Gastric cancer is the fourth most common cancer worldwide. Despite the high incidence of gastric cancer, efficient chemotherapy treatments still need to be developed. In this study, we examined the ...anticancer effects of endoplasmic reticulum (ER) stress inducer tunicamycin in gastric cancer. Previously, we found that overexpression of WLS1/GPR177 correlated with poor prognosis in patients with gastric cancer. Furthermore, tunicamycin treatment downregulated GPR177 expression in a dose‐dependent manner. GPR177 transports WNT ligand from ER to the plasma membrane, mediating its secretion to the extracellular matrix. In gastric cancer cells, GPR177 preferentially localizes to the ER. Small interfering RNA‐mediated knockdown of GPR177 leads to sensitization to ER stress and induces apoptosis of cancer cells along with tunicamycin treatment. GPR177 suppression promoted the ER stress‐mediated proapoptotic pathway, such as PERK‐CHOP cascade. Furthermore, fluorouracil treatment combined with tunicamycin dramatically reduced cancer cell proliferation. Efficacy of tunicamycin chemotherapy treatments depended on GPR177 expression in gastric cancer cell lines. Together, our results indicate that ER stress can potentiate anticancer effects and suggest GPR177 as a potential gastric cancer therapeutic target.
GPR177 translocates in the golgi upon wnt signal‐ gpr177 suppression promoted the endoplasmic reticulum stress‐mediated proapoptotic pathway‐ tunicamycin and siRNA‐mediated GPR177 knockdown additively reduce gastric cancer cell viability.
We conducted a large surveillance study among members of an integrated healthcare delivery system in Pacific Northwest of the United States to estimate medical costs attributable to medically ...attended acute gastroenteritis (MAAGE) on the day care was sought and during 30-day follow-up. We used multivariable regression to compare costs of MAAGE and non-MAAGE cases matched on age, gender, and index time. Differences accounted for confounders, including race, ethnicity, and history of chronic underlying conditions. Analyses included 73,140 MAAGE episodes from adults and 18,617 from children who were Kaiser Permanente Northwest members during 2014-2016. Total costs were higher for MAAGE cases relative to non-MAAGE comparators as were costs on the day care was sought and costs during follow-up. Costs of MAAGE are substantial relative to the cost of usual-care medical services, and much of the burden accrues during short-term follow-up.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Social status hierarchies are ubiquitous in vertebrate social systems, including humans. It is well known that social rank can influence quality of life dramatically among members of social groups. ...For example, high-ranking individuals have greater access to resources, including food and mating prerogatives that, in turn, have a positive impact on their reproductive success and health. In contrast low ranking individuals typically have limited reproductive success and may experience lasting social and physiological costs. Ultimately, social rank and behavior are regulated by changes in gene expression. However, little is known about mechanisms that transduce social cues into transcriptional changes. Since social behavior is a dynamic process, we hypothesized that a molecular mechanism such as DNA methylation might play a role these changes. To test this hypothesis, we used an African cichlid fish, Astatotilapia burtoni, in which social rank dictates reproductive access. We show that manipulating global DNA methylation state strongly biases the outcomes of social encounters. Injecting DNA methylating and de-methylating agents in low status animals competing for status, we found that animals with chemically increased methylation states were statistically highly likely to ascend in rank. In contrast, those with inhibited methylation processes and thus lower methylation levels were statistically highly unlikely to ascend in rank. This suggests that among its many roles, DNA methylation may be linked to social status and more generally to social behavior.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
From the viewpoint of histogenesis, lung adenocarcinoma can be subdivided into two groups: terminal respiratory unit (TRU) and non‐TRU types. We recently reported a non‐TRU type adenocarcinoma ...designated as ciliated adenocarcinoma (we now prefer central type adenocarcinoma). We suggest reasons that mucinous adenocarcinoma should encompass central type adenocarcinoma to represent its biological characteristics as non‐TRU type adenocarcinoma.
Methods and results
Mucin (MUC)5AC and MUC5B were expressed more significantly in non‐TRU type adenocarcinoma (P < 0.01). Thirty‐five (76.1%) and 45 cases (97.8%) of 46 non‐TRU type adenocarcinoma showed positivity for MUC5AC and MUC5B. Twelve (7.6%) and eight (5.1%) cases of 157 TRU type adenocarainoma showed positivity for MUC5B and MUC5AC. NKX2‐1 gene expression was measured with quantitative reverse transcription–polymerase chain reaction (qRT–PCR). ΔΔCt of NKX2‐1 gene expression was 6.79 for TRU type adenocarcinoma and 0.6 for non‐TRU type adenocarcinoma. Overall survival and disease‐free survival were poorer in non‐TRU type adenocarcinoma (P = 0.02 and P = 0.03). A multivariate test also showed that non‐TRU type adenocarcinoma is an independent prognostic factor (P = 0.04).
Conclusion
MUC5AC and MUC5B were specific makers for non‐TRU adenocarcinoma, including both central type adenocarcinoma and mucinous adenocarcinoma. We suggest that non‐TRU type adenocarcinoma presents a poorer prognosis, so it should be regarded separately from TRU type adenocarcinoma.
In several cancers, tumor progression is associated with the infiltration of tumor-associated macrophages (TAMs). The aim was to evaluate the prognostic significance of expression of CD163 and CD68 ...(TAMs' markers) and their correlation with vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) expression in cutaneous melanoma. Diagnostic tissues from 102 patients of cutaneous melanoma were evaluated by immunohistochemistry for their CD68, CD163, VEGF, and COX-2 expression. Correlations between the proteins were then investigated. Clinicopathological features, overall survival (OS), and progression-free survival were analyzed in terms of the expression of these proteins. CD163, but not CD68, expression correlated with VEGF and COX-2 expression. High expression for CD163 was associated with a deeper Breslow thickness and an advanced stage of the disease. High expression of CD163 was associated with lower OS. No significant differences were noted in CD68 expression between the clinicopathological variables and the OS. COX-2 expression was associated with a deeper Breslow thickness and a higher frequency of lymph node involvement. Multivariate analysis revealed that CD163 expression and COX-2 expression were independent prognostic markers of lower survival outcomes. Our data confirmed that CD163 expression provides independent prognostic information in cutaneous melanoma. The correlation of CD163 with VEGF and COX-2 expression suggests various tumor-promoting actions of CD163-positive TAMs.
Background
Little is known about whether diabetes increases the risk of COVID-19 infection and whether measures of diabetes severity are related to COVID-19 outcomes.
Objective
Investigate diabetes ...severity measures as potential risk factors for COVID-19 infection and COVID-19 outcomes.
Design, Participants, Measures
In integrated healthcare systems in Colorado, Oregon, and Washington, we identified a cohort of adults on February 29, 2020 (
n
= 1,086,918) and conducted follow-up through February 28, 2021. Electronic health data and death certificates were used to identify markers of diabetes severity, covariates, and outcomes. Outcomes were COVID-19 infection (positive nucleic acid antigen test, COVID-19 hospitalization, or COVID-19 death) and severe COVID-19 (invasive mechanical ventilation or COVID-19 death). Individuals with diabetes (
n
= 142,340) and categories of diabetes severity measures were compared with a referent group with no diabetes (
n
= 944,578), adjusting for demographic variables, neighborhood deprivation index, body mass index, and comorbidities.
Results
Of 30,935 patients with COVID-19 infection, 996 met the criteria for severe COVID-19. Type 1 (odds ratio OR 1.41, 95% CI 1.27–1.57) and type 2 diabetes (OR 1.27, 95% CI 1.23–1.31) were associated with increased risk of COVID-19 infection. Insulin treatment was associated with greater COVID-19 infection risk (OR 1.43, 95% CI 1.34–1.52) than treatment with non-insulin drugs (OR 1.26, 95% 1.20–1.33) or no treatment (OR 1.24; 1.18–1.29). The relationship between glycemic control and COVID-19 infection risk was dose-dependent: from an OR of 1.21 (95% CI 1.15–1.26) for hemoglobin A1c (HbA1c) < 7% to an OR of 1.62 (95% CI 1.51–1.75) for HbA1c ≥ 9%. Risk factors for severe COVID-19 were type 1 diabetes (OR 2.87; 95% CI 1.99–4.15), type 2 diabetes (OR 1.80; 95% CI 1.55–2.09), insulin treatment (OR 2.65; 95% CI 2.13–3.28), and HbA1c ≥ 9% (OR 2.61; 95% CI 1.94–3.52).
Conclusions
Diabetes and greater diabetes severity were associated with increased risks of COVID-19 infection and worse COVID-19 outcomes.
Anxiety disorders are the most common mental health problem among youth, contribute to reduced quality of daily life, and are associated with high rates of comorbidity. However, treatment rates for ...anxiety are very low, causing a sizeable treatment gap. There is an immediate need to identify treatment interventions that are effective, affordable, and can be delivered easily to the youth population. Cognitive Bias Modification (CBM) is one potentially effective intervention that could reach youth on a large scale, especially when self-administered at home. Thus, we aim to assess the benefit of CBM to treat youth anxiety. Further, we aim to test whether adding an adherence promotion (AP) component to the CBM intervention can improve outcomes, and whether CBM delivered both with and without the AP component is cost effective.
This is a 12-month randomized controlled trial (RCT) conducted within an existing healthcare system. Potentially eligible youth (ages 12 to 17) will be identified by reviewing the electronic health record (EHR) for clinical anxiety diagnoses, which are then confirmed via research interview. We aim to enroll 498 participants and randomize them 1:1:1 to one of three arms: Arm 1 is a Low-Ratio version of the CBM program (nearly identical to the other CBM versions, but minimally effective); Arm 2 is a High-Ratio "active" CBM program; and Arm 3 is the High-Ratio CBM program with an added AP component. Participants will complete assessments at baseline, 1-, 3-, 6- and 12-months post-baseline. Youth in all three arms will self-administer the CBM program at home and will be asked to complete twelve intervention sessions over a four-week period. Arm 3 participants (High-Ratio CBM + AP) will also receive up to four telephone calls from phone coaches during the intervention period to provide technical assistance, encouragement, and motivational enhancement to increase adherence. The primary clinical outcome will be anxiety remission at 6-month follow-up.
This study protocol describes the method and design for an RCT to test whether self-administered CBM both with and without adherence promotion can be an effective at-home treatment for anxious youth.
ClinicalTrials.gov : NCT02156531, First Posted June 5, 2014.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Because periodontal ligament (PDL) cells are reported to contain progenitor or stem cell populations, they are considered a beneficial cell source for clinical periodontal regeneration. Both bone ...morphogenetic protein 4 (BMP4) and human telomerase reverse transcriptase (hTERT) have essential roles in the modulation of stem cell properties. In this study we report for the first time that the combined ectopic expression of BMP4 and hTERT significantly enhanced the multipotent differentiation efficiency and capacity of human PDL fibroblasts (PFs), as shown by osteogenic, adipogenic and neurogenic differentiation in vitro, and cementum/PDL-like tissue regeneration in vivo. These findings may be attributed, at least in part, to the original upregulation of important stem cell markers, such as scleraxis, Stro-1 and CD146, and the extremely lowered threshold for BMP concentration to activate BMP signaling by enhanced basal phosphorylation levels of Smad 1/5/8. In addition, the significantly reduced expression levels of CD146 and CD90 with the presence of Noggin confirms the direct effect of BMP4 on the stem cell-like phenotype of genetically modified PF cells (BT-PFs). Furthermore, BT-PFs exhibited a high neural differentiation capacity (>75%). After transplantation into NOD/SCID mice, genetically modified-PFs generated cementum/PDL-like structures on the surface of the carrier. The multipotency of these modified cells potentially provides an attractive source of stem cells for therapeutic purposes and regenerative medicine.
COVID-19 inequities have been well-documented. We evaluated whether higher rates of severe COVID-19 in racial and ethnic minority groups were driven by higher infection rates by evaluating if ...disparities remained when analyses were restricted to people with infection. We conducted a retrospective cohort study of adults insured through Kaiser Permanente (Colorado, Northwest, Washington), follow-up in March–September 2020. Laboratory results and hospitalization diagnosis codes identified individuals with COVID-19. Severe COVID-19 was defined as invasive mechanical ventilation or mortality. Self-reported race and ethnicity, demographics, and medical comorbidities were extracted from health records. Modified Poisson regression estimated adjusted relative risks (aRRs) of severe COVID-19 in full cohort and among individuals with infection. Our cohort included 1,052,774 individuals, representing diverse racial and ethnic minority groups (e.g., 68,887 Asian, 41,243 Black/African American, 93,580 Hispanic or Latino/a individuals). Among 7,399 infections, 442 individuals experienced severe COVID-19. In the full cohort, severe COVID-19 aRRs for Asian, Black/African American, and Hispanic individuals were 2.09 (95% CI: 1.36, 3.21), 2.02 (1.39, 2.93), and 2.09 (1.57, 2.78), respectively, compared to non-Hispanic Whites. In analyses restricted to individuals with COVID-19, all aRRs were near 1, except among Asian Americans (aRR 1.82 1.23, 2.68). These results indicate increased incidence of severe COVID-19 among Black/African American and Hispanic individuals is due to higher infection rates, not increased susceptibility to progression. COVID-19 disparities most likely result from social, not biological, factors. Future work should explore reasons for increased severe COVID-19 risk among Asian Americans. Our findings highlight the importance of equity in vaccine distribution.
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