Citations

TP53 is the most common mutated gene in human cancer. Mutant p53 protein loses its tumor-suppressor properties and gains oncogenic activity. Mutant p53 is a therapeutic target in a broad range of cancer types. However, how mutant p53 is epigenetically regulated during tumor progression remains elusive. In this study, we found that the upregulation of mutant p53 is mediated by bromodomain protein BRD4 in triple-negative breast cancer (TNBC) cells. Inhibition of BRD4 with its inhibitor JQ1 or knockdown of BRD4 suppressed the transcription of mutant p53, which led to the re-expression of p21, the inhibition of S-phase entry, and colony formation in TNBC cells. BRD4 also positively regulated the transcription of wild-type p53, whereas JQ1 treatment and knockdown of BRD4 decreased the expression of p21 in MCF-7 cells. Knockdown of BRD4 resulted in attenuation of TNBC tumor growth in vivo. Taken together, our results uncover a novel regulatory mechanism of mutant p53 via BRD4, and suggest that the bromodomain inhibitor suppresses tumorigenesis through targeting mutant p53 in TNBC.

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in the PKD1 and PKD2 genes, and it is characterized by renal cyst formation, inflammation and fibrosis. Forkhead box protein M1 (FoxM1), a transcription factor of the Forkhead box (Fox) protein super family, has been reported to promote tumor formation, inflammation and fibrosis in many organs. However, the role and mechanism of FoxM1 in regulation of ADPKD progression is still poorly understood. Here, we show that FoxM1 is an important regulator of cyst growth in ADPKD. FoxM1 is upregulated in cyst-lining epithelial cells in Pkd1 mutant mouse kidneys and human ADPKD kidneys. FoxM1 promotes cystic renal epithelial cell proliferation by increasing the expression of Akt and Stat3 and the activation of ERK and Rb. FoxM1 also regulates cystic renal epithelial cell apoptosis through NF-κB signaling pathways. In addition, FoxM1 regulates the recruitment and retention of macrophages in Pkd1 mutant mouse kidneys, a process that is associated with FoxM1-mediated upregulation of monocyte chemotactic protein 1. Targeting FoxM1 with its specific inhibitor, FDI-6, delays cyst growth in rapidly progressing and slowly progressing Pkd1 mutant mouse kidneys. This study suggests that FoxM1 is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for targeting FoxM1 as a therapeutic strategy for ADPKD treatment.

ImportanceThere is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C).ObjectiveTo determine whether the use of steroids within 2 days of admission for non–MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence.Design, Setting, and ParticipantsThis cohort study analyzed data retrospectively for children (<18 years) who required hospitalization for non–MIS-C COVID-19. Data from March 2020 through September 2021 were provided by 58 hospitals in 7 countries who participate in the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 registry.ExposureAdministration of steroids within 2 days of admission.Main Outcomes and MeasuresLength of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching.ResultsA total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score–matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators.Conclusions and RelevanceSteroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.

AbstractIschemia‐reperfusion injury (IRI) refers to a syndrome in which tissue damage is further aggravated and organ function further deteriorates when blood flow is restored after a period of tissue ischemia. Acute myocardial infarction, stress ulcer, pancreatitis, intestinal ischemia, intermittent claudication, acute tubular necrosis, postshock liver failure, and multisystem organ failure are all related to reperfusion injury. AMP‐activated protein kinase (AMPK) has been identified in multiple catabolic and anabolic signaling pathways. The functions of AMPK during health and diseases are intriguing but still need further research. Except for its conventional roles as an intracellular energy switch, emerging evidence reveals the critical role of AMPK in IRI as an energy‐sensing signal molecule by regulating metabolism, autophagy, oxidative stress, inflammation, and other progressions. At the same time, drugs based on AMPK for the treatment of IRI are constantly being researched and applied in clinics. In this review, we summarize the mechanisms underlying the effects of AMPK in IRI and describe the AMPK‐targeting drugs in treatment, hoping to increase the understanding of AMPK in IRI and provide new insights into future clinical treatment.

Autosomal dominant polycystic kidney disease (ADPKD) is a renal neoplastic disorder characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl − secretion. This study shows that the lonidamine derivative H2-GMZ inhibits Cl − secretion, cell proliferation, and cyst growth, suggesting that it might have therapeutic value for the treatment of ADPKD.

A 70-year-old man with severe valvular cardiomyopathy, permanent atrial fibrillation (AF) with a slow ventricular response, and transient atrioventricular (AV) block, was admitted to our center for severe heart failure and recurrent presyncope. While hospitalized, the coronary computed tomography angiography (CTA) showed huge atriums. We tried His bundle pacing (HBP). HB potential was observed at site A, and the His-ventricular (HV) interval was 68 ms. The duration from the stimulus signal to the onset of paced QRS (S-QRSonset) at site A was 232 ms when pacing at 60 beats per minute (BPM) with the pacing threshold of 2.0 V/0.5 ms. The S-QRSonset was longer than the HV interval and had a notable and progressive prolongation from 252 ms to 456 ms during the pacing at 90 BPM. Then, we pushed another lead a little forward, and the S-QRSonset shortened back to 68 ms, and the paced QRS morphology was the same as the intrinsic QRS morphology with the pacing threshold of 1.5 V/0.5 ms. The progressively prolonged S-QRSonset demonstrated a Wenckebach phenomenon (WP), a well-known electrophysiological characteristic of the AV node (AVN). It is the first time to report an intraoperative AVN-pacing related-WP in a patient with persistent AF. The enlarged atrium might be convenient for capturing the AVN. There are some other potential explanations for this phenomenon. The diameters of atriums decreased significantly, and the symptoms improved after the procedure. This is the first reported case in which we might achieve AVN capture in a patient with persistent AF. Although we ultimately chose HBP for better long-term pacing thresholds, the result of this case suggested that AVN pacing may be possible.

Here, we identified a cross talk between SET and MYND domain-containing lysine methyltransferase 2 (Smyd2) and transforming growth factor (TGF)-β-Smad3 signaling and a synergistic feedback loop between them, in which TGF-β stimulates expression of Smyd2 in a Smad3-dependent manner, and upregulation of Smyd2 regulates the transcription of TGF-β and other fibrotic marker genes through direct binding on their promoters or methylating histone H3 indirectly to regulate the transcription of those genes in fibroblasts. Thus, the Smyd2-TGF-β-Smad3-Smyd2 signaling axis plays an important role in promoting renal fibrosis, and targeting Smyd2 with its specific inhibitor should not only delay cyst growth but also ameliorate renal fibrosis in ADPKD.

Importance Although isotretinoin may rarely be associated with laboratory abnormalities such as hypertriglyceridemia, the optimal approach to laboratory monitoring is uncertain, and there is wide variation in clinical practice. Objective To establish a consensus for isotretinoin laboratory monitoring among a diverse, international cohort of clinical and research experts in acne. Design, Setting, and Participants Using a modified electronic Delphi process, 4 rounds of anonymous electronic surveys were administered from 2021 to 2022. For laboratory tests reaching consensus (≥70% agreement) for inclusion, questions regarding more time-specific monitoring throughout isotretinoin therapy were asked in subsequent rounds. The participants were international board-certified dermatologist acne experts who were selected on a voluntary basis based on involvement in acne-related professional organizations and research. Main Outcomes and Measures The primary outcome measured was whether participants could reach consensus on key isotretinoin laboratory monitoring parameters. Results The 22 participants from 5 continents had a mean (SD) time in practice of 23.7 (11.6) years and represented a variety of practice settings. Throughout the 4-round study, participation rates ranged from 90% to 100%. Consensus was achieved for the following: check alanine aminotransferase within a month prior to initiation (89.5%) and at peak dose (89.5%) but not monthly (76.2%) or after treatment completion (73.7%); check triglycerides within a month prior to initiation (89.5%) and at peak dose (78.9%) but not monthly (84.2%) or after treatment completion (73.7%); do not check complete blood cell count or basic metabolic panel parameters at any point during isotretinoin treatment (all >70%); do not check gamma-glutamyl transferase (78.9%), bilirubin (81.0%), albumin (72.7%), total protein (72.7%), low-density lipoprotein (73.7%), high-density lipoprotein (73.7%), or C-reactive protein (77.3%). Conclusions and Relevance This Delphi study identified a core set of laboratory tests that should be evaluated prior to and during treatment with isotretinoin. These results provide valuable data to guide clinical practice and clinical guideline development to optimize laboratory monitoring in patients treated with isotretinoin.