The contribution of acute inflammation to sensory nerve regeneration was investigated in the murine cornea using a model of corneal abrasion that removes the stratified epithelium and subbasal nerve plexus. Abrasion induced accumulation of IL-17(+) CCR6(+) γδ T cells, neutrophils, and platelets in the cornea followed by full restoration of the epithelium and ∼19% regeneration of sensory nerves within 96 hours. Mice deficient in γδ T cells (TCRδ(-/-)) or wild-type mice treated systemically with anti-IL-17 had >50% reduction in leukocyte and platelet infiltration and >50% reduction in nerve regeneration. Strategies used to prevent neutrophil and platelet accumulation (eg, wild-type mice treated with anti-Ly6G or anti-GP1bα antibody to deplete neutrophils or platelets) also resulted in >50% reductions in corneal nerve density. Infiltrating neutrophils and platelets stained positively for VEGF-A, tissue levels of VEGF-A peaked coincidentally with peak tissue levels of neutrophils and platelets, depletion of neutrophils before injury reduced tissue VEGF-A levels by >70%, and wild-type mice treated systemically with anti-VEGF-A antibody exhibited >80% reduction in corneal nerve regeneration. Given the known trophic effects of VEGF-A for neurite growth, the results in this report demonstrate a previously unrecognized beneficial role for the γδ T cell-dependent inflammatory cascade involving IL-17, neutrophils, platelets, and VEGF-A in corneal nerve regeneration.

PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (i.e., PARP1 catalytic inhibition vs. PARP1 trapping). The relative contribution of these two pathways in mediating the cytotoxicity of PARPi, however, is incompletely understood. Here we designed a series of small molecule PARP degraders. Treatment with one such compound iRucaparib results in highly efficient and specific PARP1 degradation. iRucaparib blocks the enzymatic activity of PARP1 in vitro, and PARP1-mediated PARylation signaling in intact cells. This strategy mimics PARP1 genetic depletion, which enables the pharmacological decoupling of PARP1 inhibition from PARP1 trapping. Finally, by depleting PARP1, iRucaparib protects muscle cells and primary cardiomyocytes from DNA damage-induced energy crisis and cell death. In summary, these compounds represent "non-trapping" PARP1 degraders that block both the catalytic activity and scaffolding effects of PARP1, providing an ideal approach for the amelioration of the various pathological conditions caused by PARP1 hyperactivation.

RAD51 recombinase plays a critical role in homologous recombination and DNA damage repair. Here we showed that expression of RAD51 is frequently upregulated in lung cancer tumors compared with normal tissues and is associated with poor survival (hazard ratio (HR) = 2, P = 0.0009). Systematic investigation of lung cancer cell lines revealed higher expression of RAD51 in KRAS mutant (MT) cells compared to wildtype (WT) cells. We further showed that MT KRAS, but not WT KRAS, played a critical role in RAD51 overexpression via MYC. Moreover, our results revealed that KRAS MT cells are highly dependent on RAD51 for survival and depletion of RAD51 resulted in enhanced DNA double strand breaks, defective colony formation and cell death. Together, our results suggest that mutant KRAS promotes RAD51 expression to enhance DNA damage repair and lung cancer cell survival, suggesting that RAD51 may be an effective therapeutic target to overcome chemo/radioresistance in KRAS mutant cancers.

Background Let-7a-5p is demonstrated to be a tumor inhibitor in nasopharyngeal carcinoma. However, the role of let-7a-5p in chronic rhinosinusitis with nasal polyps (CRSwNP) has not been reported. This study is designed to determine the pattern of expression and role of let-7a-5p in CRSwNP. Methods The expression level of let-7a-5p, TNF-α, IL-1β, and IL-6 in CRSwNP tissues and cells were detected by RT-qPCR. Western blot assay was carried out to measure the protein expression of the Ras-MAPK pathway. Dual luciferase reporter assay and RNA pull-down assay were used to explore the relationship between let-7a-5p and IL-6. Results Let-7a-5p was significantly downregulated in CRSwNP tissues and cells. Moreover, the mRNA expression of TNF-α, IL-1β and IL-6 was increased in CRSwNP tissues, while let-7a-5p mimic inhibited the expression of TNF-α, IL-1β and IL-6. Besides that, let-7a-5p was negatively correlated with TNF-α, IL-1β and IL-6 in CRSwNP tissues. In our study, IL-6 was found to be a target gene of let-7a-5p. Additionally, let-7-5p mimic obviously reduced the protein levels of Ras, p-Raf1, p-MEK1 and p-ERK1/2, while IL-6 overexpression destroyed the inhibitory effect of let-7a-5p on the Ras-MAPK pathway in CRSwNP. Conclusion We demonstrated that let-7a-5p/IL-6 interaction regulated the inflammatory response through the Ras-MAPK pathway in CRSwNP.

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The rate of groin breakdown after radical wide vulvar excision and inguinal lymphadenectomy for vulvar cancer remains significant despite conservative surgical approaches. An 86-year-old Latin American woman underwent wide radical excision and bilateral inguinal lymphadenectomy for vulvar cancer. The postoperative course was complicated by bilateral groin wound separation and high output lymphorrhea. The patient responded to the application of a gelatin matrix-thrombin tissue sealant (FloSeal®) to the bases of each groin with resolution in lymphorrhea and formation of granulation tissue. The application of a gelatin matrix-thrombin tissue sealant (FloSeal®) may be a viable treatment in the management of groin breakdown in selected patients when conventional therapy produces suboptimal results.

Objective. At present, the most appropriate management of Henoch–Schonlein purpura nephritis (HSPN) with nephrotic-range proteinuria still remains controversial; thus, the purpose of this study is to evaluate safety and efficacy of traditional Chinese medicine (TCM), Qingre-Lishi-Yishen Formula (QLYF), integrated with regular oral glucocorticoid and cyclophosphamide intravenous pulse therapeutic regimen in children suffered from moderately severe HSPN with nephrotic proteinuria. Methods. From 1 January 2012, to 1 January 2016, totally 150 hospitalized children suffered from HSPN with nephrotic proteinuria were included. All were treated with glucocorticoid and cyclophosphamide, and 100 of them were treated with integrative traditional Chinese decoction QLYF. Patients were followed up for 2 years. Rate of adverse event occurrence, short-term clinical effects, long-term clinical effects, and TCM therapeutic evaluation were all compared. Results. Total adverse event rate was lower in the QLYF group (χ2 = 5.357, p=0.022); rates of respiratory infection, urinary infection, poor appetite, hepatotoxity, cardiotoxicity, and neutropenia were all decreased in patients who received QLYF (p<0.05), and no cases of hepatic and renal toxicities related to the herbal medicine were observed in the QLYF group. For short-term clinical efficacy evaluation, lower levels of 24 hour proteinuria (p<0.05) and urine blood cell count (p<0.05) were found in the QLYF group. For long-term efficacy evaluation, better clinical control rate effective rate, lower recurrence rate (p<0.05), and fewer TCM syndrome score (p<0.05) were found in the QLYF group. Conclusion. Compared with merely using regular oral glucocorticoid plus cyclophosphamide pulse therapeutic regimen, the therapeutic regimen that integrates QLYF with the abovementioned western medicine might be a safe means to decrease the occurrence rate of adverse events and improve short-term and long-term clinical effects in children who suffered from moderately severe HSPN with nephrotic proteinuria.

This study purposed to construct a widely accepted prognostic nomogram in Chinese high-grade osteosarcoma (HOS) patients aged ≤ 30 years to provide insight into predicting 5-year overall survival (OS). Data of 503 consecutive HOS patients at our centre between 12/2012 and 05/2019 were retrospectively collected. The 84 clinical features, routine laboratory haematological and biochemical testing indicators of each patient at the time of diagnosis were collected. A prognostic nomogram model for predicting OS was constructed based on Cox proportional hazards model. The performance was assessed by concordance index (C-index), receiver operating characteristic curve and calibration curve. The utility was evaluated by decision curve analysis. The 5-year OS was 52.1% and 2.6% for the nonmetastatic and metastatic patients, respectively. The nomogram included nine important variables based on a multivariate analysis: tumour stage, surgical type, metastasis, preoperative neoadjuvant chemotherapy cycle, postoperative metastasis time, mean corpuscular volume, tumour-specific growth factor, gamma-glutamyl transferase and creatinine. The calibration curve showed that the nomogram was able to predict 5-year OS accurately. The C-index of the nomogram for OS prediction was 0.795 (range, 0.703-0.887). Moreover, the decision curve analysis curve also demonstrated the clinical benefit of this model. The nomogram provides an individualized risk estimate of the 5-year OS in patients with HOS aged ≤ 30 years in a Chinese population-based cohort.