YAP confers small cell lung cancer with the intratumoral heterogeneity and resistance to chemotherapy drugs.

Shear stress exerted by the blood stream modulates endothelial functions through altering gene expression. KLF2 and KLF4, the mechanosensitive transcription factors, are promoted by laminar flow to maintain endothelial homeostasis. However, how the expression of KLF2/4 is regulated by shear stress is poorly understood. Here, we showed that the activation of PIEZO1 upregulates the expression of KLF2/4 in endothelial cells. Mice with endothelial-specific deletion of Piezo1 exhibit reduced KLF2/4 expression in thoracic aorta and pulmonary vascular endothelial cells. Mechanistically, shear stress activates PIEZO1, which results in a calcium influx and subsequently activation of CaMKII. CaMKII interacts with and activates MEKK3 to promote MEKK3/MEK5/ERK5 signaling and ultimately induce the transcription of KLF2/4. Our data provide the molecular insight into how endothelial cells sense and convert mechanical stimuli into a biological response to promote KLF2/4 expression for the maintenance of endothelial function and homeostasis.

Radiotherapy is a reliable method to cure cervical cancer patients, but it could cause serious urological complications after the treatment due to the anatomical location of the cervix. The main purpose of this retrospective analysis is to study the incidence, latency, and therapeutic efficacy of urological complications caused by radical hysterectomy with postoperative radiotherapy or radiotherapy alone in patients with cervical cancer. A retrospective analysis was conducted on patients with cervical cancer who received radical hysterectomy with postoperative radiotherapy or radiotherapy alone at the First Hospital of Jilin University between January 2010 and May 2016. The urological complications were confirmed by clinical manifestation, ultrasound, computed tomography (CT), nuclear scintigraphy, and assessment of renal function. All the patients with urological complications received conventional treatment, including conservative, electrosurgery, ureteral stents, nephrectomy, and neoplasty. The onset time of radiation injury symptoms was confirmed according to the medical history and follow-up. The surveillance for the therapeutic effects for these complications was accomplished by cystoscopy, imaging, and laboratory assessment. The overall rate of urological complications after treatment was 3.26%, comprising 2.12% ureteral obstruction, 0.98% radiocystitis, and 0.16% vesicovaginal fistula. The incidence of ureteral obstruction in patients treated with radical hysterectomy with postoperative radiotherapy and radiotherapy alone was not statistically significant (2.18% vs 1.59%, P > .05). The median onset time of radiocystitis and ureteral obstruction was 10 months (0–75 months) and 12 months (2–66.3 months), respectively. The onset time of vesicovaginal fistula was 3.5 months. After the appropriate treatment, the majority of the complications were under control. The incidence of urological complications is acceptable. There was no statistical difference in the risk between patients treated with radical hysterectomy with postoperative radiotherapy and radiotherapy alone. The latency period between radiotherapy and the manifestation of urological complications may be relatively long. So it is crucial to underline long-term follow-up after radiotherapy. The majority of urological complications were alleviated after symptomatic treatment and the patients with cervical cancer achieved long-term remissions or cures.

Endothelial dysfunction-driven vascular inflammation underlies sepsis and atherosclerosis. Piezo1 serves as a central mediator for endothelial mechanotransduction and inflammatory homeostasis. Nevertheless, the transcriptional pathways linking mechanical sensing to anti-inflammatory protection and the exact composition of its downstream signaling cascade remain incompletely resolved. Here, we identify BHLHE40 as an endothelial mechanosensitive transcription factor induced by Piezo1 that coordinates ferroptosis resistance and inflammation suppression. Mechanistically, shear stress activates Piezo1, triggering Ca²⁺ influx and calcineurin-dependent NFAT2 nuclear translocation. NFAT2 recruits HDAC1 to form a transcriptional complex that directly drives BHLHE40 expression. BHLHE40 then binds the SLC7A11 promoter, upregulating this cystine transporter to inhibit ferroptosis. Rescued mitochondrial integrity, reduced ROS, and reversed lipid peroxidation demonstrated this phenomenon. Crucially, mice with endothelial-specific BHLHE40 overexpression attenuate LPS-induced lung vascular leakage, neutrophil infiltration, and pro-inflammatory cytokine release. Our work establishes the Piezo1/Ca²⁺/calcineurin/NFAT2-HDAC1/BHLHE40/SLC7A11 axis as a master mechanotransduction pathway that transcriptionally maintains endothelial homeostasis.

The present study is aimed at investigating the association of NFE2L2 gene polymorphisms with risk and clinical characteristics of acute type A aortic dissection (AAAD) in a Han Chinese population. Six SNPs (rs1806649, rs13001694, rs2364723, rs35652124, rs6721961, and rs2706110) in NFE2L2 were genotyped using SNaPshot Multiplex Kit in 94 adult patients diagnosed with AAAD at our hospital, and 208 healthy Han Chinese subjects from the 1000 Genomes Project were served as the control group. The CC genotype of rs2364723 (CC versus (GC+GG), OR = 2.069, 95% CI: 1.222‐3.502, p = 0.006) and CC genotype of rs35652124 (CC versus (CT+TT), OR = 1.889, 95% CI: 1.112‐3.210, p = 0.018) were identified as risk factors for AAAD. Multivariable linear regression analysis revealed that the CC genotype of rs2364723 (β = 5.031, 95% CI: 1.878‐8.183, p = 0.002) and CC genotype of rs35652124 (β = 4.751, 95% CI: 1.544‐7.958, p = 0.004) were associated with increased maximum ascending aorta diameter of AAAD. Patients carrying rs2364723 CC genotype had a higher incidence of coronary artery involvement (31% vs. 12%, p = 0.027), while patients carrying rs35652124 CC genotype had a higher incidence of brain ischemia (9% vs. 0%, p = 0.045). In conclusion, NFE2L2 gene polymorphisms were correlated with risk and severity of AAAD in Han Chinese population.

Endothelial dysfunction-induced platelet activation contributes to thrombosis in major cardiovascular diseases. Endothelial cells sense hemodynamic shear stress via the mechanosensitive ion channel Piezo1, which determines their physiological functions. However, the downstream transcriptional pathways of Piezo1 linking mechanical force to endothelial function remain incompletely defined. Here, nuclear receptor subfamily 4 group A member 1 (NR4A1) is identified as an endothelial mechanosensitive transcription factor induced by Piezo1 that modulates platelet activation and thrombosis. Mechanistically, shear stress is shown to activate Piezo1, resulting in calcium influx and the subsequent activation of protein kinase C δ (PKCδ), which activates extracellular signal-regulated kinase (ERK) to induce NR4A1 transcription. NR4A1 then upregulates prostaglandin-endoperoxide synthase 2 (PTGS2) expression, leading to the increased production of prostacyclin and inhibition of platelet activation and thrombosis. In vivo, mice with endothelial cell-specific deletion of Nr4a1 exhibit greater thrombus weights and faster occlusion. These data establish the Piezo1/Ca2+/PKCδ/ERK/NR4A1/PTGS2 signaling cascade as a critical endothelial mechanotransduction pathway that senses physiological shear force to transcriptionally promote an antithrombotic state.