Background Large area skin trauma has always been a great challenge for both patients and clinicians. Exosomes originating from human adipose-derived mesenchymal stem cells (hADSCs) have been a novel ...promising cell-free treatment in cutaneous damage repair. Nevertheless, the low retention rate of exosomes post-transplantation in vivo remains a significant challenge in clinical applications. Herein, we purposed to explore the potential clinical application roles of hADSCs-Exos encapsulated in functional PF-127 hydrogel in wound healing. Methods hADSCs-Exos were isolated from human hADSCs by ultracentrifugation. An injectable, biocompatible, and thermo-sensitive hydrogel Pluronic F-127 hydrogel was employed to encapsulate allogeneic hADSCs-Exos, and this complex was topically applied to a full-thickness cutaneous wound in mice. On different days post-transplantation, the mice were sacrificed, and the skin tissue was excised for histological and immunohistochemical analysis. Results Compared with hADSCs-Exos or PF-127 only, PF-127/hADSCs-Exos complexes enhanced skin wound healing, promoted re-epithelialization, increased expression of Ki67, alpha-SMA, and CD31, facilitated collagen synthesis (Collagen I, Collagen III), up-regulated expression of skin barrier proteins (KRT1, AQP3), and reduced inflammation (IL-6, TNF-alpha, CD68, CD206). By using PF-127/hADSCs-Exos complexes, hADSCs-Exos can be administrated at lower doses frequency while maintaining the same therapeutic effects. Conclusion Administration of hADSCs-Exos in PF-127 improves the efficiency of exosome delivery, maintains the bioactivity of hADSCs-Exos, and optimizes the performance of hADSCs-Exos. Thus, this biomaterial-based exosome will be a promising treatment approach for the cutaneous rejuvenation of skin wounds. Keywords: Wound healing, Adipose-derived mesenchymal stem cells, Exosomes, PF-127 hydrogel
Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than normal cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We ...established a role for let‐7a‐5p/Stat3/hnRNP‐A1/PKM2 signaling in breast cancer cell glucose metabolism. PKM2 depletion via small interfering RNA (siRNA) inhibits cell proliferation and aerobic glycolysis in breast cancer cells. Signal transducer and activator of transcription 3 (Stat3) promotes upregulation of heterogeneous nuclear ribonucleoprotein (hnRNP)‐A1 expression, hnRNP‐A1 binding to pyruvate kinase isoenzyme (PKM) pre messenger RNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let‐7a‐5p, which functionally targets Stat3, whereas hnRNP‐A1 blocks the biogenesis of let‐7a‐5p to counteract its ability to downregulate the Stat3/hnRNP‐A1/PKM2 signaling pathway. The downregulation of Stat3/hnRNP‐A1/PKM2 by let‐7a‐5p is verified using a breast cancer. These results suggest that let‐7a‐5p, Stat3, and hnRNP‐A1 form a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of breast cancer cells. These findings elucidate a new pathway mediating aerobic glycolysis in breast cancers and provide an attractive potential target for breast cancer therapeutic intervention.
In this study, we explored the role of let‐7a‐5p and pyruvate kinase isoenzyme type M2 (PKM2) in the aerobic glycolysis of breast cancer cells. We found that let‐7a‐5p, signal transducer and activator of transcription 3 (Stat3), and heterogeneous nuclear ribonucleoprotein (hnRNP)‐A1 can form a feedback loop to regulate PKM2 expression, thereby regulating the glucose metabolism and growth of breast cancer cells. Thus, the let‐7a‐5p/Stat3/hnRNP‐A1/PKM2 signaling pathway may serve as a potential target for breast cancer treatment.
Lessons Learned
This single‐arm, phase II study shows that concurrent EGFR‐tyrosine kinase inhibitor plus thoracic radiotherapy as the first‐line treatment for stage IV non‐small cell lung cancer ...harboring EGFR active mutations provides long‐term control for the primary lung lesion, and 1‐year progression‐free survival (PFS) rate and median PFS are numerically higher than those of the erlotinib monotherapy.
Serious adverse events are acceptable, although grade >3 radiation pneumonitis occurred in 20% of patients.
Background
Studies show effective local control by EGFR‐tyrosine kinase inhibitor (TKI) combined with radiotherapy at metastatic sites in advanced lung cancer harboring EGFR active mutations. Salvage local radiotherapy is associated with prolonged progression‐free survival (PFS) in local disease during EGFR‐TKI treatment. However, no prospective study has been reported on concurrent EGFR‐TKI and radiotherapy for primary lung lesions. This study investigated the efficacy and safety of first‐line EGFR‐TKI combined with thoracic radiotherapy in treating stage IV non‐small cell lung cancer (NSCLC) harboring EGFR active mutations.
Methods
We conducted a single‐arm, phase II clinical trial. Each patient received EGFR‐TKI (erlotinib 150 mg or gefitinib 250 mg per day) plus thoracic radiotherapy (54–60 Gy/27–30 F/5.5–6 w) within 2 weeks of beginning EGFR‐TKI therapy until either disease progression or intolerable adverse events (AEs) appeared.
Results
From January 2015 to March 2018, 401 patients were screened, and 10 patients (5 male and 5 female) were eligible. These patients had a median age of 55 years (40–75) and median follow‐up of 19.8 months (5.8–34). The 1‐year PFS rate was 57.1%, median PFS was 13 months, and median time to progression of irradiated lesion (iTTP) was 20.5 months. Objective response rate (ORR), was 50% and disease control rate (DCR) was 100%. The most common grade ≥3 AEs were radiation pneumonitis (20%) and rash (10%). One patient died after rejecting treatment for pneumonitis. The others received a full, systematic course of glucocorticoid therapy. Pneumonitis was all well controlled and did not relapse.
Conclusion
Concurrent EGFR‐TKI plus thoracic radiotherapy as the first‐line treatment for stage IV NSCLC harboring EGFR active mutations shows a long‐term control of primary lung lesion. The 1‐year PFS rate and median PFS of this combined therapy are numerically higher than those of the erlotinib monotherapy. The risk of serious adverse events is acceptable.
经验总结
本项研究为单臂 II 期研究，结果表明胸部放疗联合 EGFR‐酪氨酸激酶抑制剂在 EGFR 活性突变的 IV 期非小细胞肺癌患者一线治疗中，可以长期控制原发肺病灶，而且 1 年无进展生存 (PFS) 率和中位 PFS 高于厄洛替尼单药治疗。
严重不良事件的发生率可接受，尽管3 级以上放射性肺炎发生率为 20%。
摘要
背景。研究表明，EGFR 酪氨酸激酶抑制剂 (TKI) 联合放疗可有效局部控制 EGFR 活性突变的晚期肺癌转移部位。在 EGFR‐TKI 治疗过程中，挽救性局部放疗可延长局部疾病的无进展生存期 (PFS)。然而，目前还没有 EGFR‐TKI 联合放疗治疗原发肺病灶的前瞻性研究报道。本研究探讨了 EGFR‐TKI 联合胸部放疗在 EGFR 活性突变的 IV 期非小细胞肺癌 (NSCLC) 一线治疗中的疗效和安全性。
方法。研究为单臂 II 期临床试验。所有患者在开始 EGFR‐TKI 治疗后 2 周内接受 EGFR‐TKI(每天厄洛替尼 150 mg或 吉非替尼250 mg)联合胸部放疗(54‐60 Gy/ 27‐30 F/ 5.5‐6 w)，直到出现疾病进展或无法忍受的不良事件 (AE)。
结果。筛查 2015 年 1 月至 2018 年 3 月期间的 401 例患者，其中 10 例患者符合条件(男性 5 例，女性 5 例)。这些患者的中位年龄为 55 岁(40‐75 岁)，中位随访时间为 19.8 个月(5.8‐34 个月)。1 年 PFS 率为 57.1%，中位 PFS 为 13 个月，中位放射病灶至进展时间 (iTTP) 为 20.5 个月。客观有效率 (ORR) 为 50%，疾病控制率 (DCR) 为 100%。最常见的 3 级以上AE为放射性肺炎 (20%) 和皮疹 (10%)。1 例患者在拒绝接受肺炎治疗后死亡。其他患者接受了完整、系统的糖皮质激素治疗。肺炎得到很好的控制，没有复发。
结论。EGFR‐TKI 联合胸部放疗在 EGFR 活性突变的 IV 期 NSCLC 患者一线治疗中，可以长期控制原发肺病灶。这种联合疗法的 1 年 PFS 率和中位 PFS 数值上高于厄洛替尼单药治疗。严重不良事件的发生率可接受。
The long noncoding RNA H19 is overexpressed in many cancers and acts as an oncogene. Here, we explored the role of H19 in breast cancer cells, including the effect of H19 on proliferation, migration, ...and invasion of breast cancer cells. We also investigated the relation of H19 to microRNA miR‐93‐5p and signal transducers and activators of transcription 3 (STAT3), the target gene of miR‐93‐5p. Ectopic expression of H19 in MCF‐7 cells and knockdown of H19 in MDA‐MB‐231 cells showed that overexpression of H19 promoted proliferation, migration, and invasion, whereas knockdown of H19 reduced proliferation, migration, and invasion in vitro. Dual‐luciferase reporter assays and RNA‐binding protein immunoprecipitation assays proved that H19 was a target of miR‐93‐5p. In addition, H19 antagonized the downregulation of miR‐93‐5p on its target STAT3 and antagonized miR‐93‐5p‐mediated cell proliferation. Our study revealed a new network in the expression of STAT3 involving H19 and miR‐93‐5p, which may contribute to a better understanding of breast cancer pathogenesis and provide new insights into the treatment of this disease.
H19 antagonized the downregulation of miR‐93‐5p on its target signal transducers and activators of transcription 3 (STAT3) and inhibited miR‐93‐5p‐induced cell proliferation. Our study revealed a new network in the expression of STAT3 involving H19 and miR‐93‐5p, which may contribute to a better understanding of breast cancer pathogenesis and provide new insights into the treatment of this disease.
Abstract
In WSe
2
monolayers, strain has been used to control the energy of excitons, induce funneling, and realize single-photon sources. Here, we developed a technique for probing the dynamics of ...free excitons in nanoscale strain landscapes in such monolayers. A nanosculpted tapered optical fiber is used to simultaneously generate strain and probe the near-field optical response of WSe
2
monolayers at 5 K. When the monolayer is pushed by the fiber, its lowest energy states shift by as much as 390 meV (>20% of the bandgap of a WSe
2
monolayer). Polarization and lifetime measurements of these red-shifting peaks indicate they originate from dark excitons. We conclude free dark excitons are funneled to high-strain regions during their long lifetime and are the principal participants in drift and diffusion at cryogenic temperatures. This insight supports proposals on the origin of single-photon sources in WSe
2
and demonstrates a route towards exciton traps for exciton condensation.
Gastric cancer (GC) is a common malignancy and frequent cause of cancer-related death. Long non-coding RNAs (lncRNAs) have emerged as important regulators and tissue-specific biomarkers of multiple ...cancers, including GC. Recent evidence has indicated that the novel lncRNA LINC01133 plays an important role in cancer progression and metastasis. However, its function and molecular mechanism in GC remain largely unknown.
LINC01133 expression was detected in 200 GC and matched non-cancerous tissues by quantitative reverse transcription PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of LINC01133 both in vitro and in vivo. Insights into the underlying mechanisms of competitive endogenous RNAs (ceRNAs) were determined by bioinformatics analysis, dual-luciferase reporter assays, quantitative PCR arrays, TOPFlash/FOPFlash reporter assay, luciferase assay, and rescue experiments.
LINC01133 was downregulated in GC tissues and cell lines, and its low expression positively correlated with GC progression and metastasis. Functionally, LINC01133 depletion promoted cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) in GC cells, whereas LINC01133 overexpression resulted in the opposite effects both in vitro and in vivo. Bioinformatics analysis and luciferase assays revealed that miR-106a-3p was a direct target of LINC01133, which functioned as a ceRNA in regulating GC metastasis. Mechanistic analysis demonstrated that miR-106a-3p specifically targeted the adenomatous polyposis coli (APC) gene, and LINC01133/miR-106a-3p suppressed the EMT and metastasis by inactivating the Wnt/β-catenin pathway in an APC-dependent manner.
Our findings suggest that reduced expression of LINC01133 is associated with aggressive tumor phenotypes and poor patient outcomes in GC. LINC01133 inhibits GC progression and metastasis by acting as a ceRNA for miR-106a-3p to regulate APC expression and the Wnt/β-catenin pathway, suggesting that LINC01133 may serve as a potential prognostic biomarker and anti-metastatic therapeutic target for GC.
Although many methods and new therapeutic drugs have been developed, the overall survival rate and long‐term survival rate of patients with gastric cancer (GC) are still not satisfactory. In this ...study, we investigated the effects of microRNA miR‐133a‐3p and transcription factor FOXP3 on proliferation and autophagy of GC cells and their interactions. Our results showed that knockdown of FOXP3 increased the proliferation and autophagy of GC cells. The relationship between FOXP3 and autophagy has not been reported previously. In addition, FOXP3 could directly bind the promoter region of TP53 and inhibit its expression. miR‐133a‐3p increased the proliferation and autophagy via decreasing the protein level of FOXP3 by targeting its 3′‐UTR. Our research provides new insights into the development of GC and provides new ideas and theoretical basis for the clinical treatment of GC and the development of new drug targets.
miR‐133a‐3p increased the proliferation and autophagy via decreasing the protein level of FOXP3 by targeting its 3′‐untranslated region. Our research provides new insights into the development of gastric cancer and provides new ideas and theoretical basis for the clinical treatment of gastric cancer and the development of new drug targets.
Anaplastic thyroid cancer (ATC) is one of the most aggressive and virulent solid tumors. The ubiquitin proteasome system presents in all eukaryotic cells and is essential for cellular homeostasis. ...While its underlying role in ATC remains largely unclear. TRIM11 is an E3 ubiquitin ligase and has been reported to act as an oncogene in several human cancers. The present study aims to reveal the oncogenic function of TRIM11 in ATC. Western blot was used to measure the protein expression of TRIM11 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; wound-healing assay and transwell assay were used to measure the migration ability of ATC. The xeno-graft tumor model was used for
study. Immuno-precipitation assay was used to detect the interaction domain between YAP and TRIM11. And the ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. TRIM11 depletion significantly decreases cell proliferation and migration capabilities of ATC cells, and elevates cell sensitivity to chemotherapy, which effect could be further rescued by YAP overexpression. TRIM11 depletion decreases YAP protein level and YAP/TEAD target genes, such as CTGF, ANKRD1 and CYR61 in ATC. Indicating that TRIM11 is a regulator of Hippo signaling pathway. Immuno-precipitation assay shows that the RING domain of TRIM11 is essential for the interaction with WW domain of YAP. Further mechanistic analysis suggests that TRIM11 promotes the mono-ubiquitination of YAP, thus prolongs its protein half. Furthermore, TRIM11 promoter analysis revealed that SOX13 activates TRIM11 transcription by binding to the promoter of TRIM11. In summary, our study describes the oncogenic function of TRIM11 in ATC, which acts as a post-translational modulating factor of Hippo pathway. Targeting TRIM11 may be a potential therapeutic method for ATC treatment.
SUMMARY
Malvids is one of the largest clades of rosids, includes 58 families and exhibits remarkable morphological and ecological diversity. Here, we report a high‐quality chromosome‐level genome ...assembly for Euscaphis japonica, an early‐diverging species within malvids. Genome‐based phylogenetic analysis suggests that the unstable phylogenetic position of E. japonica may result from incomplete lineage sorting and hybridization event during the diversification of the ancestral population of malvids. Euscaphis japonica experienced two polyploidization events: the ancient whole genome triplication event shared with most eudicots (commonly known as the γ event) and a more recent whole genome duplication event, unique to E. japonica. By resequencing 101 samples from 11 populations, we speculate that the temperature has led to the differentiation of the evergreen and deciduous of E. japonica and the completely different population histories of these two groups. In total, 1012 candidate positively selected genes in the evergreen were detected, some of which are involved in flower and fruit development. We found that reddening and dehiscence of the E. japonica pericarp and long fruit‐hanging time promoted the reproduction of E. japonica populations, and revealed the expression patterns of genes related to fruit reddening, dehiscence and abscission. The key genes involved in pentacyclic triterpene synthesis in E. japonica were identified, and different expression patterns of these genes may contribute to pentacyclic triterpene diversification. Our work sheds light on the evolution of E. japonica and malvids, particularly on the diversification of E. japonica and the genetic basis for their fruit dehiscence and abscission.
Significance Statement
Malvids is one of the largest clades of rosids and include 58 families, and its phylogenetic position is still contested. Euscaphis japonica, an early‐diverging species within malvids, is mainly distributed in Southeast Asia with deciduous or evergreen and two types: deciduous and evergreen. We assembled a high‐quality chromosome level genome of E. japonica, and found that E. japonica experienced a unique whole genome duplication event approximately 53 Mya. Genome‐based phylogenetic analysis suggests that the unstable phylogenetic position of E. japonica may result from incomplete lineage sorting and hybridization event during the diversification of the ancestral population of malvids. By resequencing 101 samples from 11 populations, we speculate that the temperature has led to the differentiation of the evergreen and deciduous of E. japonica and the completely different population histories of these two groups. Candidate positively selected genes related to the flower and fruit development in the evergreen were detected. We found that reddening and dehiscence of the E. japonica pericarp and long fruit‐hanging time promoted the reproduction of E. japonica populations, and revealed the expression patterns of genes related to fruit reddening, dehiscence, and abscission. The key genes involved in pentacyclic triterpene synthesis in E. japonica were identified, and different expression patterns of these genes may contribute to pentacyclic triterpene diversification. In summary, the present study has important scientific significance because it describes the phylogeny of the malvids, how the ancestor E. japonica differentiates into the evergreen and deciduous, and the evolutionary significance of the fruit.
High expression of estrogen receptor α (ERα) is associated with a poor prognosis that correlates closely with cellular proliferation in breast cancer. However, the exact molecular mechanism by which ...ERα controls breast cancer cell proliferation is not clear. Here we report that ERα regulates the cell cycle by suppressing p53/p21 and up‐regulating proliferating cell nuclear antigen (PCNA) and proliferation‐related Ki–67 antigen (Ki–67) to promote proliferation of MCF–7 cells. In addition, 17–β–estradiol (E2) enhances ERα‐induced proliferation of MCF–7 cells by stimulating expression of PCNA and Ki–67. Knockdown of ERα significantly affects PCNA/Ki–67 and p53/p21 expression. Furthermore, ERα inhibits the transcriptional activity of p53/p21 in an estrogen response element‐dependent manner. More importantly, we provide new evidence that ERα mediates proliferation of MCF–7 cells by up‐regulating miR–17 to silence the expression of p21. Thus, these data provide new insights into the underlying effect of ERα on breast cancer proliferation.
Model for how estrogen receptor α (ERα) regulates MCF‐7 cell proliferation by p53‐p21‐PCNA‐E2F1 pathway.
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