Background and Purpose: Hypertensive disorders of pregnancy (HDP) comprise 4 subtypes. Previous studies have not investigated the relationship between stroke risk, different HDP subtypes, and follow-up time, which was the purpose of this study. Methods: Data of 17 588 women aged 18 to 45 years who had a history of HDP in Taiwan from 2000 to 2017 was retrospectively reviewed. After matching with confounders, 13 617 HDP women and 54 468 non-HDP women were recruited. Results: HDP women had an adjusted hazard ratio (aHR) of 1.71 (95% CI, 1.46−2.00) for stroke, and 1.60 (1.35−1.89) and 2.98 (2.13−4.18) for ischemic and hemorrhagic stroke, respectively ( P <0.001 for all). The overall stroke risk in the HDP group was still 2.04 times 10 to 15 years after childbirth (1.47−2.83, P <0.001). Although the risks of both ischemic and hemorrhagic stroke persisted, their risk time trends were different. The risk of ischemic stroke reached peak during 1 to 3 years after childbirth with an aHR of 2.14 (1.36–3.38), while hemorrhagic stroke risk gradually increased and had an aHR of 4.64 (2.47−8.73) after 10 to 15 years of childbirth (both P <0.001). Among the 4 HDP subtypes, chronic hypertension with superimposed preeclampsia had the highest stroke risk (aHR=3.86, 1.91−7.82, P <0.001), followed by preeclampsia–eclampsia (aHR=2.00, 1.63−2.45, P <0.001), and gestational hypertension (aHR=1.68, 1.13−2.52, P <0.05); chronic preexisting hypertension had the lowest stroke risk (aHR=1.27, 0.97−1.68, P >0.05). Furthermore, multiple HDP combined with preeclampsia had aHR of 5.48 (1.14−26.42, P <0.05). Conclusions: The effect of HDP on the risk of future stroke persisted for up to 17 years, both for ischemic and hemorrhagic strokes. The presence of multiple HDP and preeclampsia further increase the stroke risk.
Predicting and overcoming radioresistance are crucial in radiation oncology, including in managing oral squamous cell carcinoma (OSCC). First, we used RNA-sequence to compare expression profiles of parent OML1 and radioresistant OML1-R OSCC cells in order to select candidate genes responsible for radiation sensitivity. We identified IRAK2, a key immune mediator of the IL-1R/TLR signaling, as a potential target in investigating radiosensitivity. In four OSCC cell lines, we observed that intrinsically low IRAK2 expression demonstrated a radioresistant phenotype (i.e., OML1-R and SCC4), and vice versa (i.e., OML1 and SCC25). Next, we overexpressed IRAK2 in low IRAK2-expression OSCC cells and knocked it down in high IRAK2-expression cells to examine changes of irradiation response. After ionizing radiation (IR) exposure, IRAK2 overexpression enhanced the radiosensitivity of radioresistant cells and synergistically suppressed OSCC cell growth both in vitro and in vivo, and vice versa. We found that IRAK2 overexpression restored and enhanced radiosensitivity by enhancing IR-induced cell killing via caspase-8/3-dependent apoptosis. OSCC patients with high IRAK2 expression had better post-irradiation local control than those with low expression (i.e., 87.4% vs. 60.0% at five years, P = 0.055), showing that IRAK2 expression was associated with post-radiation recurrence. Multivariate analysis confirmed high IRAK2 expression as an independent predictor for local control (HR, 0.11; 95% CI, 0.016 – 0.760; P = 0.025). In conclusion, IRAK2 enhances radiosensitivity, via modulating caspase 8/3-medicated apoptosis, potentially playing double roles as a predictive biomarker and a novel therapeutic target in OSCC.
Radiotherapy (RT) is a crucial treatment modality in managing cancer patients. However, irradiation dose sprinkling to tumor-adjacent normal tissues is unavoidable, generating treatment toxicities, such as radiation-associated cardiovascular dysfunction (RACVD), particularly for those patients with combined therapies or pre-existing adverse features/comorbidities. Radiation oncologists implement several efforts to decrease heart dose for reducing the risk of RACVD. Even applying the deep-inspiration breath-hold (DIBH) technique, the risk of RACVD is though reduced but still substantial. Besides, available clinical methods are limited for early detecting and managing RACVD. The present study reviewed emerging challenges of RACVD in modern radiation oncology, in terms of clinical practice, bench investigation, and multidisciplinary care. Several molecules are potential for serving as biomarkers and therapeutic targets. Of these, miRNAs, endogenous small non-coding RNAs that function in regulating gene expression, are of particular interest because low-dose irradiation, i.e., 200 mGy (one-tenth of conventional RT daily dose) induces early changes of pro-RACVD miRNA expression. Moreover, several miRNAs, e.g., miR-15b and miR21, involve in the development of RACVD, further demonstrating the potential bio-application in RACVD. Remarkably, many RACVDs are late RT sequelae, characterizing highly irreversible and progressively worse. Thus, multidisciplinary care from oncologists and cardiologists is crucial. Combined managements with commodities control (such as hypertension, hypercholesterolemia, and diabetes), smoking cessation, and close monitoring are recommended. Some agents show abilities for preventing and managing RACVD, such as statins and angiotensin-converting enzyme inhibitors (ACEIs); however, their real roles should be confirmed by further prospective trials.
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