Effect of proton pump inhibitors versus histamine-2 receptor antagonists on acute kidney injury in septic patients at high risk for developing stress ulcers.

BACKGROUND: To compare the effects of proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) use on the occurrence of acute kidney injury (AKI) in septic patients at high risk for developing stress ulcers. METHODS: Using the Medical Information Mart for Intensive Care IV version 2.2 database, septic patients with high-risk factors for stress ulcers (i.e., shock, coagulopathy, invasive mechanical ventilation, or chronic liver diseases) were included. Exposures included PPIs and H2RAs within 24 h of intensive care unit (ICU) admission or prior to ICU admission. The primary end point was severe sepsis-associated AKI as defined by the Kidney Disease Improving Global Outcomes criteria stage 3 (KDIGO-3). Propensity score matching (PSM) was performed to balance baseline characteristics. Multivariable Cox proportional hazards regression was used to estimate the effect size. RESULTS: 4731 PPI users and 4903 H2RA users were included. After PSM, there were 1785 pairs exposed to PPIs and H2RAs. In the PSM cohort, the cumulative incident KDIGO-3 rate was higher in the PPI group than in the H2RA group (log-rank test, p = 0.009). Regression analyses showed that PPI exposure [adjusted hazard ratio 1.32, 95% confidence interval (CI) 1.11-1.58, p = 0.002] was associated with incident KDIGO-3 compared with H2RA use. This association remained consistent in sensitivity analyses. Additionally, the PPI group had a higher need for kidney replacement therapy compared with the H2RA group (3.6% vs. 2.1%, P = 0.012). CONCLUSIONS: Among septic patients at high risk for developing stress ulcers, PPI exposure was associated with incident KDIGO-3 AKI compared with H2RA use.

Medium-Term Prognostic Implications of Cardiac Magnetic Resonance Imaging in Patients With Myocardial Infarction With Nonobstructive Coronary Arteries (MINOCA): A Systematic Review and Meta-Analysis.

BACKGROUND: This study aimed to evaluate the medium-term prognostic implications of cardiac magnetic resonance (CMR) imaging in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA). METHODS: A systematic literature search of Embase, PubMed, and The Cochrane Library was performed. Eligible studies reported outcomes of CMR-assessed MINOCA with a mean follow-up period of >6 months. The primary endpoint was all-cause death. Secondary endpoints included cardiac death, reinfarction, and cardiovascular rehospitalisation. The pooled effect sizes with 95% confidence interval (CIs) were estimated using a random effect model. RESULTS: A total of 3,050 patients from twenty-one studies were included in the meta-analysis. The prevalence of myocarditis, "true" myocardial infarction, Takotsubo cardiomyopathy, and normal CMR imaging was 36%, 25%, 14%, and 19%, respectively. Pooled data showed that the annualised event rates for all-cause mortality, cardiac mortality, reinfarction, and cardiovascular rehospitalisation were 1.01% (95% CI 0.59%-1.51%), 0.06% (95% CI 0.00%-0.39%), 0.68% (95% CI 0.18%-1.38%), and 5.67% (95% CI 3.11%-8.85%), respectively. Compared with patients with a diagnosis of myocarditis on CMR, patients with Takotsubo cardiomyopathy (RR 7.11; 95% CI 3.04-16.66) and "true" myocardial infarction (RR 3.82; 95% CI 1.65-8.86) were associated with a significantly higher risk of all-cause mortality, whereas a similar risk of all-cause mortality was observed in patients with normal imaging (RR 1.01; 95% CI 0.28-3.59). No association was found between CMR diagnoses and the risk of secondary endpoints in MINOCA. CONCLUSIONS: In patients with MINOCA assessed by CMR, the overall absolute incidence rates of mortality and reinfarction were low. However, certain imaging diagnoses were associated with a higher risk of all-cause mortality, with most deaths attributed to non-cardiac causes. Additionally, these patients experienced a high burden of cardiovascular rehospitalisation. REGISTRATION: PROSPERO (CRD42022323615).

Association between short-term systemic use of glucocorticoids and prognosis of cardiogenic shock: a retrospective analysis.

OBJECTIVE: To investigate the prescription rate of short-term systemic use of glucocorticoids during hospitalization in patients with cardiogenic shock (CS), and outcomes related with glucocorticoid use. METHODS: We extracted patients' information from the Medical Information Mart for Intensive Care IV version 2.0 (MIMIC-IV v2.0) database. The primary endpoint was 90-day all-cause mortality. Secondary safety endpoints were infection identified by bacterial culture and at least one episode of hyperglycemia after ICU admission. Propensity score matching (PSM) was used to balance baseline characteristics. The difference in cumulative mortality rate between these treated with and without glucocorticoids was assessed by Kaplan-Meier curve with log-rank test. Independent risk factors for endpoints were identified by Cox or Logistic regression analysis. RESULTS: A total of 1528 patients were enrolled, and one-sixth of these patients received short-term systemic therapy of glucocorticoids during hospitalization. These conditions, including rapid heart rate, the presence of rheumatic disease, chronic pulmonary disease and septic shock, high lactate level, the requirements of mechanical ventilation and continuous renal replacement therapy, were associated with an increase in glucocorticoid administration (all P ≤ 0.024). During a follow-up of 90 days, the cumulative mortality rate in patients treated with glucocorticoids was significantly higher than that in these untreated with glucocorticoids (log-rank test, P < 0.001). Multivariable Cox regression analysis showed that glucocorticoid use (hazard ratio 1.48, 95% confidence interval [CI] 1.22-1.81; P < 0.001) was independently associated with an increased risk for 90-day all-cause mortality. This result was consistent irrespective of age, gender, the presence of myocardial infarction, acute decompensated heart failure and septic shock, and inotrope therapy, but was more evident in low-risk patients as assessed by ICU scoring systems. Additionally, multivariable Logistic regression analysis showed that glucocorticoid exposure was an independent predictor of hyperglycemia (odds ratio 2.14, 95% CI 1.48-3.10; P < 0.001), but not infection (odds ratio 1.23, 95% CI 0.88-1.73; P = 0.221). After PSM, glucocorticoid therapy was also significantly related with increased risks of 90-day mortality and hyperglycemia. CONCLUSIONS: Real-world data showed that short-term systemic use of glucocorticoids was common in CS patients. Importantly, these prescriptions were associated with increased risks of adverse events.

High Expression of ROMO1 Aggravates the Malignancy of Hepatoblastoma.

Hepatoblastoma (HB) is a kind of tumor that occurs frequently in children and is highly malignant. Here, the function of ROS modulator 1 (ROMO1) was identified in the development of HB. In this study, the mRNA expression of ROMO1 was measured by RT-qPCR. Colony formation assay, MTT assay, and flow cytometric analysis were applied to detect cell viability. The cell migrative and invasive ability was measured by wound healing and transwell assays. Tumor xenografts were performed to examine tumor growth. The results showed that upregulation of ROMO1 was identified in liver hepatocellular carcinoma (LIHC) tissues and predicted poor prognosis in LIHC patients. And ROMO1 expression was also increased in HB tissues and cells. Functionally, ROMO1 knockdown restrained cell viability, migration, and invasion in HB. In addition, knockdown of ROMO1 was found to suppress tumor formation in vivo. In conclusion, upregulation of ROMO1 promotes tumor growth and cell aggressiveness in HB.

Endothelial function as predictor in patients with coronary syndrome treated by percutaneous coronary intervention.

We aimed at identifying the predictive role of endothelial function assessed by the RH-PAT index (RHI) for future major cardiovascular events (MACEs) in acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). We measured RHI in 308 subjects with ACS, and they were divided into the normal endothelial function (NEF) group and the endothelial dysfunction (DEF) group according to the RHI. The subjects were followed up for a mean of 16 months (interquartile range [IQR]: 14-20 months) after PCI treatment, and their MACEs were also recorded. Cumulative incidence curves were constructed for time-to-event variables with Kaplan-Meier estimates and compared using the log-rank test. The overall incidence of MACEs was 25.39% in the DEF group and 15.96% in the NEF group (P<0.05). Kaplan-Meier analysis also demonstrated a significantly higher probability of MACEs in the DEF group than in the NEF group (log-rank test: P<0.05). Multivariate Cox hazard analysis identified RHI (Model 2, adjusted by blood pressure, hazard ratio [HR]: 0.425; 95% confidence interval [CI]: 0.198-0.914; P=0.029) and SYNTAX score (HR: 1.043; 95% CI: 1.019-1.067; P<0.001) as independent predictors of future MACEs after PCI treatment in ACS patients. Endothelial function measured by reactive hyperemia-peripheral arterial tonometry (RH-PAT) is impaired in ACS subjects treated with PCI. The RHI was an independent predictor of MACEs, suggesting that RHI may be useful as a candidate biomarker in the risk stratification of patients with ACS after PCI treatment.

Function of focal adhesion kinase scaffolding to mediate endophilin A2 phosphorylation promotes epithelial-mesenchymal transition and mammary cancer stem cell activities in vivo.

Tyrosine kinases have been shown to play critical roles in cancer development and progression, and their inhibitors hold the potential as effective targeted therapies for breast and other cancers. However, some of these kinases like focal adhesion kinase (FAK) also possess scaffolding functions in intracellular signaling, but such kinase-independent functions of FAK or other kinases have not been examined in cancer directly in vivo. Here, we report that disruption of the function of FAK scaffolding through its Pro-878/881 motif suppressed mammary tumor growth and metastasis in a well characterized murine model of human breast cancer. P878A/P881A mutation in the endogenous FAK gene decreased the expression of markers for epithelial-mesenchymal transition (EMT) and mammary cancer stem cell (MaCSC) activities in tumors derived from mutant mice. This mutation disrupted the function of FAK scaffolding to mediate endophilin A2 phosphorylation at Tyr-315 by Src, leading to the decreased surface expression of MT1-MMP, as observed previously in transformed fibroblasts in vitro. Inhibition of the downstream components of this FAK scaffolding function by Y315F endophilin A2 mutant or MT1-MMP knockdown reduced markers for EMT and MaCSC activities. Conversely, bypass of the scaffolding function using the phosphorylation mimic mutant Y315E endophilin A2 or endophilin A2 knockdown rescued the decreased markers for EMT and MaCSCs as well as surface expression of MT1-MMP in tumor cells harboring the P878A/P881A mutation. Together, these results identify a novel role of FAK scaffolding function in breast cancer, which could serve as a new target in combination with kinase inhibition for more effective treatment strategies.

Compensatory function of Pyk2 protein in the promotion of focal adhesion kinase (FAK)-null mammary cancer stem cell tumorigenicity and metastatic activity.

Mammary cancer stem cells (MaCSCs) have been identified as a rare population of cells capable of self-renewal to drive mammary tumorigenesis and metastasis. Nevertheless, relatively little is known about the intracellular signaling pathways regulating self-renewal and metastatic activities of MaCSCs in vivo. Using a recently developed breast cancer mouse model with focal adhesion kinase (FAK) deletion in mammary tumor cells (MFCKO-MT mice), here we present evidence suggesting a compensatory function of Pyk2, a FAK-related kinase, in the regulation of MaCSCs and metastasis in these mice. Increased expression of Pyk2 was found selectively in pulmonary metastatic nodules of MFCKO-MT mice, and its inhibition significantly reduced mammary tumor development and metastasis in these mice. Consistent with the idea of metastasis driven by MaCSCs, we detected selective up-regulation of Pyk2 in MaCSCs, but not bulk mammary tumor cells, of primary tumors developed in MFCKO-MT mice. We further showed that inhibition of Pyk2 in FAK-null MaCSCs significantly decreased their tumorsphere formation and migration in vitro as well as self-renewal, tumorigenicity, and metastatic activity in vivo. Last, we identified PI3K/Akt signaling as a major mediator of FAK regulation of MaCSCs as well as a target for the compensatory function of Pyk2 in FAK-null MaCSCs. Together, these results further advance our understanding of FAK and its related tyrosine kinase Pyk2 in regulation of MaCSCs in breast cancer and suggest that pharmaceutically targeting these kinases may hold promise as a novel treatment for the disease by targeting and eradicating MaCSCs.

Regulation of Integrin ß 1 recycling to lipid rafts by Rab1a to promote cell migration.

Rab1a is a member of the Rab family of small GTPases with a well characterized function in the regulation of vesicle trafficking from the endoplasmic reticulum to the Golgi apparatus and within Golgi compartments. The integrin family heterodimeric transmembrane proteins serve as major receptors for extracellular matrix proteins, which play essential roles in cell adhesion and migration. Although effects on intracellular trafficking of integrins or other key cargos by Rab1a could influence cell migration, the regulatory mechanisms linking Rab1a to cell migration are not well understood. Here, we report identification of Rab1a as a novel regulator of cell migration using an unbiased RNAi screen targeting GTPases. Inhibition of Rab1a reduced integrin-mediated cell adhesion and spreading on fibronectins, reduced integrin ß1 localization to lipid rafts, and decreased recycling of integrin ß1 to the plasma membrane. Analysis of Rab1a effector molecules showed that p115 mediated Rab1a regulation of integrin recycling and lipid raft localization in cell migration. Taken together, these results suggest a novel function for Rab1a in the regulation of cell migration through controlling integrin ß1 recycling and localization to lipid rafts via a specific downstream effector pathway.

Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells.

Focal adhesion kinase (FAK) has been implicated in the development of cancers, including those of the breast. Nevertheless, the molecular and cellular mechanisms by which FAK promotes mammary tumorigenesis in vivo are not well understood. Here, we show that targeted deletion of FAK in mouse mammary epithelium significantly suppresses mammary tumorigenesis in a well-characterized breast cancer model. Ablation of FAK leads to the depletion of a subset of bipotent cells in the tumor that express both luminal marker keratin 8/18 and basal marker keratin 5. Using mammary stem/progenitor markers, including aldehyde dehydrogenase, CD24, CD29, and CD61, we further revealed that ablation of FAK reduced the pool of cancer stem/progenitor cells in primary tumors of FAK-targeted mice and impaired their self-renewal and migration in vitro. Finally, through transplantation in NOD-SCID mice, we found that cancer stem/progenitor cells isolated from FAK-targeted mice have compromised tumorigenicity and impaired maintenance in vivo. Together, these results show a novel function of FAK in maintaining the mammary cancer stem/progenitor cell population and provide a novel mechanism by which FAK may promote breast cancer development and progression.

SNAP-25/syntaxin 1A complex functionally modulates neurotransmitter gamma-aminobutyric acid reuptake.

Neurotransmitter gamma-aminobutyric acid (GABA) release to the synaptic clefts is mediated by the formation of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, which includes two target SNAREs syntaxin 1A and SNAP-25 and one vesicle SNARE VAMP-2. The target SNAREs syntaxin 1A and SNAP-25 form a heterodimer, the putative intermediate of the SNARE complex. Neurotransmitter GABA clearance from synaptic clefts is carried out by the reuptake function of its transporters to terminate the postsynaptic signaling. Syntaxin 1A directly binds to the neuronal GABA transporter GAT-1 and inhibits its reuptake function. However, whether other SNARE proteins or SNARE complex regulates GABA reuptake remains unknown. Here we demonstrate that SNAP-25 efficiently inhibits GAT-1 reuptake function in the presence of syntaxin 1A. This inhibition depends on SNAP-25/syntaxin 1A complex formation. The H3 domain of syntaxin 1A is identified as the binding sites for both SNAP-25 and GAT-1. SNAP-25 binding to syntaxin 1A greatly potentiates the physical interaction of syntaxin 1A with GAT-1 and significantly enhances the syntaxin 1A-mediated inhibition of GAT-1 reuptake function. Furthermore, nitric oxide, which promotes SNAP-25 binding to syntaxin 1A to form the SNARE complex, also potentiates the interaction of syntaxin 1A with GAT-1 and suppresses GABA reuptake by GAT-1. Thus our findings delineate a further molecular mechanism for the regulation of GABA reuptake by a target SNARE complex and suggest a direct coordination between GABA release and reuptake.

Morphine withdrawal increases glutamate uptake and surface expression of glutamate transporter GLT1 at hippocampal synapses.

Opiate abuse causes adaptive changes in several processes of synaptic transmission in which the glutamatergic system appears a critical element involved in opiate tolerance and dependence, but the underlying mechanisms remain unclear. In the present study, we found that glutamate uptake in hippocampal synaptosomes was significantly increased (by 70% in chronic morphine-treated rats) during the morphine withdrawal period, likely attributable to an increase in the number of functional glutamate transporters. Immunoblot analysis showed that expression of GLT1 (glutamate transporter subtype 1) was identified to be upregulated in synaptosomes but not in total tissues, suggesting a redistribution of glutamate transporter expression. Moreover, the increase in glutamate uptake was reproduced in cultured neurons during morphine withdrawal, and the increase of uptake in neurons could be blocked by dihydrokainate, a specific inhibitor of GLT1. Cell surface biotinylation and immunoblot analysis showed that morphine withdrawal produced an increase in GLT1 expression rather than EAAC1 (excitatory amino acids carrier 1), a neuronal subtype, at the cultured neuronal cell surface, whereas no significant change was observed in that of cultured astrocytes. Electron microscopy also revealed that GLT1 expression was markedly increased in the nerve terminals of hippocampus and associated with the plasma membrane in vivo. These results suggest that GLT1 in hippocampal neurons can be induced to translocate to the nerve terminals and express on the cell surface during morphine withdrawal. The translocation of GLT1 at synapses during morphine withdrawal provides a neuronal mechanism for modulation of excitatory neurotransmission during opiate abuse.