GSDMB interacts with IGF2BP1 to suppress colorectal cancer progression by modulating DUSP6-ERK pathway.

There is growing evidence that the protein family of Gasdermins (GSDMs) play an essential role during the progression of colorectal cancer (CRC). However, it is not completely clear that how GSDMB, abundantly expressed in epithelial cells of gastrointestinal tract, regulates the tumorigenesis of CRC. A wealth of evidence linking GSDMB to the pathogenesis of cancer has come from genome-wide association studies. Here, we provide evidence that aberrantly upregulated GSDMB is responsible for suppressing the CRC progression by using in vitro cell and intestinal organoid, as well as in vivo GSDMB transgenic mice models. Mechanistically, GSDMB interacts with insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which directly binds to and recognizes the 3'-UTR of dual specificity phosphatase 6 (DUSP6) mRNA, enhances the translation of DUSP6 protein and inhibits downstream ERK phosphorylation, thereby facilitating cell death and restraining cell proliferation. Our results suggest that GSDMB has potential as a novel therapeutic target for CRC treatment.

A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration.

Directed differentiation of stem cells toward chondrogenesis in vitro and in situ to regenerate cartilage suffers from off-target differentiation and hypertrophic tendency. Here, we generated a cartilaginous organoid system from human expanded pluripotent stem cells (hEPSCs) carrying a COL2A1mCherry and COL10A1eGFP double reporter, enabling real-time monitoring of chondrogenesis and hypertrophy. After screening 2,040 FDA-approved drugs, we found that α-adrenergic receptor (α-AR) antagonists, especially phentolamine, stimulated chondrogenesis but repressed hypertrophy, while α2-AR agonists reduced chondrogenesis and induced hypertrophy. Phentolamine prevented cartilage degeneration in hEPSC cartilaginous organoid and human cartilage explant models and stimulated microfracture-activated endogenous skeletal stem cells toward hyaline-like cartilage regeneration without fibrotic degeneration in situ. Mechanistically, α2-AR signaling induced hypertrophic degeneration via cyclic guanosine monophosphate (cGMP)-dependent secretory leukocyte protease inhibitor (SLPI) production. SLPI-deleted cartilaginous organoid was degeneration resistant, facilitating large cartilage defect healing. Ultimately, targeting α2-AR/SLPI was a promising and clinically feasible strategy to regenerate cartilage via promoting chondrogenesis and repressing hypertrophy.

Air pollution exposure during pregnancy and preterm birth in Brazil.

Ambient air pollution is a significant environmental risk factor for adverse pregnancy outcomes, including preterm birth. However, the impact of different pollutants across various regions and trimesters of pregnancy has not been fully investigated in Brazil. This study aimed to examine the associations between exposure to PM2.5, NO2, and O3 during different trimesters of pregnancy and the risk of preterm birth across five regions of Brazil. We used logistic regression models to estimate the odds ratios (OR) of preterm birth associated with PM2.5, NO2, and O3 adjusting for potential confounders such as maternal age, education, and socioeconomic status. Our study included over 9.9 million live births from 2001 to 2018, with data obtained from the Ministry of Health in Brazil. On average, for each 1-µg/m3 increase in PM2.5, we estimated a 0.26 % (95 % CI: 0.08-0.44 %) increase in the risk of preterm birth nationally in the first trimester. For NO2, each 1ppb increase was associated with a percentage increase in preterm birth risk of 7.26 % (95 % CI: 4.77-9.74 %) in the first trimester, 8.05 % (95 % CI: 5.73-10.38 %) in the second trimester, and 7.48 % (95 % CI: 5.25-9.72 %) in the third trimester. For O3, each 1ppb increase was associated with a percentage increase in preterm birth risk of 1.24 % (95 % CI: 0.29-2.18 %) in the first trimester, 1.51 % (95 % CI: 0.60-2.41 %) in the second trimester, and 0.72 % (95 % CI: -0.18-1.62 %) in the third trimester. This study highlights the significant impact of ambient air pollution on preterm birth risk in Brazil, with significant regional variations. Our findings underscore the need for targeted public health interventions to mitigate the effects of air pollution on pregnancy outcomes, particularly in the most affected regions.

Adrenal Vein Sampling for Primary Aldosteronism: Recommendations From the Australian and New Zealand Working Group.

Adrenal vein sampling (AVS) is the current recommended procedure for identifying unilateral subtypes of primary aldosteronism (PA), which are amenable to surgery with the potential for cure. AVS is a technically challenging procedure usually undertaken by interventional radiologists at tertiary centres. However, there are numerous variations in AVS protocols relating to patient preparation, sampling techniques and interpretation which may impact the success of AVS and patient care. To reduce practice variations, improve the success rates of AVS and optimise patient outcomes, we established an Australian and New Zealand AVS Working Group and developed evidence-based expert consensus recommendations for the preparation, performance and interpretation of AVS. These recommendations can be used by all healthcare professionals in a multidisciplinary team who look after the diagnosis and management of PA.

Relationship Between Renin, Aldosterone, Aldosterone-to-Renin Ratio and Arterial Stiffness and Left Ventricular Mass Index in Young Adults.

BACKGROUND: Primary aldosteronism, characterized by renin-independent aldosterone production, is associated with adverse cardiovascular remodeling and outcomes. Elevated cardiovascular risk is observed even in subclinical forms of primary aldosteronism according to studies conducted primarily in middle-aged and elderly populations. This study aimed to assess whether early changes in primary aldosteronism biomarkers during young adulthood are associated with arterial stiffness and left ventricular mass index (LVMI) before the onset of overt disease. METHODS: The Raine Study is a longitudinal, population-based cohort study in Western Australia that enrolled women during pregnancy. We analyzed the data from the offspring of these women at 17 (2006-2009) and 27 (2016-2018) years of age. Participants with elevated high-sensitivity C-reactive protein (>10 mg/L) and female participants who were on oral contraception were excluded. Pulse wave velocity and aortic augmentation index were measured by SphygmoCor Pulse Wave System at both ages, and aortic distensibility and LVMI were measured by cardiac magnetic resonance imaging at 27 years. Multivariable linear regression was used to examine the relationship between plasma renin, aldosterone, or aldosterone-to-renin ratio and arterial stiffness and LVMI. Mediation analysis was used to test the role of systolic blood pressure. RESULTS: This study included 859 participants at 17 (38.0% female) and 758 participants at 27 (33.2% female) years of age. Females had lower renin concentration at both 17 (20.7 mU/L versus 25.7 mU/L; P<0.001) and 27 (12.0 mU/L versus 15.4 mU/L; P<0.001) years of age; hence, the aldosterone-to-renin ratio was significantly higher at both 17 (18.2 versus 13.5; P<0.001) and 27 (21.0 versus 15.6; P<0.001) years of age in females compared with males. At 27 years of age, a significant association was detected between aldosterone and LVMI in males (ß=0.009 [95% CI, 0.001-0.017]; P=0.027) and between aldosterone-to-renin ratio and LVMI in females (ß=0.098 [95% CI, 0.001-0.196]; P=0.050) independently of systolic blood pressure and other confounders. No association was found between primary aldosteronism biomarkers and measures of arterial stiffness (pulse wave velocity, aortic augmentation index, and aortic distensibility) at either age. CONCLUSIONS: Aldosterone concentration and aldosterone-to-renin ratio were positively associated with the LVMI in young males and females, respectively, independently of systolic blood pressure. Long-term follow-up is required to determine whether the relationship persists over time, and clinical trials are needed to assess the cardiovascular benefits of early interventions to block aldosterone.

A dynamic approach for MR T2-weighted pelvic imaging.

OBJECTIVE: T2-weighted 2D fast spin echo sequence serves as the standard sequence in clinical pelvic MR imaging protocols. However, motion artifacts and blurring caused by peristalsis present significant challenges. Patient preparation such as administering antiperistaltic agents is often required before examination to reduce artifacts, which discomfort the patients. This work introduce a novel dynamic approach for T2 weighted pelvic imaging to address peristalsis-induced motion issue without any patient preparation. Approach: A rapid dynamic data acquisition strategy with complementary sampling trajectory is designed to enable highly undersampled motion-resistant data sampling, and an unrolling method based on deep equilibrium model is leveraged to reconstruct images from the dynamic sampled k-space data. Moreover, the fix-point convergence of the equilibrium model ensures the stability of the reconstruction. The high acceleration factor in each temporal phase, which is much higher than that in traditional static imaging, has the potential to effectively freeze pelvic motion, thereby transforming the imaging problem from conventional motion prevention or removal to motion reconstruction. Main results: Experiments on both retrospective and prospective data have demonstrated the superior performance of the proposed dynamic approach in reducing motion artifacts and accurately depicting structural details compared to standard static imaging. Significance: The proposed dynamic approach effectively captures motion states through dynamic data acquisition and deep learning-based reconstruction, addressing motion-related challenges in pelvic imaging.

Discovery of GJC1 as a prognostic biomarker in glioma cells: insights into its cell-cycle relationship and differential expression in non-neuronal cells.

Background: Gliomas, originating from the most common non-neuronal cells in the brain (glial cells), are the most common brain tumors and are associated with high mortality and poor prognosis. Glioma cells exhibit a tendency to disrupt normal cell-cycle regulation, leading to abnormal proliferation and malignant growth. This study investigated the predictive potential of GJC1 in gliomas and explored its relationship with the cell cycle. Methods: Retrospective analysis of RNA-seq and single-cell sequencing data was conducted using the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. The differential expression of GJC1 in gliomas with various pathological features and in different non-neuronal cell groups was analyzed. Functional data were examined using gene set variation analysis (GSVA). Furthermore, CellMiner was used to evaluate the relationship between GJC1 expression and predicted treatment response across these databases. Results: GJC1 expression was enriched in high-grade gliomas and 1p/19q non-codeletion gliomas. GJC1 enrichment was observed in classical and mesenchymal subtypes within the TCGA glioma subtype group. In single-cell subgroup analysis, GJC1 expression was higher in glioma tissues compared to other non-neuronal cells. Additionally, the TCGA classical subtype of glioma cells exhibited more GJC1 expression than the other subgroups. GJC1 emerged as an independent prognostic factor for overall survival in glioma. GSVA unveiled potential mechanisms by which GJC1 may impact cell-cycle regulation in glioma. Finally, a significant correlation was observed between GJC1 expression and the sensitivity of multiple anti-cancer drugs. Conclusion: These findings confirmed GJC1 as a novel biomarker and provided insights into the differential gene expression in non-neuronal cells and the impact of the cell cycle on gliomas. Consequently, GJC1 may be used to predict glioma prognosis and has potential therapeutic value.

Randomized, double-blind, phase 1a single-ascending dose and food effect studies assessing safety and pharmacokinetics of EC5026 in healthy volunteers.

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.

Effect of moxibustion on ATP-sensitive potassium channel (KATP) of bladder in detrusor overactivity rats. / 隔姜隔盐灸"神阙"å¯¹é€¼å°¿è‚Œè¿‡åº¦æ´»åŠ¨å¤§é¼ è†€èƒ±ATP敏感性钾离子通道的影响.

OBJECTIVES: To observe the effect of ginger-salt-partitioned moxibustion on ATP-sensitive potassium (KATP) channel of bladder in detrusor overactivity (DO) rats. METHODS: Female SD rats were randomly divided into sham operation, model, moxibustion and antagonist groups (n=9 in each group). Thorax (T) 10 spinal cord transection was performed by surgery. Ginger-salt partitioned moxibustion was applied to "Shenque" (CV8) for 3 cones, once daily for 14 consecutive days. Rats of the antagonist group were intraperitoneally injected with KATP channel specific antagonist glibenclamide (10 µg·kg-1·d-1) once daily for 14 consecutive days. Urodynamic tests were performed after treatment. The distribution and expression of KATP channel tetrameric subunit (SUR2B) in the bladder of rats was observed by immunofluorescence. The protein and mRNA expression levels of SUR2B in bladder tissue were detected by Western blot and qPCR respectively. RESULTS: Compared with the sham operation group, rats of the model group showed intensive and large phasic contractions of the detrusor during bladder filling, the frequency and amplitude of phasic contractions of the detrusor 5 min before leakage were significantly increased (P<0.001)；the voiding threshold pressure was significantly decreased (P<0.001)；the bladder perfusion volume was increased (P<0.001)；the SUR2B protein and mRNA expression in bladder tissue were significantly reduced (P<0.001). Compared with the model group and the antagonist group, the above-mentioned indicators in the moxibustion group were all reversed (P<0.01, P<0.001, P<0.05). CONCLUSIONS: Ginger-salt partitioned moxibustion can reduce the frequency and amplitude of detrusor phase contraction during bladder filling and prolong the time of first phase contraction in DO rats, which may be associated with up-regulating the expression level of KATP channel protein and mRNA, promoting the outflow of potassium ions, and inhibiting the inflow of calcium ions, thus improve the stability of detrusor during storage.