Autocrine Activation of the MET Receptor Tyrosine Kinase in Acute Myeloid Leukemia

Although the treatment of acute myeloid leukemia (AML) has improved significantly, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified aberrant expression of the hepatocyte growth factor (HGF) as a critical factor in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance due to compensatory upregulation of HGF expression, leading to restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked compensatory HGF upregulation, resulting in sustained logarithmic cell kill both in vitro and in xenograft models in vivo. Our results demonstrate widespread dependence of AML cells on autocrine activation of MET, as well as the importance of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers

Chewing Efficiency, Global Cognitive Functioning, and Dentition: A Cross-sectional Observational Study in Older People With Mild Cognitive Impairment or Mild to Moderate Dementia

10.3389/fnagi.2020.00225FRONTIERS IN AGING NEUROSCIENCE1

Mind your teeth—The relationship between mastication and cognition

This article explores the multifactorial relationship between mastication and cognition, with a focus on dementia. Older persons, especially those with dementia, are at great risk of suffering from oral health problems such as orofacial pain and loss of natural teeth. A possible explanation could be that the cognitive and motor impairments resulting from dementia cause a decrease in self-care and as such, a worsening of oral health. An alternative explanation is that cognition and oral health influence each other. Animal studies show that a decrease in masticatory activity, for example, due to a soft diet or loss of teeth, causes memory loss and neuronal degeneration. The relationship between mastication and cognition has also been researched in human studies, but a cause-effect relationship has not been proven. It is likely that multiple factors play a role in this relationship, such as self-care, nutrition, stress and pain

Oral hygiene and oral health in older people with dementia: a comprehensive review with focus on oral soft tissues

Background: The number of older people with dementia and a natural dentition is growing. Recently, a systematic review concerning the oral health of older people with dementia with the focus on diseases of oral hard tissues was published. Objective: To provide a comprehensive literature overview following a systematic approach of the level of oral hygiene and oral health status in older people with dementia with focus on oral soft tissues. Methods: A literature search was conducted in the databases PubMed, CINAHL, and the Cochrane Library. The following search terms were used: dementia and oral health or stomatognathic disease. A critical appraisal of the included studies was performed with the Newcastle-Ottawa scale (NOS) and Delphi list. Results: The searches yielded 549 unique articles, of which 36 were included for critical appraisal and data extraction. The included studies suggest that older people with dementia had high scores for gingival bleeding, periodontitis, plaque, and assistance for oral care. In addition, candidiasis, stomatitis, and reduced salivary flow were frequently present in older people with dementia. Conclusions: The studies included in the current systematic review suggest that older people with dementia have high levels of plaque and many oral health problems related to oral soft tissues, such as gingival bleeding, periodontal pockets, stomatitis, mucosal lesions, and reduced salivary flow. Scientific rationale for study: With the aging of the population, a higher prevalence of dementia and an increase in oral health problems can be expected. It is of interest to have an overview of the prevalence of oral problems in people with dementia. Principal findings: Older people with dementia have multiple oral health problems related to oral soft tissues, such as gingival bleeding, periodontal pockets, mucosal lesions, and reduced salivary flow. Practical implications: The oral health and hygiene of older people with dementia is not sufficient and could be improved with oral care education of formal and informal caregivers and regular professional dental care to people with dementia

Orofacial pain during rest and chewing in dementia patients admitted to acute hospital wards: Validity testing of the orofacial pain scale for non-verbal individuals

Aims: To assess the validity of the resting and chewing components of the recently developed observational diagnostic tool, the Orofacial Pain Scale for Non-Verbal Individuals (OPS-NVI). Methods: This cross-sectional observational study was carried out in two UK hospitals. A total of 56 participants with dementia who were admitted to the acute hospital were observed for 3 minutes during rest and during chewing, and the OPS-NVI was used to identify orofacial pain. Afterwards, the participants were asked about the presence of orofacial pain using self-report pain scales. The sensitivity, specificity, and area under the receiver operating curve (AUROC) of the OPS-NVI were calculated for each activity. Spearman coefficient was calculated to assess the correlation between the number of positively scored behavior items of the OPS-NVI and the presence of orofacial pain according to self-report. Results: According to the OPS-NVI, orofacial pain was present in 5.4% of participants during rest and in 9.1% during chewing. According to self-report, the prevalence of orofacial pain was 5.4% during rest and 10.7% during chewing. The specificity of the OPS-NVI was 98.1% to 100%, the sensitivity was 66.7% to 83.3%, and the AUROC was 0.824 to 0.917. The predictive validity showed a strong correlation (0.633 to 0.930, P < .001) between the number of positive behavior items and the self-reported presence of orofacial pain. Conclusion: The resting and chewing components of the OPS-NVI showed promising concurrent and predictive validity. Nevertheless, further validation is required and highly recommended

Psychometric evaluation of the Orofacial Pain Scale for Non-Verbal Individuals as a screening tool for orofacial pain in people with dementia

Objective: The aim of this study was to describe the psychometric evaluation of the Orofacial Pain Scale for Non-Verbal Individuals (OPS-NVI) as a screening tool for orofacial pain in people with dementia. Background: The OPS-NVI has recently been developed and needs psychometric evaluation for clinical use in people with dementia. The pain self-report is imperative as a reference standard and can be provided by people with mild-to-moderate cognitive impairment. Methods: The presence of orofacial pain during rest, drinking, chewing and oral hygiene care was observed in people with mild cognitive impairment (MCI) and dementia using the OPS-NVI. Participants who were considered to present a reliable self-report were asked about pain presence, and in all participants, the oral health was examined by a dentist for the presence of potential painful conditions. After item-reduction, inter-rater reliability and criterion validity were determined. Results: The presence of orofacial pain in this population was low (0%-10%), resulting in an average Positive Agreement of 0%-100%, an average Negative Agreement of 77%-100%, a sensitivity of 0%-100% and a specificity of 66%-100% for the individual items of the OPS-NVI. At the same time, the presence of oral problems, such as ulcers, tooth root remnants and caries was high (64.5%). Conclusion: The orofacial pain presence in this MCI and dementia population was low, resulting in low scores for average Positive Agreement and sensitivity and high scores for average Negative Agreement and specificity. Therefore, the OPS-NVI in its current form cannot be recommended as a screening tool for orofacial pain in people with MCI and dementia. However, the inter-rater reliability and criterion validity of the individual items in this study provide more insight for the further adjustment of the OPS-NVI for diagnostic use. Notably, oral health problems were frequently present, although no pain was reported or observed, indicating that oral health problems cannot be used as a new reference standard for orofacial pain, and a regular oral examination by care providers and oral hygiene care professionals remains indispensable

Orofacial pain and its potential oral causes in older people with mild cognitive impairment or dementia

10.1111/joor.12724JOURNAL OF ORAL REHABILITATION46123-3

Orofacial pain and its potential oral causes in older people with mild cognitive impairment or dementia

BACKGROUND: The number of people with dementia and natural dentition is growing. As dementia progresses, the degree of self-care decreases and the risk of oral health problems and orofacial pain increases. OBJECTIVES: To examine and compare the presence of orofacial pain and its potential causes in older people with Mild Cognitive Impairment (MCI) or dementia. METHODS: In this cross-sectional observational study, the presence of orofacial pain and its potential causes was studied in 348 participants with MCI or dementia with all levels of cognitive impairment in two outpatient memory clinics and ten nursing homes. RESULTS: Orofacial pain was reported by 25.7% of the 179 participants who were considered to present a reliable pain self-report (Mini-Mental State Examination score ≥14 points), while it could not be determined in people with more severe cognitive impairment. The oral health examination of the 348 participants indicated that potential painful conditions, such as coronal caries, root caries, tooth root remnants or ulcers were present in 50.3%. There was a significant correlation between the level of cognitive impairment and the number of teeth, r = 0.185, P = 0.003, teeth with coronal caries, r = -0.238, P < 0.001, and the number of tooth root remnants, r = -0.229, P = 0.004, after adjusting for age. CONCLUSIONS: This study indicated that orofacial pain and its potential causes were frequently present in participants with MCI or dementia. Therefore, a regular oral examination by (oral) healthcare providers in people with MCI or dementia remains imperative, even if no pain is reported