Abstract
DNA damage tolerance and mutagenesis are hallmarks and enabling characteristics of neoplastic cells that drive tumorigenesis and allow cancer cells to resist therapy. The ‘Y-family’ ...trans-lesion synthesis (TLS) DNA polymerases enable cells to replicate damaged genomes, thereby conferring DNA damage tolerance. Moreover, Y-family DNA polymerases are inherently error-prone and cause mutations. Therefore, TLS DNA polymerases are potential mediators of important tumorigenic phenotypes. The skin cancer-propensity syndrome xeroderma pigmentosum-variant (XPV) results from defects in the Y-family DNA Polymerase Pol eta (Polη) and compensatory deployment of alternative inappropriate DNA polymerases. However, the extent to which dysregulated TLS contributes to the underlying etiology of other human cancers is unclear. Here we consider the broad impact of TLS polymerases on tumorigenesis and cancer therapy. We survey the ways in which TLS DNA polymerases are pathologically altered in cancer. We summarize evidence that TLS polymerases shape cancer genomes, and review studies implicating dysregulated TLS as a driver of carcinogenesis. Because many cancer treatment regimens comprise DNA-damaging agents, pharmacological inhibition of TLS is an attractive strategy for sensitizing tumors to genotoxic therapies. Therefore, we discuss the pharmacological tractability of the TLS pathway and summarize recent progress on development of TLS inhibitors for therapeutic purposes.
Background. Although prostate cancer patients initially respond to androgen deprivation therapy, most patients progress to a resistant phenotype. Castration resistance is due, in part, to ...intratumoral and/or adrenal synthesis of androgens, overexpression or mutation of the androgen receptor (AR), stabilization of AR by chaperones, and ligand-independent activation of AR. Increasing evidence also links disruption of calcium homeostasis to progression of prostate cancer. Our previous study shows that heavy metal cadmium activates the AR through a ligand-independent mechanism. Cadmium mimics calcium in biological systems due to their similar ionic charge and radius. This study determines whether calcium activates AR and whether first- and second-generation antiandrogens block the ability of calcium to activate the receptor. Methods. The expression of androgen-responsive genes and calcium channels was measured in prostate cells using a quantitative real-time polymerase chain reaction assay. Cell growth was measured. Results. To ask whether calcium activates AR, prostate cells were treated with calcium in the absence and presence of the first-generation antiandrogens hydroxyflutamide and bicalutamide and the second-generation antiandrogen enzalutamide, and the expression of androgen-responsive genes and cell growth was measured. In the normal PWR-1E cells and HEK293T cells transiently expressing AR, treatment with calcium increased the expression of androgen-responsive genes by approximately 3-fold. The increase was blocked by enzalutamide but was not consistently blocked by the first-generation antiandrogens. In LNCaP cells which contain a mutant AR, treatment with calcium also increased the expression of androgen-responsive genes by approximately 3-fold, and the increase was more effectively blocked by enzalutamide than by hydroxyflutamide or bicalutamide. Treatment with calcium also increased cell growth that was blocked by enzalutamide. To ask whether dysregulation of calcium channels is associated with castration resistance, calcium channels were measured in the normal PWR-1E prostate cells, the hormone-responsive LNCaP cells, and the castration-resistant VCaP and 22RV1 cells. Compared to normal prostate cells, the hormone-responsive and hormone-resistant cells overexpressed several calcium channels. Conclusions. The results of this study show that calcium activates AR and increases cell growth and that calcium channels are overexpressed in hormone-responsive and hormone-resistant prostate cancer cells. Taken together, the results suggest a novel role of calcium in the castration-resistant phenotype.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Loss or dysfunction of tumor suppressor retinoblastoma (RB) is a common feature in various tumors, and contributes to cancer cell stemness and drug resistance to cancer therapy. However, the strategy ...to suppress or eliminate Rb-deficient tumor cells remains unclear. In the present study, we accidentally found that reduction of DNA replication licensing factor MCM7 induced more apoptosis in RB-deficient tumor cells than in control tumor cells. Moreover, after a drug screening and further studies, we demonstrated that statin drug Simvastatin and Atorvastatin were able to inhibit MCM7 and RB expressions. Further study showed that Simvastatin and Atorvastatin induced more chromosome breaks and gaps of Rb-deficient tumor cells than control tumor cells. In vivo results showed that Simvastatin and Atorvastatin significantly suppressed Rb-deficient tumor growth than control in xenograft mouse models. The present work demonstrates that 'old' lipid-lowering drugs statins are novel weapons against RB-deficient tumors due to their effects on suppressing MCM7 protein levels.
Pulmonary arterial hypertension (PAH) is a progressive, fatal disease. Current prognostic models are not ideal, and identifying more accurate prognostic variables is needed. The objective of this ...study was to evaluate the relative prognostic value of the right atrial pressure/pulmonary artery wedge pressure (RAP/PAWP) ratio in PAH patients. We hypothesized that the RAP/PAWP ratio is more predictive of survival than any of the other measured or calculated hemodynamic variables.
We performed a secondary analysis of a PAH cohort (Cohort 1) and validated our results in a separate cohort (Cohort 2). Cohort 1 included primarily patients enrolled in prospective, short-term, randomized clinical trials and subsequently followed long term. Cohort 2 included patients prospectively enrolled in a PAH registry at a tertiary PAH referral center.
Cohort 1 (n = 847) and Cohort 2 (n = 697) had a mean age of 47 and 54 years, respectively. Most were female (78% and 73%, respectively), Caucasian (83% and 82%), with advanced functional class disease status (New York Heart Association Functional Class III/IV 85% and 68%) and with significantly elevated hemodynamics (mean RAP/PAWP ratio: 1.2 and 1.0; pulmonary vascular resistance: 13.5 and 9.4 Wood units). RAP/PAWP ratio indicated a 1-year hazard ratio of 1.44 (p = 0.0001) and 1.35, respectively (p < 0.0001), and was the most consistently predictive hemodynamic variable across the 2 cohorts. These results remain valid even when adjusted for other covariables in multivariable regression models.
The RAP/PAWP ratio is a more specific predictor of survival than any other hemodynamic variable, and we recommend that it be used in clinical prognostication and PAH predictive models.
Reduced cerebral blood flow (CBF) in the temporoparietal region and gray matter volumes (GMVs) in the temporal lobe were previously reported in patients with mild cognitive impairment (MCI) and ...Alzheimer's disease (AD). However, the temporal relationship between reductions in CBF and GMVs requires further investigation. This study sought to determine if reduced CBF is associated with reduced GMVs, or vice versa. Data came from 148 volunteers of the Cardiovascular Health Study Cognition Study (CHS-CS), including 58 normal controls (NC), 50 MCI, and 40 AD who had perfusion and structural MRIs during 2002-2003 (Time 2). Sixty-three of the 148 volunteers had follow-up perfusion and structural MRIs (Time 3). Forty out of the 63 volunteers received prior structural MRIs during 1997-1999 (Time 1). The relationships between GMVs and subsequent CBF changes, and between CBF and subsequent GMV changes were investigated. At Time 2, we observed smaller GMVs (p<0.05) in the temporal pole region in AD compared to NC and MCI. We also found associations between: (1) temporal pole GMVs at Time 2 and subsequent declines in CBF in this region (p=0.0014) and in the temporoparietal region (p=0.0032); (2) hippocampal GMVs at Time 2 and subsequent declines in CBF in the temporoparietal region (p=0.012); and (3) temporal pole CBF at Time 2 and subsequent changes in GMV in this region (p = 0.011). Therefore, hypoperfusion in the temporal pole may be an early event driving its atrophy. Perfusion declines in the temporoparietal and temporal pole follow atrophy in this temporal pole region.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Large-scale gut microbiome sequencing has revealed key links between microbiome dysfunction and metabolic diseases such as type 2 diabetes (T2D). To date, these efforts have largely focused on ...Western populations, with few studies assessing T2D microbiota associations in Middle Eastern communities where T2D prevalence is now over 20%. We analyzed the composition of stool 16S rRNA from 461 T2D and 119 non-T2D participants from the Eastern Province of Saudi Arabia. We quantified the abundance of microbial communities to examine any significant differences between subpopulations of samples based on diabetes status and glucose level.
In this study we performed the largest microbiome study ever conducted in Saudi Arabia, as well as the first-ever characterization of gut microbiota T2D versus non-T2D in this population. We observed overall positive enrichment within diabetics compared to healthy individuals and amongst diabetic participants; those with high glucose levels exhibited slightly more positive enrichment compared to those at lower risk of fasting hyperglycemia. In particular, the genus Firmicutes was upregulated in diabetic individuals compared to non-diabetic individuals, and T2D was associated with an elevated Firmicutes/Bacteroidetes ratio, consistent with previous findings.
Based on diabetes status and glucose levels of Saudi participants, relatively stable differences in stool composition were perceived by differential abundance and alpha diversity measures. However, community level differences are evident in the Saudi population between T2D and non-T2D individuals, and diversity patterns appear to vary from well-characterized microbiota from Western cohorts. Comparing overlapping and varying patterns in gut microbiota with other studies is critical to assessing novel treatment options in light of a rapidly growing T2D health epidemic in the region. As a rapidly emerging chronic condition in Saudi Arabia and the Middle East, T2D burdens have grown more quickly and affect larger proportions of the population than any other global region, making a regional reference T2D-microbiome dataset critical to understanding the nuances of disease development on a global scale.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present a new tri-electrode topology for reducing the control voltage for electrostatic actuators. Conventional parallel plate actuators are dual-electrode systems, formed by the MEMS structure ...and the drive electrode. By placing a perforated intermediate electrode between these elements, a tri-electrode configuration is formed. This topology enables a low voltage on the intermediate electrode to modulate the electrostatic force on the MEMS device, while the higher voltage on the drive electrode remains fixed. Results presented show that in comparison to conventional parallel plate electrostatic actuators, the intermediate electrode’s modulating voltage can be as low as 20% of normal, while still providing the full actuation stroke.
The continued emergence of new COVID-19 variants highlights the importance of vaccination in the effort to reduce disease transmission and burden. The objective of this study is to evaluate the ...processes and outcomes associated with a novel in-home COVID-19 vaccination program aimed at vaccinating high-risk populations in New York, USA.
To evaluate program processes, we described the program itself and reflected on some key lessons learned. To evaluate program outcomes, we analyzed data reported by vaccine recipients. These outcomes included the percentage of vaccine recipients that successfully received the full course of vaccinations, and the demographic and health characteristics of vaccine recipients. We additionally assessed demographic differences in motivations for receiving in-home care, using chi-squared tests to assess statistical significance. Data were collected and reported via dynamic online intake forms.
The median age of vaccine recipients was 79 ±
9.0 years. The oldest vaccine recipient was 107 years old. Of those with non-missing data, more than half of vaccine recipients were female (63%), identified as part of a racial/ethnic minority (66%), reported an annual income of < $25,000 (58%), and received a high school degree or less (68%). Most vaccine recipients reported having one or more health conditions associated with increased risk of severe COVID-19 disease (72%). Vaccine recipients were most likely to report receiving in-home vaccination because they were home-bound due to disability. Motivations for receiving in-home vaccination differed by demographic subgroup.
The population receiving vaccinations from this in-home care delivery program comprised seniors who were mostly female and non-white, indicated socioeconomic vulnerability, and reported one or more COVID-related health conditions; this signified that the program met its goal of vaccinating those most at risk for severe COVID-19 disease.
Evaluate the performance of glycated albumin (GA) monitoring by comparing it to other measures of glycemic control during intensification of antidiabetic therapy.
This 12-week, prospective, ...multicenter study compared the diagnostic clinical performance of GA to glycated hemoglobin A1C (A1C), fructosamine corrected for albumin (FRA), fasting plasma glucose (FPG), and mean blood glucose (MBG) estimated from self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM) in 30 patients with suboptimally controlled type 1 or 2 diabetes.
Mean A1C decreased from 9.5% to 8.1%. Mean SMBG correlated closely with CGM (Pearson r = 0.783 for daily estimates and r = 0.746 for weekly estimates, P<.0001). Both GA and FRA levels significantly correlated with changes from baseline in A1C and mean weekly SMBG (P<.001). The lowest observed median GA occurred at 4 weeks, followed by a small increase and then a slight reduction, mirroring changes in overall mean SMBG values. The median A1C fell throughout the treatment period, failing to reflect short-term changes in SMBG. A ≥1% reduction in GA at 4 weeks was significantly associated with a ≥0.5% change in A1C at 12 weeks (odds ratio OR = 19.0, 95% confidence interval CI: 1.4, 944, P = .018).
In patients receiving glucose-lowering therapy, changes in GA at 4 weeks were concordant with changes in A1C at 12 weeks, and both GA and FRA more accurately reflected short-term blood glucose fluctuations than A1C.
Abstract only β-carotene (BC) from plants is strong antioxidant and is the precursor of vitamin A in animals. Human studies show that elevated BC blood levels correlate with lower incidence of heart ...disease, but the molecular mechanisms are unclear. While humans accumulate high amounts of BC in blood, rodents completely metabolize BC to vitamin A, precluding the possibility of studying if BC influences heart disease using mouse models. To overcome this, we used a mouse model lacking the enzyme that converts BC to vitamin A (BC oxygenase 1, BCO1) and studied if BC plays a role in atherosclerosis, the main cause of heart disease. We first crossed Bco1 -/- mice with Ldlr -/- mice to generate Bco1 -/- / Ldlr -/- mice. These mice were fed Western diet (WD) containing BC (WD-BC) for 12 wks, accumulated levels of BC in blood comparable to those observed in humans (12±2 μM), as well as in atherosclerotic lesions, while Ldlr -/- mice fed WD-BC only accumulated trace amounts of BC in blood (0.3±0.1 μM). Ldlr -/- mice fed WD-BC showed delayed atherosclerosis progression (40% reduction in plaque size, n=10-12 mice/group) when compared to those fed WD without BC (WD-noBC). These changes were accompanied by decreased plasma cholesterol (35%) and triglyceride (~55%) levels (n=10-12 mice/group). People typically present for treatment of atherosclerotic disease after plaques have advanced. Thus, we next tested whether BC plays a role in atherosclerosis regression after lipid lowering. For this purpose, we utilized a LDLR antisense oligonucleotide (LDLR-ASO) strategy to block expression of the LDLR to induce hypercholesterolemia. Wild-type and Bco1 -/- mice were fed WD-noBC and simultaneously treated with LDLR-ASO for 16 wks. After LDLR-ASO treatment was stopped, plasma cholesterol levels fell from 700mg/mL to 70mg/mL. Mice were also switched to WD-BC or continued with WD-noBC for 3 wks. Wild-type mice, but not Bco1 -/- mice, fed WD-BC showed a reduced content of plaque macrophages (30%) and newly recruited monocytes (25%) (n=7 to 12 mice/group) when compared to those fed WD-noBC. We are currently in the process of elucidating the molecular mechanisms responsible of these beneficial effects of BC on atherosclerosis progression and regression.
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