSION: Diabetic adults with a higher familial risk of diabetes have a worse glycemic control, higher BMI, and higher triglycerides. Obtaining family history of the disease is crucial in identifying and targeting high risk diabetic patients who may require more stringent lifestyle changes as well as pharmaceutical intervention.