Building effective public dental care programs: The critical role of implementation evaluation.

There are significant income-related inequities in oral health and access to oral health care. Public dental programs generally aim to increase access to oral health care for individuals with financial barriers through government payments for appointments. Low engagement from both oral health care providers and intended patients are common challenges in delivery of public dental programs, and are impediments to program impact and outcomes. Still, these programs rarely address the systemic issues that affect the experiences of intended users. This accentuates the importance of monitoring of program delivery to refine or adapt programs to better meet needs of service providers and users. As such, specifying program goals and developing a related monitoring strategy are critical as Canada begins to implement a national public dental program. Drawing on an example of a pediatric public dental program for children from low-income families or with severe disabilities in Ontario, Canada, this article illustrates how an implementation and evaluation framework could be applied to measure implementation and impact of the national program. The RE-AIM framework measures performance across five domains: (1) Reach, (2) Effectiveness (patient level), (3) Adoption, (4) Implementation (provider, setting, and policy levels), and (5) Maintenance (all levels). Given the disparities in oral disease and access to oral health care, the results can be used most effectively to adapt programs if relevant stakeholders participate in reviewing data, investigating quality gaps, and developing improvement strategies.

Detection of Bacteria-Induced Early-Stage Dental Caries Using Three-Dimensional Mid-Infrared Thermophotonic Imaging.

Tooth decay, or dental caries, is a widespread and costly disease that is reversible when detected early in its formation. Current dental caries diagnostic methods including X-ray imaging and intraoral examination lack the sensitivity and specificity required to routinely detect caries early in its formation. Thermophotonic imaging presents itself as a highly sensitive and non-ionizing solution, making it suitable for the frequent monitoring of caries progression. Here, we utilized a treatment protocol to produce bacteria-induced caries lesions. The lesions were imaged using two related three-dimensional photothermal imaging modalities: truncated correlation photothermal coherence tomography (TC-PCT) and its enhanced modification eTC-PCT. In addition, micro-computed tomography (µ-CT) and visual inspection by a clinical dentist were used to validate and quantify the severities of the lesions. The observational findings demonstrate the high sensitivity and depth profiling capabilities of the thermophotonic modalities, showcasing their potential use as a non-ionizing clinical tool for the early detection of dental caries.

Effects of chloroquine and hydroxychloroquine on the sensitivity of pancreatic cancer cells to targeted therapies.

Approaches to improve pancreatic cancer therapy are essential as this disease has a very bleak outcome. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is a cancer which is difficult to effectively treat as it is often detected late in the disease process. Almost all PDACs (over 90%) have activating mutations in the GTPase gene KRAS. These mutations result in constitutive KRas activation and the mobilization of downstream pathways such as the Raf/MEK/ERK pathway. Small molecule inhibitors of key components of the KRas/Raf/MEK/ERK pathways as well as monoclonal antibodies (MoAbs) specific for upstream growth factor receptors such insulin like growth factor-1 receptor (IGF1-R) and epidermal growth factor receptors (EGFRs) have been developed and have been evaluated in clinical trials. An additional key regulatory gene frequently mutated (∼75%) in PDAC is the TP53 tumor suppressor gene which controls the transcription of multiple genes involved in cell cycle progression, apoptosis, metabolism, cancer progression and other growth regulatory processes. Small molecule mutant TP53 reactivators have been developed which alter the structure of mutant TP53 protein and restore some of its antiproliferative activities. Some mutant TP53 reactivators have been examined in clinical trials with patients with mutant TP53 genes. Inhibitors to the TP53 negative regulator Mouse Double Minute 2 (MDM2) have been developed and analyzed in clinical trials. Chloroquine and hydroxychloroquine are established anti-malarial and anti-inflammatory drugs that also prevent the induction of autophagy which can have effects on cancer survival. Chloroquine and hydroxychloroquine have also been examined in various clinical trials. Recent studies are suggesting effective treatment of PDAC patients may require chemotherapy as well as targeting multiple pathways and biochemical processes.

Inadequacy of self-Implemented preventive measures to control caries increment due to poor dietary habits in 6 and 12 years old children in Riga, Latvia.

AIM: This study investigated whether the self-implemented preventive measures practiced among the 6 and 12 years olds in Riga, Latvia can control the caries increment due to poor dietary habits among this age groups. MATERIAL AND METHODS: Caries examination was performed on Thirty-eight 6 and thirty-nine 12 years olds by visual and bitewing radiographic examination at baseline and after 3 years. All participants and/or their parents completed dietary habits questionnaires. The data was analyzed using t-test, chi-square test, ANOVA and frequency tables, Wilcoxon and Fisher's tests (α=0.05). RESULTS: The mean (SD) values of caries experience at baseline/3-year period in 6- vs.12-year olds were as follows. DMFS: 0.72 (1.02)/3.13 (3.13) (p=0.0000) vs. 6.79 (5.14)/14.79 (9.86) (p=0.0000); dmfs: 11.26(8.71)/7.74 (4.86) (p=0.078) vs. 3.57 (2.03)/1.5 (0.71) (p=0.317). The statistical significance was reported only for the consumption of soft drinks (p=0.032) and sugared tea (p=0.018) for the 6 years olds, and for sugared tea (p=0.017) and number of teaspoons of sugar added to tea (p=0.0095) for the 12-years olds. There was positive caries increment in all the 6 and 12 years olds that reported significant increase in consumption of soft drinks and sugared tea, and increase daily number of teaspoons of sugar used in tea. CONCLUSIONS: The present study demonstrated high cariogenic diet among the children in Riga, which is associated with increased caries experience that the currently practiced self-implemented oral hygiene measures was not capable of controlling.

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression.

Approximately 90% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is the fourth leading cause of cancer death world-wide. Therapies for PDAC are largely ineffective due to the dense desmoplastic tumor microenvironment which prevents chemotherapeutic drugs and small molecule inhibitors from exerting effective anti-cancer effects. In this review, we will discuss the roles of TP53 and miRs on the PDAC tumor microenvironment and how loss of the normal functions of TP53 promote tumor progression. The TP53 gene is mutated in approximately 50% of pancreatic cancers. Often, these TP53 mutations are point mutations which confer additional functions for the TP53 proteins. These are called gain of function (GOF) mutations (mut). Another class of TP53 mutations are deletions which result in loss of the TP53 protein; these are referred to TP53-null mutations. We have organized this review into various components/properties of the PDAC microenvironment and how they may be altered in the presence of mutant TP53 and loss of certain miR expression.

The Effect of MI Varnish™ on Caries Increment and Dietary Habits among 6- and 12-Year-Old Children in Riga, Latvia: A 3-Year Randomized Controlled Trial.

Aims: This randomized controlled trial investigated the effect of MI Varnish™ (5% NaF/CPP-ACP) on caries increment in 6- and 12-year-old children in Riga, Latvia within 36 months. Methods: Forty-eight 6-year-old children (Group 1) and forty-seven 12-year-old children (Group 3) received quarterly varnish application, while forty-eight 6-year-old children (Group 2) and thirty-seven 12-year-old children (Group 4) did not have varnish applied. All children/parents received the same preventive advice. All children were visually examined using ICDAS-II criteria. Questionnaires on dietary habits were completed by the children/parents at baseline and after 36 months. DMFS and dfs were calculated from ICDAS data. The statistical analysis was performed (α = 0.05) using a Chi-squared test, paired t-test (Welch test) and the Pearson correlation coefficient. The trial registration number is ISRCTN10584414. Results: In Group 1 versus Group 2, the DMFS(SD) (Baseline/36 months) values were 5.02(5.85)/13.21(6.67) (p < 0.001) versus 2.65(4.54)/10.81(6.14) (p < 0.001), respectively; the dfs(SD) (Baseline/36 months) values were 36.75(12.96)/24.04(12.9) (p < 0.001) versus 33.67(12.74)/23.88(11.91) (p < 0.001), respectively. In Group 3 versus Group 4, the DMFS(SD) (Baseline/36 months) values were 48.62(23.18)/70.96(23.28) (p < 0.001) versus 34.73(17.99)/54.95(16.09) (p < 0.001), respectively; the dfs(SD) (Baseline/36 months) values were 1.7(4.4)/0 (p < 0.05) versus 2(6.39)/0 (p = 0.06), respectively. The prevalence of caries (dfs + DMFS) decreased by 4.52 (p < 0.001) and 1.63 (p < 0.001) in Groups 1 and 2, respectively, but increased by 20.64 (p < 0.001) and 18.22 (p < 0.001) in Groups 3 and 4, respectively. An analysis of the questionnaires indicated the habitual, frequent consumption of a sugary diet by all the children. A significant correlation (r = 0.321; p < 0.05) was observed between caries increment and the frequency of daily intake of sugary snacks, soft drinks and tea with sugar at baseline only in Group 1. Conclusions: A quarterly application of MI varnish (CPP-ACP/fluoride) reduced caries increment in 6- and 12-year-old children in Riga, Latvia.

Wild type and gain of function mutant TP53 can regulate the sensitivity of pancreatic cancer cells to chemotherapeutic drugs, EGFR/Ras/Raf/MEK, and PI3K/mTORC1/GSK-3 pathway inhibitors, nutraceuticals and alter metabolic properties.

TP53 is a master regulator of many signaling and apoptotic pathways involved in: aging, cell cycle progression, gene regulation, growth, apoptosis, cellular senescence, DNA repair, drug resistance, malignant transformation, metastasis, and metabolism. Most pancreatic cancers are classified as pancreatic ductal adenocarcinomas (PDAC). The tumor suppressor gene TP53 is mutated frequently (50-75%) in PDAC. Different types of TP53 mutations have been observed including gain of function (GOF) point mutations and various deletions of the TP53 gene resulting in lack of the protein expression. Most PDACs have point mutations at the KRAS gene which result in constitutive activation of KRas and multiple downstream signaling pathways. It has been difficult to develop specific KRas inhibitors and/or methods that result in recovery of functional TP53 activity. To further elucidate the roles of TP53 in drug-resistance of pancreatic cancer cells, we introduced wild-type (WT) TP53 or a control vector into two different PDAC cell lines. Introduction of WT-TP53 increased the sensitivity of the cells to multiple chemotherapeutic drugs, signal transduction inhibitors, drugs and nutraceuticals and influenced key metabolic properties of the cells. Therefore, TP53 is a key molecule which is critical in drug sensitivity and metabolism of PDAC.

Protocol for a Case Control Study to Evaluate Oral Health as a Biomarker of Child Exposure to Adverse Psychosocial Experiences.

BACKGROUND: The early identification of children who have experienced adversity is critical for the timely delivery of interventions to improve coping and reduce negative consequences. Self-report is the usual practice for identifying children with exposure to adversity. However, physiological characteristics that signal the presence of disease or other exposures may provide a more objective identification strategy. This protocol describes a case-control study that assesses whether exposure to adversity is more common in children with tooth enamel anomalies compared to children without such anomalies. METHODS: For 150 mother-child pairs from a pediatric dental clinic in Toronto, Canada, maternal interviews will assess the child's adverse and resilience-building experiences. Per child, one (exfoliated or extracted) tooth will be assessed for suspected enamel anomalies. If anomalies are present, the child is a case, and if absent, the child is a control. Tooth assessment modalities will include usual practice for dental exams (visual assessment) and modalities with greater sensitivity to identify anomalies. CONCLUSION: If structural changes in children's teeth are associated with exposure to adversity, routine dental exams could provide an opportunity to screen children for experiences of adversity. Affected children could be referred for follow-up.

Effects of the Mutant TP53 Reactivator APR-246 on Therapeutic Sensitivity of Pancreatic Cancer Cells in the Presence and Absence of WT-TP53.

The TP53 tumor suppressor is mutated in ~75% of pancreatic cancers. The mutant TP53 protein in pancreatic ductal adenocarcinomas (PDAC) promotes tumor growth and metastasis. Attempts have been made to develop molecules that restore at least some of the properties of wild-type (WT) TP53. APR-246 is one such molecule, and it is referred to as a mutant TP53 reactivator. To understand the potential of APR-246 to sensitize PDAC cells to chemotherapy, we introduced a vector encoding WT-TP53 into two PDAC cell lines, one lacking the expression of TP53 (PANC-28) and one with a gain-of-function (GOF) mutant TP53 (MIA-PaCa-2). APR-246 increased drug sensitivity in the cells containing either a WT or mutant TP53 protein with GOF activity, but not in cells that lacked TP53. The introduction of WT-T53 into PANC-28 cells increased their sensitivity to the TP53 reactivator, chemotherapeutic drugs, and signal transduction inhibitors. The addition of WT-TP53 to PDAC cells with GOF TP53 also increased their sensitivity to the drugs and therapeutics, indicating that APR-246 could function in cells with WT-TP53 and GOF TP53. These results highlight the importance of knowledge of the type of TP53 mutation that is present in cancer patients before the administration of drugs which function through the reactivation of TP53.

Comparison of Long-Wave and Mid-Wave Infrared Imaging Modalities for Photothermal Coherence Tomography of Human Teeth.

The ability to detect dental caries at early stages lies at the heart of minimal intervention dentistry, enabling the curing or arresting of carious lesions before they advance to the cavity stage. Enhanced truncated-correlation photothermal coherence tomography (eTC-PCT) using mid-wave infrared (MWIR) cameras has recently been shown to offer tomographic visualization of early caries. The tomographic slicing ability of such systems, however, is believed to be limited by direct radiative thermal emission through the translucent dental enamel in the 3-5 µm MWIR spectral range. Such radiative emissions can dominate the delayed conductive thermal contributions needed for tomographic reconstruction of internal dental defects. It has been hypothesized that long-wave infrared (LWIR) eTC-PCT systems may offer better tomographic performance by taking advantage of the intrinsic attenuation of direct radiative emission by dental enamel in the LWIR spectral range, enabling more effective delayed conductive thermal contributions from subsurface caries. More than an order of magnitude lower cost of the system is another key attribute of LWIR eTC-PCT which can open the door for downstream translation of the technology to clinics. In this report, we offer a systematic comparison of the performance/effectiveness of caries detection with LWIR and MWIR eTC-PCT systems for detecting natural caries, bacterial caries, and artificially demineralized enamel surfaces. Our results suggest that the low-cost LWIR based eTC-PCT system provides 3D visualization and 2D slice-by-slice images of early caries and internal micro-cracks similar to those obtained from the more expensive MWIR-based eTC-PCT system, albeit with ∼1.3dB lower signal-to-noise ratio.

APR-246-The Mutant TP53 Reactivator-Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. In ~75% of PDAC, the tumor suppressor TP53 gene is mutated. Novel approaches to treat cancer involve compounds called mutant TP53 reactivators. They interact with mutant TP53 proteins and restore some of their growth suppressive properties, but they may also interact with other proteins, e.g., TP63 and TP73. We examined the ability of the TP53 reactivator APR-246 to interact with eleven modified berberine compounds (NAX compounds) in the presence and absence of WT-TP53 in two PDAC cell lines: the MIA-PaCa-2, which has gain of function (GOF) TP53 mutations on both alleles, and PANC-28, which lacks expression of the WT TP53 protein. Our results indicate the TP53 reactivator-induced increase in therapeutic potential of many modified berberines.

Effects of the MDM2 inhibitor Nutlin-3a on sensitivity of pancreatic cancer cells to berberine and modified berberines in the presence and absence of WT-TP53.

Approaches to improve pancreatic cancer therapy are essential as this disease has a very bleak outcome. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). A key regulatory gene frequently mutated (∼75%) in PDAC is the TP53 tumor suppressor gene which controls the transcription of multiple genes involved in cell cycle progression, apoptosis, cancer progression and other growth regulatory processes. The mouse double minute 2 homolog (MDM2) gene product is a nuclear-localized E3 ubiquitin ligase and negatively regulates the TP53 protein which results in its proteasomal degradation. Various MDM2 inhibitors have been isolated and examined in clinical trials, especially in patients with hematological malignancies. Nutlin-3a is one of the first MDM2 inhibitors isolated. Berberine (BBR) is a natural product found in many fruits and berries and used in traditional medicine for centuries. It has many biological effects, and some are anti-proliferative in nature. BBR may activate the expression of TP53 and inhibit cell cycle progression as well as other events important in cell growth. To understand more about the potential of compounds like BBR and chemical modified BBRs (NAX compounds) to sensitize PDAC cells to MDM2 inhibitors, we introduced either WT-TP53 or the pLXSN empty vector control into two PDAC cell lines, one lacking expression of TP53 (PANC-28) and one with gain-of-function mutant TP53 on both alleles (MIA-PaCa-2). Our results indicate that nutlin-3a was able to increase the sensitivity to BBR and certain NAX compounds. The effects of nutlin-3a were usually more substantial in those cells containing an introduced WT TP53 gene. These results highlight the importance of knowledge of the type of TP53 mutation that is present in cancer patients before the administration of drugs which function by stabilization of the TP53 protein.

GSK-3ß Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals.

Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate the roles of GSK-3ß in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3ß. Transfection of MIA-PaCa-2 cells with WT-GSK-3ß increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3ß often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3ß and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3ß reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3ß decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects of GSK-3 on MCF-7 breast cancer cells, which have mutant PIK3CA, were examined. KD-GSK-3ß increased the resistance of MCF-7 cells to chemotherapeutic drugs and certain signal transduction inhibitors. Thus, altering the levels of GSK-3ß can have dramatic effects on sensitivity to drugs and signal transduction inhibitors which may be influenced by the background of the tumor.

Detection and monitoring of early dental caries and erosion using three-dimensional enhanced truncated-correlation photothermal coherence tomography imaging.

SIGNIFICANCE: Dental caries is the most common oral disease, with significant effects on healthcare systems and quality of life. Developing diagnostic methods for early caries detection is key to reducing this burden and enabling non-invasive treatment as opposed to the drill-and-fill approach. AIM: The application of a thermophotonic-based 3D imaging modality [enhanced truncated-correlation photothermal coherence tomography (eTC-PCT)] to early dental caries is investigated. To this end, the detection threshold, sensitivity, and 3D lesion reconstruction capability of eTC-PCT in imaging artificially generated caries and surface erosion are evaluated. APPROACH: eTC-PCT employs a diode laser with pulsed excitation, a mid-IR camera, and an in-house developed image reconstruction algorithm to produce depth-resolved 2D images and 3D reconstructions. Starting with healthy teeth, dental caries and surface erosion are simulated in vitro through application of specific demineralizing/eroding acidic solutions. RESULTS: eTC-PCT can detect artificial caries as early as 2 days after onset of artificial demineralization and after 45 s of surface erosion, with a laser power equivalent to 64% of maximum permissible exposure. In both cases, the lesion is not visible to the eye and undetected by x-rays. eTC-PCT is capable of monitoring lesion progression in 2-day increments and generating 3D tomographic reconstructions of the advancing lesion. CONCLUSIONS: eTC-PCT shows great potential for further development as a dental imaging modality combining low detection threshold, high sensitivity to lesion progression, 3D reconstruction capability, and lack of ionizing radiation. These features enable early diagnosis and frequent monitoring, making eTC-PCT a promising technology for facilitating preventive dentistry.

Sensitivity of pancreatic cancer cells to chemotherapeutic drugs, signal transduction inhibitors and nutraceuticals can be regulated by WT-TP53.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy. Approximately 85% of pancreatic cancers are classified as PDACs. The survival of PDAC patients is very poor and only 5-10% of patients survive 5 years after diagnosis. Mutations at the KRAS and TP53 gene are frequently observed in PDAC patients. The PANC-28 cell line lacks wild-type (WT) TP53. In the following study, we have investigated the effects of restoration of WT TP53 activity on the sensitivity of PANC-28 pancreatic cancer cells to various drugs which are used to treat PDAC patients as well as other cancer patients. In addition, we have examined the effects of signal transduction inhibitors which target critical pathways frequently deregulated in cancer. The effects of the anti-diabetes drug metformin and the anti-malarial drug chloroquine were also examined as these drugs may be repurposed to treat other diseases. Finally, the effects of certain nutraceuticals which are used to treat various ailments were also examined. Introduction of WT-TP53 activity in PANC-28 PDAC cells, can increase their sensitivity to various drugs. Attempts are being made clinically to increase TP53 activity in various cancer types which will often inhibit cell growth by multiple mechanisms.

Therapeutic resistance in breast cancer cells can result from deregulated EGFR signaling.

The epidermal growth factor receptor (EGFR) interacts with various downstream molecules including phospholipase C (PLC)/protein kinase C (PKC), Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/GSK-3, Jak/STAT and others. Often these pathways are deregulated in human malignancies such as breast cancer. Various therapeutic approaches to inhibit the activity of EGFR family members including small molecule inhibitors and monoclonal antibodies (MoAb) have been developed. A common problem with cancer treatments is the development of drug-resistance. We examined the effects of a conditionally-activated EGFR (v-Erb-B:ER) on the resistance of breast cancer cells to commonly used chemotherapeutic drugs such as doxorubicin, daunorubicin, paclitaxel, cisplatin and 5-flurouracil as well as ionizing radiation (IR). v-Erb-B is similar to the EGFR-variant EGFRvIII, which is expressed in various cancers including breast, brain, prostate. Both v-Erb-B and EGFRvIII encode the EGFR kinase domain but lack key components present in the extracellular domain of EGFR which normally regulate its activity and ligand-dependence. The v-Erb-B oncogene was ligated to the hormone binding domain of the estrogen receptor (ER) which results in regulation of the activity of the v-Erb-ER construct by addition of either estrogen (E2) or 4-hydroxytamoxifen (4HT) to the culture media. Introduction of the v-Erb-B:ER construct into the MCF-7 breast cancer cell line increased the resistance to the cells to various chemotherapeutic drugs, hormonal-based therapeutics and IR. These results point to the important effects that aberrant expression of EGFR kinase domain can have on therapeutic resistance.

Cancer therapy and treatments during COVID-19 era.

The COVID-19 pandemic has put a serious strain on health treatments as well at the economies of many nations. Unfortunately, there is not currently available vaccine for SARS-Cov-2/COVID-19. Various types of patients have delayed treatment or even routine check-ups and we are adapting to a virtual world. In many cases, surgeries are delayed unless they are essential. This is also true with regards to cancer treatments and screening. Interestingly, some existing drugs and nutraceuticals have been screened for their effects on COVID-19. Certain FDA approved drugs, vitamin, natural products and trace minerals may be repurposed to treat or improve the prevention of COVID-19 infections and disease progression. This review article will summarize how the treatments of various cancer patients has changed during the COVID-19 era as well as discuss the promise of some existing drugs and other agents to be repurposed to treat this disease.

GSK-3 and miRs: Master regulators of therapeutic sensitivity of cancer cells.

Glycogen synthetase kinase-3 (GSK-3) and microRNAs (miRs) affect many critical signaling pathways important in cell growth. GSK-3 is a serine/threonine (S/T) protein kinase. Often when GSK-3 phosphorylates other proteins, they are inactivated and the signaling pathway is shut down. The PI3K/PTEN/AKT/GSK3/mTORC1 pathway plays key roles in regulation of cell growth, apoptosis, drug resistance, malignant transformation and metastasis and is often deregulated in cancer. When GSK-3 is phosphorylated by AKT it is inactivated and this often leads to growth promotion. When GSK-3 is not phosphorylated by AKT or other kinases at specific negative-regulatory residues, it can modify the activity of many proteins by phosphorylation, some of these proteins promote while others inhibit cell proliferation. This is part of the conundrum regarding GSK-3. The central theme of this review is the ability of GSK-3 to serve as either a tumor suppressor or a tumor promoter in cancer which is likely due to its diverse protein substrates. The effects of multiple miRs which bind mRNAs encoding GSK-3 and other signaling molecules and how they affect cell growth and sensitivity to various therapeutics will be discussed as they serve to regulate GSK-3 and other proteins important in controlling proliferation.

Influences of TP53 and the anti-aging DDR1 receptor in controlling Raf/MEK/ERK and PI3K/Akt expression and chemotherapeutic drug sensitivity in prostate cancer cell lines.

BACKGROUND: TP53 plays critical roles in sensitivity to chemotherapy, and aging. Collagen is very important in aging. The molecular structure and biochemical properties of collagen changes during aging. The discoidin domain receptor (DDR1) is regulated in part by collagen. Elucidating the links between TP53 and DDR1 in chemosensitivity and aging could improve therapies against cancer and aging. RESULTS: Restoration of WT-TP53 activity resulted in increased sensitivity to chemotherapeutic drugs and elevated expression of key components of the Raf/MEK/ERK, PI3K/Akt and DDR1 pathways. DDR1 could modulate the levels of Raf/MEK/ERK and PI3K/Akt pathways as well as sensitize the cells to chemotherapeutic drugs. In contrast, suppression of WT TP53 with a dominant negative (DN) TP53 gene, suppressed DDR1 protein levels and increased their chemoresistance. CONCLUSION: Restoration of WT TP53 activity or increased expression of the anti-aging DDR1 collagen receptor can result in enhanced sensitivity to chemotherapeutic drugs. Our innovative studies indicate the important links between WT TP53 and DDR1 which can modulate Raf/MEK/ERK and PI3K/Akt signaling as well as chemosensitivity and aging. METHODS: We investigated the roles of wild type (WT) and mutant TP53 on drug sensitivity of prostate cancer cells and the induction of Raf/MEK/ERK, PI3K/Akt and DDR1 expression and chemosensitivity.

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer.

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/ß-catenin signaling and ß-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.