DCS, a novel classifier system based on disulfidptosis reveals tumor microenvironment heterogeneity and guides frontline therapy for clear cell renal carcinoma

Background: Emerging evidence suggests that cell deaths are involved in tumorigenesis and progression, which may be treated as a novel direction of cancers. Recently, a novel type of programmed cell death, disulfidptosis, was discovered. However, the detailed biological and clinical impact of disulfidptosis and related regulators remains largely unknown. Methods: In this work, we first enrolled pancancer datasets and performed multi-omics analysis, including gene expression, DNA methylation, copy number variation and single nucleic variation profiles. Then we deciphered the biological implication of disulfidptosis in clear cell renal cell carcinoma (ccRCC) by machine learning. Finally, a novel agent targeting at disulfidptosis in ccRCC was identified and verified. Results: We found that disulfidptosis regulators were dysregulated among cancers, which could be explained by aberrant DNA methylation and genomic mutation events. Disulfidptosis scores were depressed among cancers and negatively correlated with epithelial mesenchymal transition. Disulfidptosis regulators could satisfactorily stratify risk subgroups in ccRCC, and a novel subtype, DCS3, owning with disulfidptosis depression, insensitivity to immune therapy and aberrant genome instability were identified and verified. Moreover, treating DCS3 with NU1025 could significantly inhibit ccRCC malignancy. Conclusion: This work provided a better understanding of disulfidptosis in cancers and new insights into individual management based on disulfidptosis.

Dynamic navigation system-guided trans-inferior alveolar nerve implant placement in the atrophic posterior mandible: A case report

BACKGROUND In atrophic posterior mandibular areas,where the bone height superior to the inferior alveolar nerve(IAN)is less than 6 mm,short implants are not applicable.Conventional alternatives such as IAN transposition and various alveolar bone augmentation approaches are technically demanding and prone to complications.CASE SUMMARY Computer-guided dynamic navigation implantation improves the accuracy,predictability,and safety of implant placement.This case report presents a dynamic navigation system-guided trans-IAN implant placement technique,which can successfully treat a posterior mandibular dentition defect when the bone height is only 4.5 mm.The implant was inserted into the buccal side of the IAN and was 1.7 mm away from the IAN.The implantation deviations were controlled within a satisfying range,and the long-term restoration outcome was stable.CONCLUSION Dynamic navigation system-guided trans-IAN implant placement might be a recommended technique for patients with extremely insufficient residual bone height and sufficient bone width in the posterior mandibular area.

Prediction of Th17/Treg cell balance on length of stay in intensive care units of patients with sepsis

Background Prolonged length of stay(LOS)of sepsis can drain a hospital's material and human resources.This study investigated the correlations between T helper type 17(Th17)and regulatory T(Treg)balance with LOS in sepsis.Methods A prospective clinical observational study was designed in Changhai Hospital affiliated to Naval Medical University in Shanghai,China,from January to October 2020.The patients diagnosed with sepsis and who met the inclusion and exclusion criteria were recruited and whether the levels of cytokines,procalcitonin,subtypes,and biomarkers of T cells in the peripheral blood were detected.We analyzed the correlation between these and LOS.Results Sixty septic patients were classified into two groups according to whether their intensive care unit(ICU)stay exceeded 14 days.The patients with LOS≥14 days were older([72.6±7.5]years vs.[63.3±10.4]years,P=0.015)and had higher Sequential Organ Failure Assessment(SOFA)(median[interquartile range]:6.5[5.0–11.0]vs.4.0[3.0–6.0],P=0.001)and higher Acute Physiology and Chronic Health Evaluation(APACHE)II scores(16.0[13.0–21.0]vs.8.5[7.0–14.0],P=0.001).There was no difference in other demographic characteristics and cytokines,interleukin-6,tumor necrosis factor-α,and interleukin-10 between the two groups.The Th17/Treg ratio of sepsis with LOS<14 days was considerably lower(0.48[0.38–0.56]vs.0.69[0.51–0.98],P=0.001).For patients with LOS≥14 days,the area under the receiver operating characteristic curve for the Th17/Treg ratio was 0.766.It improved to 0.840 and 0.850 when combined with the SOFA and APACHE II scores,respectively.Conclusions The Th17/Treg ratio was proportional to septic severity and can be used as a potential predictor of ICU stay in sepsis,presenting a new option for ICU practitioners to better care for patients with sepsis.

Tanshinone ⅡA prevents acute lung injury by regulating macrophage polarization

Objective: Acute lung injury(ALI) is a serious respiratory dysfunction caused by pathogen or physical invasion. The strong induced inflammation often causes death. Tanshinone ⅡA(Tan-ⅡA) is the major constituent of Salvia miltiorrhiza Bunge and has been shown to display anti-inflammatory effects. The aim of the current study was to investigate the effects of Tan-ⅡA on ALI.Methods: A murine model of lipopolysaccharide(LPS)-induced ALI was used. The lungs and serum samples of mice were extracted at 3 days after treatment. ALI-induced inflammatory damages were confirmed from cytokine detections and histomorphology observations. Effects of Tan-ⅡA were investigated using in vivo and in vitro ALI models. Tan-ⅡA mechanisms were investigated by performing Western blot and flow cytometry experiments. A wound-healing assay was performed to confirm the Tan-ⅡA function.Results: The cytokine storm induced by LPS treatment was detected at 3 days after LPS treatment, and alveolar epithelial damage and lymphocyte aggregation were observed. Tan-ⅡA treatment attenuated the LPS-induced inflammation and reduced the levels of inflammatory cytokines released not only by inhibiting neutrophils, but also by macrophage. Moreover, we found that macrophage activation and polarization after LPS treatment were abrogated after applying the Tan-ⅡA treatment. An in vitro assay also confirmed that including the Tan-ⅡA supplement increased the relative amount of the M2 subtype and decreased that of M1. Rebalanced macrophages and Tan-ⅡA inhibited activations of the nuclear factor-κB and hypoxia-inducible factor pathways. Including Tan-ⅡA and macrophages also improved alveolar epithelial repair by regulating macrophage polarization.Conclusion: This study found that while an LPS-induced cytokine storm exacerbated ALI, including Tan-ⅡA could prevent ALI-induced inflammation and improve the alveolar epithelial repair, and do so by regulating macrophage polarization.