Introduction: Limited studies have examined racial disparities in long-term survival after acute ischemic stroke (AIS) with inconsistent findings. We examined these disparities among Medicare fee-for-service (FFS) beneficiaries in U.S. Methods: We analyzed data on 1,997,487 Medicare FFS beneficiaries aged ≥65 years hospitalized with incident AIS (ICD-10 code I63) and survived >30 days from January 1, 2000 to December 31, 2017, and were followed-up until December 31, 2022. Cox proportional hazard models estimated the adjusted hazard ratio (aHR, 95% CI) and adjusted survival curves by race/ethnicity (non-Hispanic White (White), non-Hispanic Black (Black), Hispanic and Other). Models were adjusted for age, sex, and comorbidities. Results: The median age at AIS hospitalization was 78 years (IQR 72.0-84.0); 57.0% were women; 81.8%, 10.8%, 4.8% and 2.6% were White, Black, Hispanic and Other, respectively. Over a median follow-up of 4.9-years (IQR 1.7-8.8), there were 1,738,452 all-cause deaths. Adjusted 5-year survival after AIS improved from 2000-2004 to 2015-2017 for White (46.5% (95% CI 46.4-46.6) to 50.9% (50.7-51.1)), and Black (46.0% (45.8-46.3) to 48.9% (48.3-49.2)). For Hispanic and Other, survival remained largely unchanged: 54.4% (54.1-54.8) to 54.2% (53.6-54.8)) for Hispanic and 55.9% (55.4-56.4) to 54.7% (54.0-55.5) for Other. A clear pattern of long-term survival after AIS emerged by race/ethnicity showing similar survival between Hispanic and Other and between White and Black people (Figure). Stroke mortality risk was ~25% higher for White and Black compared to Hispanic and Other (aHR 1.25 (1.24-1.26)). This pattern was consistent across age groups and sex. Conclusions: Long-term survival after AIS has improved for White and Black Medicare FFS beneficiaries over time, while it remained largely unchanged for Hispanic and Other groups. This indicates persistent racial disparities in stroke outcomes.
Recent studies have indicated that using statins to inhibit the mevalonate pathway induces mutant p53 degradation by impairing the interaction of mutant p53 with DnaJ subfamily A member 1 (DNAJA1). However, the role of the C-terminus of DNAJA1 with a CAAX box for farnesylation in the binding, folding, and translocation of client proteins such as mutant p53 is not known. In the present study, we used a genetically engineered mouse model of pancreatic carcinoma and showed that atorvastatin significantly increased animal survival and inhibited pancreatic carcinogenesis. There was a dramatic decrease in mutant p53 protein accumulation in the pancreatic acini, pancreas intraepithelial neoplasia lesions, and adenocarcinoma. Supplementation with farnesyl pyrophosphate, a substrate for protein farnesylation, rescued atorvastatin-induced mutant p53 degradation in pancreatic cancer cells. Tipifarnib, a farnesyltransferase inhibitor, mirrored atorvastatin's effects on mutant p53, degraded mutant p53 in a dose-dependent manner, and converted farnesylated DNAJA1 into unfarnesylated DNAJA1. Farnesyltransferase gene knockdown also significantly promoted mutant p53 degradation. Coimmunoprecipitation either by an anti-DNAJA1 or p53 antibody confirmed the direct interaction of mutant p53 and DNAJA1 and higher doses of atorvastatin treatments converted more farnesylated DNAJA1 into unfarnesylated DNAJA1 with much less mutant p53 pulled down by DNAJA1. Strikingly, C394S mutant DNAJA1, in which the cysteine of the CAAX box was mutated to serine, was no longer able to be farnesylated and lost the ability to maintain mutant p53 stabilization. Our results show that farnesylated DNAJA1 is a crucial chaperone in maintaining mutant p53 stabilization and targeting farnesylated DNAJA1 by atorvastatin will be critical for inhibiting p53 mutant cancer.
Background: Use of IV tPA has increased over time, as has the adherence to the NQF endorsed performance measure for receipt of IV tPA within 3 hours. Little is known about trends in the reasons for patient ineligibility for IV tPA. This study examines trends in reasons for not providing IV tPA over time and by race and gender among acute ischemic stroke patients in the Paul Coverdell National Acute Stroke Registry (PCNASR), a quality improvement program for acute stroke implemented by state health departments. Methods: There were 13,164 PCNASR patients enrolled from 2008- 2010 with a clinical diagnosis of acute ischemic stroke with documentation of LKW and who arrived within 2 hours of LKW. Cochran-Armitage tests were used to test for trend on accepted reasons for not providing IV tPA within 3 hours of time last known well (LKW). Chi-square tests were used to test for differences among reasons between men and women and between non-Hispanic whites and minorities. Multiple reasons for not giving tPA could be selected. Results: Among 13,164 acute ischemic patients admitted between 2008 and 2010 with documentation of LKW and who arrived within 2 hours of LKW, 3781 (28.7%) received IV tPA, 7284 (55.3%) had documented reasons for not receiving IV tPA, and 2099 (16.0%) did not receive IV tPA. Contraindications to IV tPA, advanced age, rapid improvement and inability to determine eligibility increased over time. Mild stroke decreased over time. Conditions with warning, advanced age, limited life expectancy and family refusal were more common in women; mild stroke and rapid improvement were more common in men. Contraindications were more common in minorities; advanced age, mild stroke and rapid improvement, and family refusal were more common in non-Hispanic whites. When advanced age was selected, 46.6% of patients were over age 90 and 3.4% were under age 80. When stroke too mild was selected, 44.8% of patients had missing NIHSS scores, 42.1% of scores were 0-4, 8.8% were 5-9, and 4.3% were ≥ 10. The three most common reasons for not providing tPA were rapid improvement (40.9%), mild stroke (33.0%), and contraindications (29.2%) in 2010. Conclusions: More than half of ischemic stroke patients arriving within 2 hours of LKW were ineligible to receive IV tPA. There was little use of advanced age for patients under age 80. Documentation of stroke too mild was not substantiated by an NIHSS score in nearly half of patients. Better documentation of NIHSS score should be provided.
B cell-mediated humoral immunity plays a vital role in viral infections, including chronic hepatitis B virus (HBV) infection, which remains a critical global public health issue. Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections, the reduced immune functional capacity of B cells was identified, which was also correlated with chronic hepatitis B (CHB) progression. In addition to B cells, T follicular helper (Tfh) cells, which assist B cells to produce antibodies, might also be involved in the process of anti-HBV-specific antibody production. Here, we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity. Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.
Cyclooxygenase 2 (COX-2) is a key enzyme in the conversion of arachidonic acid to prostaglandins, and COX-2 overexpression plays an important role in carcinogenesis. Exposure to UVB strongly increased COX-2 protein expression in mouse 308 keratinocytes, and this induction was inhibited by apigenin, a nonmutagenic bioflavonoid that has been shown to prevent mouse skin carcinogenesis induced by both chemical carcinogens and UV exposure. Our previous study suggested that one pathway by which apigenin inhibits UV-induced and basal COX-2 expression is through modulation of USF transcriptional activity in the 5′ upstream region of the COX-2 gene. Here, we found that apigenin treatment also increased COX-2 mRNA stability, and the inhibitory effect of apigenin on UVB-induced luciferase reporter gene activity was dependent on the AU-rich element of the COX-2 3′-untranslated region. Furthermore, we identified two RNA-binding proteins, HuR and the T-cell-restricted intracellular antigen 1-related protein (TIAR), which were associated with endogenous COX-2 mRNA in 308 keratinocytes, and apigenin treatment increased their localization to cell cytoplasm. More importantly, reduction of HuR levels by small interfering RNA inhibited apigenin-mediated stabilization of COX-2 mRNA. Cells expressing reduced TIAR showed marked resistance to apigenin's ability to inhibit UVB-induced COX-2 expression. Taken together, these results indicate that in addition to transcriptional regulation, another mechanism by which apigenin prevents COX-2 expression is through mediating TIAR suppression of translation.
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