Unchecked inflammation is a hallmark of inflammatory tissue injury in diseases such as acute respiratory distress syndrome (ARDS). Yet the mechanisms of inflammatory lung injury remain largely unknown. Here we showed that bacterial endotoxin lipopolysaccharide (LPS) and cecal ligation and puncture–induced (CLP-induced) polymicrobial sepsis decreased the expression of transcription factor cAMP response element binding (CREB) in lung endothelial cells. We demonstrated that endothelial CREB was crucial for VE-cadherin transcription and the formation of the normal restrictive endothelial adherens junctions. The inflammatory cytokine IL-1β reduced cAMP generation and CREB-mediated transcription of VE-cadherin. Furthermore, endothelial cell–specific deletion of CREB induced lung vascular injury whereas ectopic expression of CREB in the endothelium prevented the injury. We also observed that rolipram, which inhibits type 4 cyclic nucleotide phosphodiesterase–mediated (PDE4-mediated) hydrolysis of cAMP, prevented endotoxemia-induced lung vascular injury since it preserved CREB-mediated VE-cadherin expression. These data demonstrate the fundamental role of the endothelial cAMP-CREB axis in promoting lung vascular integrity and suppressing inflammatory injury. Therefore, strategies aimed at enhancing endothelial CREB-mediated VE-cadherin transcription are potentially useful in preventing sepsis-induced lung vascular injury in ARDS.

Background:Widespread neural and microvascular injuries are common in chronic kidney disease (CKD), increasing risks of neurovascular complications and mortality. Early detection of such changes helps assess the risks of neurovascular complications for CKD patients. As an extension of central nervous system, the retina provides a characteristic window to observe neurovascular alterations in CKD. This study aimed to determine the presence of retinal neurovascular impairment in different stages of CKD.Methods:One hundred fifteen non-diabetic and non-dialytic CKD patients of all stages and a control group of 35 healthy subjects were included. Retinal neural and microvascular parameters were obtained by optical coherence tomography angiography (OCTA) examination.Results:CKD 1–2 group (versus control group) had greater odds of having decreased retinal ganglion cell-inner plexiform layer thickness (GC-IPLt) (odds ratio [OR]: 0.92; 95% confidence interval [CI]: 0.86–0.98), increased ganglion cell complex-focal loss volume (GCC-FLV) (OR: 3.51; 95% CI: 1.27–9.67), and GCC-global loss volume (GCC-GLV) (OR: 2.48; 95% CI: 1.27–4.82). The presence of advanced stages of CKD (CKD 3–5 group versus CKD 1–2 group) had greater odds of having decreased retinal vessel density in superficial vascular plexus (SVP)-WholeImage (OR: 0.77, 95% CI: 0.63–0.92), SVP-ParaFovea (OR: 0.83, 95% CI: 0.71–0.97), SVP-ParaFovea (OR: 0.76, 95% CI: 0.63–0.91), deep vascular plexus (DVP)-WholeImage (OR: 0.89, 95% CI: 0.81–0.98), DVP-ParaFovea (OR: 0.88, 95% CI: 0.78–0.99), and DVP-PeriFovea (OR: 0.90, 95% CI: 0.83–0.98). Besides, stepwise multivariate linear regression among CKD patients showed that β2-microglobulin was negatively associated with GC-IPLt (β: –0.294; 95% CI: –0.469 ∼ –0.118), and parathyroid hormone was positively associated with increased GCC-FLV (β: 0.004; 95% CI: 0.002∼0.006) and GCC-GLV (β: 0.007; 95% CI: 0.004∼0.01). Urine protein to creatinine ratio was positively associated with increased GCC-FLV (β: 0.003; 95% CI: 0.001∼0.004) and GCC-GLV (β: 0.003; 95% CI: 0.001∼0.006).Conclusion:Retinal neuronal impairment is present in early stages of CKD (stages 1–2), and it is associated with accumulation of uremic toxins and higher UACR, while retinal microvascular hypoperfusion, which is associated with worse eGFR, was only observed in relatively advanced stages of CKD (stages 3–5). The results highlight the importance of monitoring retinal neurovascular impairment in different stages of CKD.

In this retrospective review of a single institution’s experience, the efficacy and safety of the long-term use of nimotuzumab in combination with intensity-modulated radiotherapy (IMRT) and chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma (NPC) were studied. Between August 2008 and March 2014, 39 newly diagnosed patients with stages III‐IV NPC were treated with IMRT, chemotherapy, and nimotuzumab. Twenty patients were diagnosed with stage III (51.3%), 14 with stage IVA (35.9%), and 5 with stage IVB (12.8%) disease. All patients received at least one cycle of cisplatin-based induction chemotherapy followed by IMRT and more than nine cycles of nimotuzumab at 200 mg/week. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group. Accumulated survival was calculated according to the Kaplan‐Meier method. The log-rank test was used to compare survival differences. With a median follow-up of 46 months (range, 22‐86 months), the estimated 3-year local recurrence-free, regional recurrence-free, distant metastasis-free, progression failure-free, and overall survival rates were 92.1%, 89.7%, 82.5%, 77.6%, and 86.8%, respectively. Univariate analysis showed that clinical stage and the cycle of induction chemotherapy were related with prognosis. The median cycle for the addition of nimotuzumab was 12 weeks. Grade 3 radiation-induced mucositis was observed in 15.8% of the treated patients. No skin rash or infusion reaction was observed, which is distinctly different from what was reported in patients treated with nimotuzumab. The major toxicities observed were grades I‐II mucositis and leukocytopenia. Long-term use of nimotuzumab plus IMRT showed promising outcomes in terms of locoregional control and survival, without increasing the incidence of radiation-related toxicities in patients.

Renal interstitial fibrosis is an important mechanism in the progression of chronic kidney disease (CKD) to end-stage kidney disease. However, we lack specific treatments to slow or halt renal fibrosis. Ribosome profiling identified upregulation of a secreted micropeptide, C4orf48 (Cf48), in mouse diabetic nephropathy. Cf48 RNA and protein levels were upregulated in tubular epithelial cells in human and experimental CKD. Serum Cf48 levels were increased in human CKD and correlated with loss of kidney function, increasing CKD stage, and the degree of active interstitial fibrosis. Cf48 overexpression in mice accelerated renal fibrosis, while Cf48 gene deletion or knockdown by antisense oligonucleotides significantly reduced renal fibrosis in CKD models. In vitro, recombinant Cf48 (rCf48) enhanced TGF-β1–induced fibrotic responses in renal fibroblasts and epithelial cells independently of Smad3 phosphorylation. Cellular uptake of Cf48 and its profibrotic response in fibroblasts operated via the transferrin receptor. RNA immunoprecipitation–sequencing identified Cf48 binding to mRNA of genes involved in the fibrotic response, including Serpine1 , Acta2 , Ccn2 , and Col4a1 . rCf48 binds to the 3′UTR of Serpine1 and increases mRNA half-life. We identify the secreted Cf48 micropeptide as a potential enhancer of renal fibrosis that operates as an RNA-binding peptide to promote the production of extracellular matrix.

Mutp53 level is widely variable among individual cancer cells in tumor tissues, and within cells a higher level of mutp53 is usually observed in the nucleus as compared to the cytoplasm. This spatial heterogeneity in mutp53 expression has been well documented and likely plays an important role in tumor therapeutic resistance. However, its underlying mechanism remains poorly understood. In this study, we first revealed a critical role of micro-environmental reducing status in regulating mutp53 stability and spatially heterogeneous accumulation. Immunofluorescence and ThiolTracker Violet dye staining demonstrated a clear correlation between the cellular mutp53 level and the reducibility in the patient-derived tumor tissues and mutp53-expressing cancer cell lines. The nucleus exhibited both higher reducibility and more mutp53 accumulation than the cytoplasm did. Supplementing GSH exacerbated the accumulation of mutp53, while consuming GSH led to extensive depletion of mutp53, suggesting that the environmental reducing status kept mutp53 stability. Mechanistically, S-glutathionylation could trigger ubiquitination and proteasomal degradation of mutp53. A highly-reducing local environment preserved mutp53 stability by inhibiting glutathionylation and subsequent proteasomal degradation of mutp53, which also provided an explanation for the differential accumulation of mutp53 proteins in the nucleus and cytoplasm. Thirdly, we revealed that the expression level of glutathione reductase (GR) was positively correlated with mutp53 accumulation across the cultured mutp53-expressing cell lines, patient-derived tumor tissues and patient databases. Over-expression of GR reinforced the environmental reducibility, affected glutathionylation and improved mutp53 accumulation, while inhibiting GR either by chemical inhibitors or genetic approach induced massive clearance of a variety of mutp53 and effectively retarded the growth of p53-mutated cell-derived xenografts in mice. These studies provided an explanation for the widely-observed spatial heterogeneous accumulation of mutp53 proteins, and inhibiting GR or directly consuming GSH represented a promising strategy for mutp53 carrying cancer therapy.