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Background: Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics often prescribed for long-term treatment. Many of these treatments cause cardiotoxicity with limited cure. We aim to clarify molecular mechanisms of TKI-induced cardiotoxicity so as to find potential targets for treating the adverse cardiac complications. Methods: Eight TKIs with different levels of cardiotoxicity reported are selected. Phenotypic and transcriptomic responses of human cardiomyocytes to TKIs at varying doses and times are profiled and analyzed. Stress responses and signaling pathways that modulate cardiotoxicity induced by three TKIs are validated in cardiomyocytes and rat hearts. Results: Toxicity rank of the eight TKIs determined by measuring their effects on cell viability, contractility, and respiration is largely consistent with that derived from database or literature, indicating that human cardiomyocytes are a good cellular model for studying cardiotoxicity. When transcriptomes are measured for selected TKI treatments with different levels of toxicity in human cardiomyocytes, the data are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib, and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress (ERS). All three TKIs induce ERS in rat primary cardiomyocytes and ponatinib activates the IRE1α-XBP1s axis downstream of ERS in the hearts of rats underwent a 7-day course of drug treatment. To look for potential triggers of ERS, we find that the three TKIs induce transient reactive oxygen species followed by lipid peroxidation. Inhibiting either PERK or IRE1α downstream of ERS blocks TKI-induced cardiac damages, represented by the induction of cardiac fetal and pro-inflammatory genes without causing more cell death. Conclusions: Our data contain rich information about phenotypic and transcriptional responses of human cardiomyocytes to eight TKIs, uncovering potential molecular mechanisms in modulating cardiotoxicity. ER stress is activated by multiple TKIs and leads to cardiotoxicity through promoting expression of pro-inflammatory factors and cardiac fetal genes. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) is common and associated with adverse outcomes as well as important healthcare costs. However, evidence examining the epidemiology of acute kidney disease (AKD)-recently defined as AKI persisting between 7 and 90 days-remains limited. The aims of this study were to establish the rates of early AKI recovery, progression to AKD and non-recovery; examine risk factors associated with non-recovery and investigate the association between recovery timing and adverse outcomes, in a population-based cohort.Methods: All adult residents of Tayside & Fife, Scotland, UK, with at least one episode of community or hospital-managed AKI using KDIGO creatinine-based definition during the period 1 January 2010 to 31 December 2018 were identified. Logistic regression was used to examine factors associated with non-recovery, and Cox modelling was used to establish associations between AKI recovery timing and risks of mortality and development of de novo CKD.Results: Over 9 years, 56,906 patients with at least one AKI episode were identified with 18,773 (33%) of these progressing to AKD. Of those progressing to AKD, 5059 (27%) had still not recovered at day 90 post AKI diagnosis. Risk factors for AKD included: increasing AKI severity, pre-existing cancer or chronic heart failure and recent use of loop diuretics. Compared with early AKI recovery, progression to AKD was associated with increased hazard of 1-year mortality and de novo CKD (HR = 1.20, 95% CI 1.13 to 1.26 and HR = 2.21, 95% CI 1.91 to 2.57 respectively).Conclusions: These findings highlight the importance of early AKI recognition and management to avoid progression to AKD and long-term adverse outcomes. [ABSTRACT FROM AUTHOR]

Background: The associations of maternal cigarette smoking with congenital anomalies in offspring have been inconsistent. This study aimed to clarify the associations of the timing and intensity of maternal cigarette smoking with 12 subtypes of birth congenital anomalies based on a nationwide large birth cohort in the USA.Methods: We used nationwide birth certificate data from the US National Vital Statistics System during 2016-2019. Women reported the average daily number of cigarettes they consumed 3 months before pregnancy and in each subsequent trimester during pregnancy. Twelve subtypes of congenital anomalies were identified in medical records. Poisson regression analysis was used to estimate the risk ratios (RRs) with 95% confidence intervals (CIs) for 12 subtypes of congenital anomalies associated with the timing (i.e., before pregnancy, and during three different trimesters of pregnancy) and intensity (i.e., number of cigarettes consumed per day) of maternal cigarette smoking.Results: Among the 12,144,972 women included, 9.3% smoked before pregnancy and 7.0%, 6.0%, and 5.7% in the first, second, and third trimester, respectively. Maternal smoking before or during pregnancy significantly increased the risk of six subtypes of birth congenital anomalies (i.e., congenital diaphragmatic hernia, gastroschisis, limb reduction defect, cleft lip with or without cleft palate, cleft palate alone, and hypospadias), even as low as 1-5 cigarettes per day. The adjusted RRs (95% CIs) for overall birth congenital anomalies (defined as having any one of the congenital malformations above significantly associated with maternal cigarette smoking) among women who smoked 1-5, 6-10, and ≥ 11 cigarettes per day before pregnancy were 1.31 (1.22-1.41), 1.25 (1.17-1.33), and 1.35 (1.28-1.43), respectively. Corresponding values were 1.23 (1.14-1.33), 1.33 (1.24-1.42), 1.33 (1.23-1.43), respectively, for women who smoked cigarettes in the first trimester; 1.32 (1.21-1.44), 1.36 (1.26-1.47), and 1.38 (1.23-1.54), respectively, for women who smoked cigarettes in the second trimester; and 1.33 (1.22-1.44), 1.35 (1.24-1.47), and 1.35 (1.19-1.52), respectively, for women who smoked cigarettes in the third trimester. Compared with women who kept smoking before and throughout pregnancy, women who never smoked had significantly lower risk of congenital anomalies (RR 0.77, 95% CI 0.73-0.81), but women who smoked before pregnancy and quitted during each trimester of pregnancy had no reduced risk (all P > 0.05).Conclusions: Maternal smoking before or during pregnancy increased the risk of several birth congenital anomalies, even as low as 1-5 cigarettes per day. Maternal smokers who stopped smoking in the subsequent trimesters of pregnancy were still at an increased risk of birth congenital anomalies. Our findings highlighted that smoking cessation interventions should be implemented before pregnancy. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) has the lowest overall survival rate primarily due to the late onset of symptoms and rapid progression. Reliable and accurate tests for early detection are lacking. We aimed to develop a noninvasive test for early PDAC detection by capturing the circulating tumour DNA (ctDNA) methylation signature in blood.Methods: Genome-wide methylation profiles were generated from PDAC and nonmalignant tissues and plasma. Methylation haplotype blocks (MHBs) were examined to discover de novo PDAC markers. They were combined with multiple cancer markers and screened for PDAC classification accuracy. The most accurate markers were used to develop PDACatch, a targeted methylation sequencing assay. PDACatch was applied to additional PDAC and healthy plasma cohorts to train, validate and independently test a PDAC-discriminating classifier. Finally, the classifier was compared and integrated with carbohydrate antigen 19-9 (CA19-9) to evaluate and maximize its accuracy and utility.Results: In total, 90 tissues and 546 plasma samples were collected from 232 PDAC patients, 25 chronic pancreatitis (CP) patients and 323 healthy controls. Among 223 PDAC cases with known stage information, 43/119/38/23 cases were of Stage I/II/III/IV. A total of 171 de novo PDAC-specific markers and 595 multicancer markers were screened for PDAC classification accuracy. The top 185 markers were included in PDACatch, from which a 56-marker classifier for PDAC plasma was trained, validated and independently tested. It achieved an area under the curve (AUC) of 0.91 in both the validation (31 PDAC, 26 healthy; sensitivity = 84%, specificity = 89%) and independent tests (74 PDAC, 65 healthy; sensitivity = 82%, specificity = 88%). Importantly, the PDACatch classifier detected CA19-9-negative PDAC plasma at sensitivities of 75 and 100% during the validation and independent tests, respectively. It was more sensitive than CA19-9 in detecting Stage I (sensitivity = 80 and 68%, respectively) and early-stage (Stage I-IIa) PDAC (sensitivity = 76 and 70%, respectively). A combinatorial classifier integrating PDACatch and CA19-9 outperformed (AUC=0.94) either PDACatch (0.91) or CA19-9 (0.89) alone (p < 0.001).Conclusions: The PDACatch assay demonstrated high sensitivity for early PDAC plasma, providing potential utility for noninvasive detection of early PDAC and indicating the effectiveness of methylation haplotype analyses in discovering robust cancer markers. [ABSTRACT FROM AUTHOR]